Bicyclic benzylamido pyridine derivatives as SOS1 inhibitors

Abstract

The present invention encompasses compounds of formula (I) wherein the groups R1 to R4, A1, A2, A3, ring system B, V, W, p, q and r have the meanings given in the claims and specification, their use as inhibitors of SOS1, pharmaceutical compositions which contain compounds of this kind and their use as medicaments / medical uses, especially as agents for treatment and / or prevention of oncological diseases.

Description

[0001] BICYCLIC BENZYLAMIDO PYRIDINE DERIVATIVES AS SOS1 INHIBITORS

[0002] Field of the invention

[0003] The present invention relates to small molecules and their salts capable of inhibiting SOS1 (Son of Sevenless). Specifically, the present invention relates to new substituted bicyclic benzylamido pyridines and derivatives of formula (I) wherein the groups R1to R4, A1, A2, A3, ring system B, V, W, p, q and r have the meanings given in the claims and specification, as well as the synthesis of these compounds. Furthermore, the invention relates to pharmaceutical compositions and combinations comprising these compounds, as well as their use in methods for the treatment of diseases associated with or modulated by SOS1. Pharmaceutical compositions comprising the compounds of general formula (I) are suitable for the therapy of diseases characterized by excessive or abnormal cell proliferation such as cancer.

[0004] Background of the invention

[0005] RAS-family proteins including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene) and MRAS (muscle RAS oncogene homolog) and any mutants thereof are small GTPases that exist in cells in either GTP-bound or GDP-bound states and which have a weak intrinsic GTPase activity and slow nucleotide exchange rates (Moore et al., Nat Rev Drug Discov., 2020 Aug; 19(8):533-552). Binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS-family proteins. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote release of GDP from RAS-family proteins, enabling GTP binding. When in the GTP-bound state, RAS-family proteins are active and engage effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF / mitogen or extracellular signal- regulated kinases (MEK / ERK) pathway, PI3K / AKT / mammalian target of rapamycin (mTOR) pathway and RaIGDS (Rai guanine nucleotide dissociation stimulator) pathway. These pathways affect diverse cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth (Moore et al., Nat Rev Drug Discov., 2020 Aug;19(8):533-552).

[0006] Cancer-associated mutations in RAS-family proteins suppress their intrinsic and GAP- induced GTPase activity leading to an increased population of GTP-bound / active RAS- family proteins. This in turn leads to persistent activation of effector pathways (e.g. MEK / ERK, PI3K / AKT / mTOR, RaIGDS pathways) downstream of RAS-family proteins. KRAS mutations (e.g. amino acids G12, G13, Q61 , A146) are found in a variety of human cancers including lung cancer, colorectal cancer and pancreatic cancer. Mutations in HRAS (e.g. amino acids G12, G13, Q61) and NRAS (e.g. amino acids G12, G13, Q61 , A146) are also found in a variety of human cancer types however typically at a lower frequency compared to KRAS mutations (Moore et al., Nat Rev Drug Discov., 2020 Aug;19(8):533- 552). MRAS (e.g. amino acid G23V and T68I) have been described in Noonan syndrome (Young & Rodriguez-Viciana, Cold Spring Harbor Perspect Med. 2018 Dec 3;8(12):a033621). Alterations (e.g. mutation, over-expression, gene amplification) in RAS- family proteins 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 (Eberlein et al., Cancer Res., 2015, 75(12):2489-500). Resistance mechanisms were also described upon treatment with G12Ci (adagrasib, sotorasib), including the enrichment for secondary KRAS mutations as well as other oncogenic alleles (Awad et al, N Engl J Med 2021 ; 384:2382-239). Published data furthermore indicate Son of Sevenless 1 (SOS1) inhibitors could overcome acquired resistance to KRAS G12C inhibition mediated by KRAS secondary mutations (Koga T. et al., Journal of Thoracic Oncology 2021 , 16, 8, 1321 - 1332) or upregulation of RAS expression (e.g. MRAS;Thatikonda, et al. Nat Cancer 2024, 5, 1352-1370 ), therefore highlighting the potential of combination approaches involving combinations including a SOS1 inhibitor.

[0007] SOS1 is a multi-domain protein with two binding sites for RAS-family proteins: a catalytic site that binds GDP-bound RAS-family proteins to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS-family proteins, the latter causing further increase in the catalytic GEF function of SOS1. Published data indicate a critical involvement of SOS1 in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168, Hofmann, Gmachl, Ramharter et al, Cancer Discov. 2021 , 11 (1): 142-15). Depleting SOS1 levels decreased the proliferation rate and survival of tumor cells carrying a KRAS mutation whereas no effect was observed in KRAS wild type cell lines and the effect of loss of SOS1 could not be rescued by introduction of a catalytic site mutated SOS1.

[0008] Alterations in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonal rhabdomyosarcomas, sertoli cell testis tumors, granular cell tumors of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52), lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014, 511(7511):543-50), bladder cancer (Watanabe et al., IlIBMB Life., 2000, 49(4):317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009, 35(4):751-60). In addition to cancer, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies e.g. Noonan syndrome (NS) (Pierre et al., Biochem. Pharmacol., 2011 , 82(9): 1049-56).

[0009] SOS1 homolog in mammalian cells, Son of Sevenless 2 (SOS2) also acts as a GEF for the activation of RAS-family proteins. Data from mouse knock-out models suggests a redundant role for SOS1 and SOS2 in homeostasis in the adult mouse and the data suggest that selective targeting of individual SOS isoforms (e.g. selective SOS1 targeting) may be adequately tolerated to achieve a therapeutic index between SOS1 / RAS-family protein driven cancers (or other SOS1 / RAS-family protein pathologies) and normal cells and tissues.

[0010] In publications, small molecules inhibiting SOS1 are for example described in WO 2021 / 074227, WO 2022 / 146698, WO 2022 / 187266 and CN116041344.

[0011] Selective pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS- family proteins was shown to prevent SOS1 -mediated activation of RAS-family proteins to the GTP-bound form (Hofmann, Gmachl, Ramharter et al, Cancer Discov. 2021 , 11(1): 142- 15). Such SOS1 inhibitor compounds are expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g. ERK phosphorylation). In cancer cells associated with dependence on RAS-family proteins (e.g. KRAS mutant cancer cell lines), SOS1 inhibitor compounds are expected to deliver anti-cancer efficacy (e.g. inhibition of proliferation, survival etc.). High potency towards inhibition of SOS1 :RAS-family protein binding and ERK phosphorylation are therefore desirable characteristics for a S0S1 inhibitor compound, preferably coupled with a good metabolic stability suitable for oral absorption.

[0012] Due to the high potential that combination therapy approaches with SOS1 inhibitors promise (Kessler, et al. Curr Opinion Chem Biol. 2021 , 62:109-118), the risks of drug-drug interactions (DDI) need to be evaluated early to prevent adverse effects. In this regard, especially cytochrome P450 (CYP) inhibition is a major DDI concern. The reversible CYP inhibition where the inhibitor binds to the CYP enzyme and is released in a reversible binding scheme is time-independent. Whereas the irreversible binding, also called mechanism-based inhibition, is time-dependent coming from formation of a covalent bond between an inhibitor or its metabolite and the CYP enzyme. Therefore, desirable SOS1 inhibitors show a decreased risk of time-dependent and time-independent inhibition of cytochromes to help prevent adverse effects from drug combinations.

[0013] Summary of the invention

[0014] Compounds according to the present invention are highly potent inhibitors of SOS1 (see Table 1 for KRAS::SOS1 alphascreen binding assay and Table 2 for Erk phosphorylation assay) which show good stability in hepatocytes (see Table 3) and low risk in CYP inhibition and mechanism based inhibition (see Table 4 and Table 5 for CYP assays).

[0015] The compounds of formula (I) or the salts thereof as defined herein are particularly suitable for the treatment of pathophysiological processes associated with or modulated by SOS1 inhibition, particularly for the treatment of primary and metastatic tumors associated with dependence on RAS-family protein signaling. Therefore, the compounds of formula (I) or the salts thereof as defined herein are particularly suited for the treatment of cancer associated with dependence on RAS-family protein signaling, including sizeable proportions of NSCLC (non-small cell lung cancer) patients.

[0016] In one aspect, the invention relates to compounds of formula (I) in their salt free forms. In another aspect, the invention relates to the method of treatment involving the compounds of formula (I) or the salts thereof. In another aspect, the invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof as a medicament. In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of general formula (I). In another aspect, the invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the invention relates to the use of a compound of general formula (I) in a medicament combination which comprises further active substances. In another embodiment, the invention provides the general synthesis schemes for compounds of general formula (I) including examples and methods.

[0017] Detailed description of the invention

[0018] The present invention therefore relates to compounds of formula (I) wherein the groups R1to R4, A1, A2, A3, ring system B, V, W, p, q and r have one of the meanings given hereafter, or salts thereof which are particularly suitable for the treatment of pathophysiological processes associated with or modulated by SOS1 -inhibition, particularly for the treatment of cancer, particularly for the treatment of MAPK pathway dependent tumors.

[0019] The compounds of the present invention exhibit several advantageous properties, such as high potency shown in vitro by inhibiting the interaction between SOS1 and KRAS alleles G12D and G12C with ICso values below 300 nM, preferably below 200 nM, more preferably below 100 nM, most preferably below 70 nM (see Table 1). Favorable binding affinity to human SOS1 in combination with favorable cellular activity, as shown by the in vitro ERK phosphorylation assay, and favorable pharmacokinetic properties can enable lower doses for pharmacological efficacy. Lower doses have the advantages of lower "drug load" or "drug burden" (parent drug and metabolites thereof) for the patient causing potentially fewer side effects, and lower production costs for the drug product.

[0020] Furthermore, the high cellular potency of the compounds of the present invention is displayed by ICso values below 600 nM, preferably below 300 nM, more preferably below 200 nM, most preferably below 100 nM in an in vitro ERK phosphorylation assay (see Table 2). In addition to the affinity assay demonstrating the binding of the compounds of the invention to the target, the cellular ERK phosphorylation assays are used to examine the potency with which compounds inhibit the SOS1-mediated signal transduction in a KRAS mutant human cancer cell line. This demonstrates the molecular mode of action of compounds by interfering with the RAS-family protein signal transduction cascade. Low ICso values are indicative of high potency of the SOS1 inhibitor compounds in this assay setting. It is observed that the compounds of the invention demonstrate an inhibitory effect on ERK phosphorylation in a KRAS mutant human cancer cell line, thus confirming the molecular mode of action of the SOS1 inhibitor compounds on RAS-family protein signal transduction. Further, the compounds of the present invention are metabolically stable in human hepatocytes (metabolically stable in human hepatocytes in this respect is defined as below or equal to 45 % QH, preferably below or equal to 35 %QH, more preferably below or equal to 25% QH, most preferably below or equal to 20%QH, (see Table 3 3) and the definition of how to calculate the %QH= hepatic blood flow herein below). Therefore, the compounds of the present invention are expected to have a favorable in vivo clearance and thus the desired duration of action in humans.

[0021] In addition, the compounds of the present invention are characterized by a low DDI risk based on the cytochrome P450 (CYP) inhibition. The DDI perpetrator risk can be indicated by the reversible inhibition of CYP3A4 isoform, wherein an ICso >50pM represents a low inhibition (see Table 4). Another aspect of the perpetrator potential can be evaluated by mechanism-based inhibition (MBI) of CYP3A. Further, the compounds of the present invention show a low risk for mechanism-based inhibition as defined by the remaining CYP3A activities: preferably above or equal to 75% Ctrl, after a preincubation with 25 pM compound for 30 min; most preferably above or equal to 90% Ctrl, (see Table 5 and the definition of how to calculate the %ctrl. is outlined below).

[0022] In summary, the compounds according to the present invention are highly potent inhibitors of the protein-protein interaction between SOS1 and RAS, especially KRAS mutated in position 12 or 13, preferably G12C or G12D mutant KRAS, display high cellular potency as seen in an in vitro ERK phosphorylation assay, are metabolically stable in human hepatocytes and show a low DDI risk.

[0023] Compounds

[0024] In one aspect, the invention relates to compounds of formula (I) wherein each R1is independently selected from the group consisting of Ci-ealkyl, Ci-ehaloalkyl and halogen; p denotes 1 , 2 or 3;

[0025] R2is H, Me or Et;

[0026] V is nitrogen (-N=) or carbon

[0027] W is nitrogen (-N=) or carbon at least one of V and W is nitrogen (-N=);

[0028] A1, A2and A3are each independently selected from nitrogen (-N=) or carbon (=CH- or =CR3-); single or double bond; each R3, if present, is independently selected from the group consisting of Ci-ealkyl, 12-0516-WO-1 C1-6alkoxy, halogen and C1-6haloalkyl; qdenotes 0, 1 or 2;ring system B is selected from C3-10cycloalkyl, C4-10cycloalkenyl, 4-13 memberedheterocyclyl, 5r denotes 0, 1, 2, 3 or 4;each R4, if present, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, -CN, -C(=O)R6, -C(=O)OR6, -C(=O)NR6R6, -NHC(=O)OR6and the bivalent substituent =O; 10 each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 4-11 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl and 4-11membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8;15 each R7 is independently selected from the group consisting of -OH, -NH2, -NHR8, -NR8R8,halogen, -CN, and C1-6alkoxy;each R8is independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl and 4-11 membered20 heterocyclyl, are each independently optionally substituted with one or more, identical or different R9; each R9is -OH, halogen or C1-6alkoxy; or a salt thereof. In another aspect, the invention relates to the compound of formula (I), or a salt thereof,25 wherein the ring selected from the group consisting of 12-0516-WO-1 and is optionally substituted with one or two, identical or different R3.In another aspect, the invention relates to the compound of formula (I), or a salt thereof,wherein A1, A2, A3, V and W form a triazole.In another aspect, the invention relates to the compound of formula (I), or a salt thereof,5 wherein the ring selected from the group consisting of and is optionally substituted with R3. In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein q is 0 to 2 and each R3, if present, is independently selected from the groupconsisting of C1-6alkyl, C1-6alkoxy, halogen and C1-6haloalkyl.10 In another aspect, the invention relates to the compound of formula (I), or a salt thereof,wherein q is 0 to 2 and each R3, if present, is C1-6alkyl.In another aspect, the invention relates to the compound of formula (I), or a salt thereof,wherein q is 0 to 2 and each R3, if present, is Me, Et or Pr.In another aspect, the invention relates to the compound of formula (I), or a salt thereof,15 wherein q is 0 to 2 and each R3, if present, is Me. 12-0516-WO-1 In another aspect, the invention relates to the compound of formula (I), or a salt thereof,wherein q is 1 and R3 is Me.In another aspect, the invention relates to the compound of formula (I), or a salt thereof,wherein q is 0.5 In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein p is 1.In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein p is 2.In another aspect, the invention relates to the compound of formula (I), or a salt thereof10 wherein p is 2 and each R1 is independently selected from the group consisting of Me,-CFH2, -CF2H, -CF3, -CFMeH, -CFMe2, -CF2Me, F.In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein p is 2 and each R1 is independently selected from the group consisting of Me,-CF2H, -CF3, F. 15 In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein R2 is Me.In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein R2 is Me, p is 2 and each R1 is independently selected from the group consisting ofMe, -CFH2, -CF2H, -CF3, -CFMeH, -CFMe2, -CF2Me, F. 20 In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein R2 is Me, p is 2 and each R1 is independently selected from the group consisting ofMe, -CFH2, -CF3, F. In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is selected from C3-10cycloalkyl, and C4-10cycloalkenyl; and the25 C3-10cycloalkyl, and C4-10cycloalkenyl is optionally and independently substituted with r,identical or different R4.In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is selected from C5-7cycloalkyl, and C5-7cycloalkenyl; and theC5-7cycloalkyl, and C5-7cycloalkenyl is optionally and independently substituted with r,30 identical or different R4. In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is selected from cyclohexyl, and cyclohexenyl; and the cyclohexyl, and cyclohexenyl is optionally and independently substituted with r, identical or different R4.

[0029] In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is cyclohexyl; and the cyclohexyl is optionally and independently substituted with r, identical or different R4.

[0030] In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is cyclohexenyl; and the cyclohexenyl is optionally and independently substituted with r, identical or different R4. In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is a 4-13 membered heterocyclyl; and the 4-13 membered heterocyclyl is optionally and independently substituted with r, identical or different R4.

[0031] In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is a piperidine. In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is selected from the group consisting of wherein ring system B can be attached to the compound of formula (I) and R4, if present, at any ring position by removal of a hydrogen atom.

[0032] In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein ring system B is selected from the group consisting of wherein ring system B can be attached to the compound of formula (I) and R4, if present, at any ring position by removal of a hydrogen atom.

[0033] In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein r is 0, 1 , 2, or 3.

[0034] In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein r is 0, 1 , or 2.

[0035] In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein r is 0 or 1.

[0036] In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein r is 1.

[0037] In another aspect, the invention relates to the compound of formula (I), or a salt thereof, wherein r is 0.

[0038] In another aspect, the invention relates to the compound of formula (I), or a salt thereof 12-0516-WO-1 wherein each R4, if present, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, and -CN;5 each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 4-11 membered heterocyclyl,wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl and4-11 membered heterocyclyl, are each independently optionally substituted with one ormore, identical or different R7and / or R8; 10 each R7is independently selected from the group consisting of -OH, -NH2, -NHR8, -NR8R8, halogen, -CN, and C1-6alkoxy;each R8is independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, whereinthe C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-1115 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R9; each R9is -OH, halogen or C1-6alkoxy. In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein each R4, if present, is independently selected from the group consisting of R5and20 R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, and -CN; each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl25 and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; each R7 is independently selected from the group consisting of -OH, -NH2, -NHR8, -NR8R8,halogen, -CN, and C1-6alkoxy;each R8is independently selected from the group consisting of C1-6alkyl, C1-6alkoxy,30 C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, wherein 12-0516-WO-1 the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R9; each R9is -OH, halogen or C1-6alkoxy. 5 In another aspect, the invention relates to the compound of formula (I), or a salt thereof wherein each R4, if present, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, and -CN; 10 each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl and 4- 11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; each R7 is independently selected from the group consisting of -OH, halogen, and15 C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or different R9; 20 each R9is -OH. In another aspect, the invention relates to the compound of the formula (I), or a salt thereof, wherein each R4, if present, is independently selected from the group consisting of ,

[0039] In one embodiment, the invention relates to compounds of formula (I) wherein each R1is independently selected from the group consisting of Me, -CFH2, -CF2H, -CF3, -CFMeH, -CFMe2, -CF2Me, F;

[0040] P is 2;

[0041] R2is Me;

[0042] V is nitrogen (-N=) or carbon

[0043] W is nitrogen (-N=) or carbon at least one of V and W is a nitrogen (-N=);

[0044] A1, A2and A3are each independently selected from nitrogen (-N=) or carbon (=CH-); at least one of A1, A2and A3is a nitrogen (-N=) single or double bond; q is 0, ring system B is a 4-13 membered heterocyclyl, r denotes 0, 1, 2, or 3 each R4, if present, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, and -NR6R6; each R6is independently selected from the group consisting of hydrogen, Ci-ealkyl, Cs- cycloalkyl, 4-11 membered heterocyclyl, wherein the Ci-ealkyl, Cs- cycloalkyl and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; each R7is independently selected from the group consisting of -OH, halogen, and Ci -ealkoxy; each R8is independently selected from the group consisting of Ci-ealkyl, Cs- cycloalkyl, and 4-11 membered heterocyclyl, wherein the Ci-ealkyl, Cs- cycloalkyl, and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R9; each R9is -OH; or a salt thereof.

[0045] In a further embodiment, the invention relates to compounds of formula (I) wherein each R1is independently selected from the group consisting of Me, -CFH2, -CF2H, -CF3, -CFMeH, -CFMe2, -CF2Me, F;

[0046] P is 2;

[0047] R2is Me;

[0048] V is nitrogen (-N=) or carbon

[0049] W is nitrogen (-N=) or carbon one of V and W is a nitrogen (-N=)

[0050] A1, A2and A3are each independently selected from nitrogen (-N=) or carbon (=CH-); at least two of A1, A2and A3are a nitrogen (-N=) 12-0516-WO-1 qis 0,ring system B is a 4-13 membered heterocyclyl,r denotes 0, 1, 2, or 3each R4, if present, is independently selected from the group consisting of R5and R6; 5 each R5is independently selected from the group consisting of -OR6, and -NR6R6; each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8;10 each R7 is independently selected from the group consisting of -OH, halogen, andC1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or15 different R9; each R9is -OH; or a salt thereof. In a further embodiment, the invention relates to compounds of formula (I) whereineach R1 is independently selected from the group consisting of Me, -CFH2, -CF2H, -CF3,20 -CFMeH, -CFMe2, -CF2Me, F; pis 2;R2is Me; Vis nitrogen (-N=);W is carbon 25 A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);A3 is nitrogen (-N=); 12-0516-WO-1 qis 0,ring system B is a 4-13 membered heterocyclyl,r denotes 0, 1, 2, or 3each R4, if present, is independently selected from the group consisting of R5and R6; 5 each R5is independently selected from the group consisting of -OR6, and -NR6R6; each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; 10 each R7is independently selected from the group consisting of -OH, halogen, and C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or15 different R9; each R9is -OH; or a salt thereof. In a further embodiment, the invention relates to compounds of formula (I) whereineach R1 is independently selected from the group consisting of -CF2H, -CF3, -and F;20 p is 2;R2is Me; Vis nitrogen (-N=);W is carbon A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);25 A3 is nitrogen (-N=);q is 0, 12-0516-WO-1 ring system B is a 5-6 membered heterocyclyl,r denotes 1 or 2each R4, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, and -NR6R6; 5 each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; each R7 is independently selected from the group consisting of -OH, halogen, and10 C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or different R9; 15 each R9is -OH; or a salt thereof. In a further embodiment, the invention relates to compounds of formula (I) whereineach R1 is independently selected from the group consisting of -CF2H, -CF3, -and F;p is 2;20 R2is Me; Vis nitrogen (-N=);W is carbon A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);A3 is nitrogen (-N=);25 q is 0,ring system B is a 5-6 membered heterocyclyl, 12-0516-WO-1 ris 1R4 is R6;R6 is a 4-11 membered heterocyclyl, wherein the 4-11 membered heterocyclyl, isoptionally substituted with one or more, identical or different R7and / or R8; 5each R7 is independently selected from the group consisting of -OH, halogen, andC1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or10 different R9; each R9is -OH; or a salt thereof. In a further embodiment, the invention relates to compounds of formula (I) whereineach R1 is independently selected from the group consisting of -CF2H, -CF3, -and F;15 p is 2;R2is Me; Vis nitrogen (-N=);W is carbon A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);20 A3 is nitrogen (-N=);q is 0,ring system B is a 5-6 membered heterocyclyl,r is 1R4 is R6;25 R6 is a 4-11 membered heterocyclyl, wherein the 4-11 membered heterocyclyl, isoptionally substituted with one or more, identical or different R7and / or R8; 12-0516-WO-1 each R7 is -OH;each R8 is independently selected from the group consisting of C1-6alkyl, and C3-10cycloalkyl;or a salt thereof. In a further embodiment, the invention relates to compounds of formula (I) wherein5 each R1 is independently selected from the group consisting of -CF2H, -CF3, -and F;p is 2;R2is Me; Vis nitrogen (-N=);W is carbon 10 A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);A3 is nitrogen (-N=);q is 0,ring system B is a C3-10cycloalkyl,r is 115 R4 is R6;R6 is a 4-11 membered heterocyclyl, wherein the 4-11 membered heterocyclyl, isoptionally substituted with one or more, identical or different R7and / or R8; each R7 is independently selected from the group consisting of -OH, halogen, andC1-6alkoxy; 20 each R8is independently selected from the group consisting of C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 memberedheterocyclyl, are each independently optionally substituted with one or more, identical or different R9; each R9is -OH; 25 or a salt thereof. 12-0516-WO-1 In a further embodiment, the invention relates to compounds of formula (I) whereineach R1 is independently selected from the group consisting of -CF2H, -CF3, -and F;p is 2;R2is Me; 5V is nitrogen (-N=);W is carbon A1 and A2 are independently nitrogen (-N=) or carbon (=CH-);A3 is nitrogen (-N=);q is 0,10 ring system B is a C3-10cycloalkyl,r is 1R4 is R6;R6is a 4-11 membered heterocyclyl, wherein the 4-11 membered heterocyclyl, is optionally substituted with one or more, identical or different R7and / or R8;15 each R7 is -OH;each R8is independently selected from the group consisting of C1-6alkyl, and C3-10cycloalkyl; or a salt thereof. In a preferred embodiment the compound of formula (I) is selected from

[0051] CF3C00H

[0052]

[0053]

[0054] or a pharmaceutically acceptable salt thereof.

[0055] It is to be understood that any two or more aspects and / or preferred embodiments of formula (I) — or subformulas thereof — may be combined in any way leading to a chemically stable structure to obtain further aspects of formula (I) — or subformulas thereof.

[0056] Preferred embodiments of the invention are example compounds E1 to E86.

[0057] Preferred embodiments of the invention are example compounds E1 to E86 and / or the pharmaceutically acceptable salts thereof.

[0058] In an aspect, the present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of a compound of formula (I) (including all embodiments thereof).

[0059] In another aspect, the invention further relates to a hydrate of a compound of formula (I) (including all aspects thereof).

[0060] In another aspect, the present invention further relates to a solvate of a compound of formula (I) (including all embodiments thereof).

[0061] Compounds of formula (I) (including all embodiments thereof) which e.g. bear ester groups are potential prodrugs the ester being cleaved under physiological conditions and are also part of the invention.

[0062] In another aspect, the present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all embodiments thereof).

[0063] In another aspect, the present invention further relates to a pharmaceutically acceptable salt of a compound of formula (I) (including all embodiments thereof) with anorganic or organic acids or bases.

[0064] Accordingly, in another aspect the present invention further relates to compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use as a medicament. Other aspects of the present invention will become apparent to the person skilled in the art directly from the foregoing and following description and examples.

[0065] Definitions

[0066] 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:

[0067] 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.

[0068] 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. Obviously, a ring structure has at least three members.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] The term ”Ci-5alkyl“ includes for example H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, 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)-.

[0073] Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CFkCFkCHa), 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),

[0074] 2.3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3),

[0075] 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,

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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,

[0081] 2.3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl,

[0082] 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.

[0083] 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.

[0084] Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

[0085] 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.

[0086] By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

[0087] Haloalkyl is derived from the previously defined alkyl 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 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.

[0088] Examples of haloalkyl are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CHFCH2CH3, -CHFCH2CF3etc.

[0089] Halogen relates to fluorine, chlorine, bromine and / or iodine atoms.

[0090] Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.

[0091] 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.

[0092] 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.

[0093] If the free valency of a cycloalkyl is saturated, then an alicycle is obtained.

[0094] Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. 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.

[0095] 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.

[0096] 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.

[0097] If the free valency of a cycloalkenyl is saturated, then an unsaturated alicycle is obtained.

[0098] Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl and cycloalkenyl 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 sulphoxide -SO-, sulphone -SO2-; nitrogen N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is part of an aromatic system.

[0099] A direct result of the derivation from cycloalkyl and cycloalkenyl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form.

[0100] 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 heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings one carbon atom (spiroatom) belongs to two rings together.

[0101] 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.

[0102] 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,

[0103] 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,

[0104] 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.

[0105] Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

[0106]

[0107] If the free valency of a heterocyclyl is saturated, then a heterocycle is obtained.

[0108] 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.

[0109] 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.

[0110] 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-AZ-oxide, indazolyl- / V-oxide, benzothiazolyl- / V- oxide, benzimidazolyl-ZV-oxide etc. Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

[0111]

[0112] 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.

[0113] If the free valency of a heteroaryl is saturated, a heteroarene is obtained. S' is a single or double bond.

[0114] 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).

[0115] 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.

[0116] 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, cis / trans / Z 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, and solvates thereof such as for instance hydrates.

[0117] Unless specifically indicated, also “pharmaceutically acceptable salts” as defined in more detail below shall encompass solvates thereof such as for instance hydrates.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] RAS-family proteins are meant to include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene) and MRAS (muscle RAS oncogene homolog) and any mutants thereof.

[0129] A SOS1 inhibitor compound is a compound, which binds to SOS1 and thereby prevents the SOS1 mediated nucleotide exchange and subsequently reduces the levels of RAS in its GTP bound form. More specifically, a SOS1 inhibitor compound shows a pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS-family proteins. Thus, such a compound interacts with SOS1 , e.g. the catalytic site on SOS1 , and reduces the level of binding to the RAS-family protein in relation to said binding without addition of a SOS1 inhibitor compound. Accordingly, it is envisaged that a SOS1 inhibitor compound at least reduces the level of binding to the RAS-family protein about 5 %, 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or even 100 % when compared to the binding that is achieved without the addition of said inhibitor compound. Suitable test systems to measure the binding to the catalytic site of SOS1 are disclosed herein. Said compound may be chemically synthesized (e.g. a small molecule) or microbiologically produced (e.g. a monoclonal antibody) and / or comprised in, for example, samples, e.g., cell extracts from, e.g., plants, animals or microorganisms. Preferably, the SOS1 inhibitor compound is a small molecule.

[0130] Pharmaceutical composition

[0131] A further object of the invention is a pharmaceutical composition comprising a compound of formula (I) — or a pharmaceutically acceptable salt thereof — and one or more pharmaceutically acceptable excipient(s).

[0132] 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 as herein defined.

[0133] Suitable pharmaceutical compositions for administering the compounds of formula (I) 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 injection (s.c., i.v. , i.m.) and infusion (injectables) — elixirs, syrups, sachets, emulsions, inhalatives or dispersible powders The content of the compounds of formula (I) 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.

[0134] Suitable tablets may be obtained, for example, by mixing the compounds of formula (I) with known pharmaceutically acceptable excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablets may also comprise several layers.

[0135] 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.

[0136] Syrups or elixirs containing one or more compounds of formula (I) 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.

[0137] 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 tetra acetic 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.

[0138] Capsules containing one or more compounds of formula (I) or combinations with one or more other pharmaceutically active substance(s) may for example be prepared by mixing the compounds with inert excipients such as lactose or sorbitol and packing them into gelatine capsules.

[0139] Suitable suppositories may be made for example by mixing with excipients provided for this purpose such as neutral fats or polyethylene glycol or the derivatives thereof.

[0140] 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 sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0141] 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 tableting 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.

[0142] For parenteral use, solutions of the compounds of formula (I) with suitable liquid excipients may be used.

[0143] The dosage range of the compounds of formula (I) applicable per day is usually from 1 mg to 2000 mg, preferably from 1 mg to 1500 mg, more preferably from 1 mg to 1000 mg, most preferably from 1 mg to 750 mg.

[0144] 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.

[0145] Thus, in a further aspect the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) — or a pharmaceutically acceptable salt thereof — and one or more pharmaceutically acceptable excipient(s).

[0146] The compounds of formula (I) — or the pharmaceutically acceptable salts thereof — and the pharmaceutical compositions comprising such compound and salts may also be coadministered with other pharmacologically active substances, e.g. with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used in combination (see combination treatment further below).

[0147] 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, enterical, 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.

[0148] The combinations may be administered at therapeutically effective single or divided daily doses. The active components of the combinations may be administered in such doses which are therapeutically effective in monotherapy, or in such doses which are lower than the doses used in monotherapy, but when combined result in a desired (joint) therapeutically effective amount.

[0149] However, when the combined use of the two or more active substances or principles leads to a synergistic effect, it may also be possible to reduce the amount of one, more or all of the substances or principles to be administered, while still achieving the desired therapeutic action. This may for example be useful for avoiding, limiting or reducing any unwanted side effects that are associated with the use of one or more of the substances or principles when they are used in their usual amounts, while still obtaining the desired pharmacological or therapeutic effect.

[0150] Thus, in a further aspect the invention also relates to a pharmaceutical composition comprising a compound of formula (I) — or a pharmaceutically acceptable salt thereof — and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

[0151] In a further aspect the invention also relates to a pharmaceutical preparation comprising a compound of formula (I) — or a pharmaceutically acceptable salt thereof — and one or more (preferably one or two, most preferably one) other pharmacologically active substance(s).

[0152] Pharmaceutical compositions to be co-administered or used in combination can also be provided in the form of a kit.

[0153] Thus, in a further aspect the invention also relates to a kit comprising a first pharmaceutical composition or dosage form comprising a compound of formula (I) and, optionally, one or more pharmaceutically acceptable excipient(s), and a second pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipient(s).

[0154] 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).

[0155] Medical Uses - Methods of Treatment

[0156] The present invention is directed to compounds of formula (I) (including all its embodiments), which are useful in the treatment and / or prevention of a disease and / or condition associated with or modulated by SOS1 , especially wherein the inhibition of the interaction of SOS1 and a RAS-family protein and / or RAC1 is of therapeutic benefit, including but not limited to the treatment and / or prevention of cancer.

[0157] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as a medicament.

[0158] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use in a method of treatment of the human or animal body.

[0159] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of a disease and / or condition wherein the inhibition of the interaction of SOS1 and a RAS-family protein and / or RAC1 is of therapeutic benefit, including but not limited to the treatment and / or prevention of cancer.

[0160] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use in the treatment and / or prevention of cancer.

[0161] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use in a method of treatment and / or prevention of cancer in the human or animal body.

[0162] In another aspect the invention relates to a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as hereinbefore defined wherein said compound is administered before, after, or together with at least one other pharmacologically active substance.

[0163] In another aspect the invention relates to a pharmacologically active substance prepared for being administered before, after, or together with a SOS1 inhibitor compound - or a pharmaceutically acceptable salt thereof - for use as hereinbefore defined for the use of the compound of formula (I).

[0164] In another aspect the invention relates to a pharmacologically active substance prepared for being administered before, after, or together with a compound of formula (I) - or a pharmaceutically acceptable salt thereof - for use as hereinbefore defined for the use of the compound of formula (I).

[0165] In another aspect the invention relates to a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for use in the treatment or in a method of treatment as hereinbefore defined.

[0166] In another aspect the invention relates to the use of a compound of formula (I), - or a pharmaceutically acceptable salt thereof - for preparing a pharmaceutical composition for the treatment and / or prevention of cancer.

[0167] In another aspect the invention relates to the use of a compound of formula (I) - or a pharmaceutically acceptable salt thereof - as hereinbefore defined wherein said compound is administered before, after, or together with at least one other pharmacologically active substance.

[0168] In another aspect the invention relates to the use of a compound of formula (I), - or a pharmaceutically acceptable salt thereof - as hereinbefore defined for the treatment. In another aspect the invention relates to a method for the treatment and / or prevention of a disease and / or condition wherein the inhibition of the interaction of SOS1 and a RAS-family protein or RAC1 is of therapeutic benefit comprising administering a therapeutically effective amount of a compound of formula (I), - or a pharmaceutically acceptable salt thereof - to a human being.

[0169] In another 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 formula (I), - or a pharmaceutically acceptable salt thereof - to a human being.

[0170] In another aspect the invention relates to a method as hereinbefore defined wherein the compound of formula (I) - or a pharmaceutically acceptable salt thereof - is administered before, after, or together with at least one other pharmacologically active substance.

[0171] In another aspect the invention relates to a method as hereinbefore defined wherein the compound of formula (I) - or a pharmaceutically acceptable salt thereof - is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

[0172] In another aspect the invention relates to a method for the treatment as hereinbefore defined.

[0173] In another aspect the invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I) - or a pharmaceutically acceptable salt thereof - and one or more pharmaceutically acceptable excipient(s).

[0174] In another aspect the invention relates to a pharmaceutical preparation comprising a compound of formula (I) - or a pharmaceutically acceptable salt thereof - and at least one (preferably one) other pharmacologically active substance.

[0175] In another aspect the pharmacologically active substance to be used together / in combination with the compound of formula (I) (including all individual embodiments or generic subsets of compounds (I)), or in the medical uses, uses, methods of treatment and / or prevention as herein (above and below) defined can be selected from any one or more of the following (preferably there is only one additional pharmacologically active substance used in all these embodiments):

[0176] 1. an inhibitor of EGFR and / or of mutants thereof a. e.g. afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816; b. preferred are cetuximab, osimertinib and sunvozertinib; c. most preferred is cetuximab

[0177] 2. an inhibitor of ErbB2 (Her2) and / or of mutants thereof a. e.g. zongertinib, tucatinib, lapatinib, trastuzumab, pertuzumab; b. preferred are zongertinib and trastuzumab; c. most preferred is zongertinib;

[0178] 3. an inhibitor of ALK and / or of mutants thereof a. e.g. crizotinib, alectinib, entrectinib, brigatinib; b. preferred are crizotinib and alectinib; c. most preferred is crizotinib;

[0179] 4. an inhibitor of BCR-ABL and / or of mutants thereof a. e.g. imatinib, dasatinib, nilotinib; b. preferred are imatinib and nilotinib; c. most preferred is imatinib;

[0180] 5. an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or of mutants thereof a. e.g. erdafitinib, infigratinib, pemigatinib, futibatinib; b. preferred are pemigatinib and futibatinib

[0181] 6. an inhibitor of R0S1 and / or of mutants thereof a. e.g. crizotinib, entrectinib, lorlatinib, ceritinib, merestinib; b. preferred are crizotinib and entrectinib; c. most preferred is crizotinib;

[0182] 7. an inhibitor of c-MET and / or of mutants thereof e.g. capmatinib, amivantamab

[0183] 8. an inhibitor of AXL and / or of mutants thereof

[0184] 9. an inhibitor of NTRK1 and / or of mutants thereof

[0185] 10. an inhibitor of RET and / or of mutants thereof

[0186] 11. an inhibitor of MEK and / or of mutants thereof a. e.g. trametinib, cobimetinib, binimetinib, selumetinib, refametinib; b. preferred are trametinib and cobimetinib; c. most preferred is trametinib;

[0187] 12. an inhibitor of GDP-bound KRAS and / or of mutants thereof a. an irreversible inhibitor of KRAS G12C i. e.g. adagrasib, sotorasib b. a reversible inhibitor of GDP-bound KRAS and / or of mutants thereof; a. e.g. BI-3706674

[0188] 13. an inhibitor of GTP-bound KRAS and / or mutants thereof a. e.g. RMC-6236 RASMULTI(ON) Inhibitor b. RAS(ON) Inhibitors targeting specific alleles e.g. RMC-6291 (KRASG12C), RMC-9805 (KRASG12D), RMC-8839 (KRASG13C)

[0189] 14. an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or of mutants thereof a. e.g. RAF-709 (= example 131 in WO 2014 / 151616), LY-3009120 (= example 1 in WO 2013 / 134243);

[0190] 15. an inhibitor of ERK and / or of mutants thereof a. e.g. ulixertinib;

[0191] 16. an inhibitor of RAS GEFs and / or of mutants thereof e.g. an inhibitor of SOS2 and / or of mutants thereof

[0192] 17. an inhibitor of PI3K and / or of mutants thereof

[0193] 18. an inhibitor of mTOR a. e.g. rapamycin, temsirolimus, everolimus, ridaforolimus;

[0194] 19. a taxane a. e.g. paclitaxel, nab-paclitaxel, docetaxel; b. preferred is paclitaxel;

[0195] 20. a platinum-containing compound a. e.g. cisplatin, carboplatin, oxaliplatin;

[0196] 21. an antf-metabolite a. e.g. 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, combination of trifluridine and tipiracil (= TAS102); b. preferred is gemcitabine;

[0197] 22. mitotic kinase inhibitor a. e.g. CDK4 / 6 inhibitor i. e.g. palbociclib, ribociclib, abemaciclib; ii. preferred are palbociclib and abemaciclib; iii. most preferred is abemaciclib;

[0198] 23. an immunotherapeutic agent a. e.g. an immune checkpoint inhibitor i. e.g. an anf / -CTLA4 mAb, anf / -PD1 mAb, anf / -PD-L1 mAb, anf / -PD-L2 mAb, anf / -LAG3 mAb, anf / -TIM3 mAb; ii. preferred is an anf / -PD1 mAb; iii. e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab); iv. preferred are nivolumab, pembrolizumab and PDR-001 (= spartalizumab); v. most preferred is pembrolizumab;

[0199] 24. an antf-angiogenic drug a. e.g. bevacizumab, nintedanib; b. most preferred is bevacizumab;

[0200] 25. a topoisomerase inhibitor a. e.g. irinotecan, liposomal irinotecan, topotecan; b. most preferred is irinotecan;

[0201] 26. an apoptosis regulator a. e.g. an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 (a “MDM2 inhibitor”); i. e.g. HDM-201 , NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115, Brigimadlin; ii. preferred are HDM-201, RG-7388 and AMG-232 b. e.g. a PARP inhibitor; c. e.g. a MCL-1 inhibitor;

[0202] 27. an epigenetic regulator a. e.g. a BET inhibitor i. e.g. JQ-1 , GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= R06870810); b. e.g. a CDK9 inhibitor;

[0203] 28. an inhibitor of IGF1 / 2 and / or of IGF1-R a. e.g. xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (= dusigitumab);

[0204] Within this invention it is to be understood that the combinations, compositions, kits, methods, uses 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 formula (I) and the at least one other pharmacologically active substance can be administered formulated either dependently or independently, such as e.g. the compound of formula (I) and the at least one other pharmacologically active substance may be administered either as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0205] 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 both 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 both 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 two compounds in the body of the patient.

[0206] The administration of the compound of formula (I) and the at least one other pharmacologically active substance 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 formula (I) and the at least one other pharmacologically active substance 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. 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.

[0207] The elements of the combinations of this invention may be administered (whether dependently or independently) by methods customary to the skilled person, e.g. by oral, enterical, 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 carriers, excipients and / or vehicles appropriate for each route of administration.

[0208] Accordingly, in one aspect of the invention the invention provides 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 formula (I) and a therapeutically effective amount of at least one other pharmacologically active substance, wherein the compound of formula (I) is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the at least one other pharmacologically active substance.

[0209] In another aspect the invention provides a compound of formula (I) for use in the treatment and / or prevention of cancer, wherein the compound of formula (I) is administered simultaneously, concurrently, sequentially, successively, alternately or separately with the at least one other pharmacologically active substance.

[0210] In another aspect the invention provides a kit comprising

[0211] • a first pharmaceutical composition or dosage form comprising a compound of formula (I), and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles, and

[0212] • at least a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and, optionally, one or more pharmaceutically acceptable carriers, excipients and / or vehicles, 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.

[0213] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered simultaneously.

[0214] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered concurrently.

[0215] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered sequentially.

[0216] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered successively.

[0217] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered alternately.

[0218] In a further embodiment of the invention the components ( / .e. the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered separately.

[0219] The “therapeutically effective amount” of the active compound(s) to be administered is the minimum amount necessary to prevent, ameliorate, or treat a disease or disorder.

[0220] The combinations of this invention may be administered at therapeutically effective single or divided daily doses. The active components of the combination may be administered in such doses which are therapeutically effective in monotherapy, or in such doses which are lower than the doses used in monotherapy, but when combined result in a desired (joint) therapeutically effective amount.

[0221] In another aspect the disease / condition / cancer to be treated / prevented with the compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment and / or prevention as herein (above and below) defined is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, gastroesophageal / gastroesophageal junction cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, skin squamous cell carcinoma and sarcomas.

[0222] In another aspect the disease / condition / cancer to be treated / prevented with the compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment and / or prevention as herein (above and below) defined is selected from the group consisting of lung cancer (preferably non-small cell lung cancer (NSCLC)), head and neck squamous cell carcinoma, cholangiocarcinoma, bladder cancer and colorectal cancer.

[0223] In another aspect the disease / condition to be treated / prevented with the compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment and / or prevention as herein (above and below) defined is a RASopathy, preferably selected from the group consisting of Neurofibromatosis type 1 (NF1), NF1 -associated Plexiform Neurofibroma, Malignant Peripheral Nerve Sheath Tumors (MPNST), Cutaneous Neurofibromas, Noonan Syndrome (NS), NS-associated congenital heart defects, 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.

[0224] In another aspect the disease / condition to be treated / prevented with the compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment for diabetes, preferably type I diabetes.

[0225] In another aspect the disease / condition / cancer to be treated / prevented with the compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment and / or prevention as herein (above and below) defined is a disease / condition / cancer defined as exhibiting one or more of the following molecular features:

[0226] 1. KRAS alterations: a. KRAS amplification (wt or mutant); b. KRAS overexpression (wt or mutant); c. KRAS mutation(s): i. G12 mutations (e.g. G12C, G12V, G12S, G12A, G12R, G12F, G12D); ii. G13 mutations (e.g. G13C, G13D, G13R, G13V, G13S, G13A) iii. T35 mutation (e.g. T35I); iv. I36 mutation (e.g. I36L, I36M); v. E49 mutation (e.g. E49K); vi. Q61 mutation (e.g. Q61 H, Q61 R, Q61 P, Q61 E, Q61 K, Q61 L; vii. K117 mutation (e.g. K117N); viii. A146 mutation (e.g. A146T, A146V);

[0227] 2. NRAS alterations: a. NRAS amplification (wt or mutant); b. NRAS overexpression (wt or mutant); c. NRAS mutation(s): i. G12 mutations (e.g. G12A, G12V, G12D, G12C, G12S, G12R); ii. G13 mutation (e.g. G13V, G13D, G13R, G13S, G13C, G13A); iii. Q61 mutation (e.g. Q61 K, Q61 L, Q61 H, Q61 P, Q61 R); iv. A146 mutation (e.g. A146T, A146V);

[0228] 3. HRAS alterations: a. HRAS amplification (wt or mutant); b. HRAS overexpression (wt or mutant); c. HRAS mutation(s); i. G12 mutation (e.g. G12C, G12V, G12S, G12A.G12R, G12F, G12D); ii. G13 mutation (e.g. G13C, G13D, G13R, G13V, G13S, G13A); iii. Q61 mutation (e.g. Q61 K, Q61 L, Q61 H, Q61 P, Q61 R);

[0229] 4. MRAS alterations: a. G23V b. T68I

[0230] 4. EGFR alterations: a. EGFR amplification (wt or mutant); b. EGFR overexpression (wt or mutant); c. EGFR mutation(s) i. e.g. exon 20 insertion, exon 19 deletion (Del19), G719X (e.g. G719A, G719C, G719S), T790M, C797S, T854A, L858R, L861Q, or any combination thereof;

[0231] 5. ErbB2 (Her2) alterations: a. ErbB2 amplification; b. ErbB2 overexpression; c. ErbB2 mutation(s) i. e.g. R678, G309, L755, D769, V777, P780, V842, R896, c.2264_2278del (L755_T759del), c.2339_2340ins (G778_P780dup), S310;

[0232] 6. c-MET alterations: a. c-MET amplification; b. c-MET overexpression; c. c-MET mutation(s) i. e.g. E168, N375, Q648, A887, E908, T1010, V1088, H1112, R1166, R1188, Y1248, Y1253, M1268, D1304, A1357, P1382;

[0233] 7. AXL alterations: a. AXL amplification; b. AXL overexpression;

[0234] 8. BCR-ABL alterations: a. chromosomal rearrangements involving the ABL gene;

[0235] 9. ALK alterations: a. ALK amplification; b. ALK overexpression; c. ALK mutation(s)

[0236] 1. e.g. 1151Tins, L1152R, C1156Y, F1174L, L1196M, L1198F, G1202R, S1206Y, G1269A; d. chromosomal rearrangements involving the ALK gene;

[0237] 10. FGFR1 alterations: a. FGFR1 amplification; b. FGFR1 overexpression;

[0238] 11. FGFR2 alterations: a. FGFR2 amplification; b. FGFR2 overexpression; c. FGFR2 mutation; d. chromosomal rearrangement involving the FGFR2 gene

[0239] 12. FGFR3 alterations: a. FGFR3 amplification; b. FGFR3 overexpression; c. chromosomal rearrangement involving the FGFR3 gene; d. FGFR3 mutation e.g. R248C

[0240] 13. FGFR4 alterations: a. FGFR4 mutations

[0241] 14. NTRK1 alterations: a. chromosomal rearrangements involving the NTRK1 gene;

[0242] 15. NF1 alterations: a. NF1 mutation(s);

[0243] 16. RET alterations: a. RET amplification; b. RET overexpression; c. chromosomal rearrangements involving the RET gene

[0244] 17. ROS1 alterations: a. R0S1 amplification; b. ROS1 overexpression; c. ROS1 mutation(s) i. e.g. G2032R, D2033N, L2155S; d. chromosomal rearrangements involving the ROS1 gene;

[0245] 18. SOS1 alterations a. SOS1 amplification; b. SOS1 overexpression; c. SOS1 mutation(s); e.g. N233Y

[0246] 19. RAC1 alterations a. RAC1 amplification; b. RAC1 overexpression; c. RAC1 mutation(s);

[0247] 20. MDM2 alterations a. MDM2 amplification b. MDM2 overexpression c. MDM2 amplification in combination with functional p53 d. MDM2 amplification in combination with wild-type p53

[0248] 21. RAS wild-type a. KRAS wild-type b. H RAS wild-type c. N RAS wild-type

[0249] 22. B-Raf mutation(s), including V600E but also other mutations e.g. class II and class III

[0250] In another aspect the disease / condition / cancer to be treated / prevented with compound of formula (I), compound of formula (I) for use, use for preparing and method for the treatment and / or prevention as herein (above and below) defined is a cancer that is resistant to a treatment with a KRAS G12C inhibitor. For example, RAS amplification (KRAS or MRAS) was published as a resistant mechanism following treatment with a KRAS G12C inhibitor that can be addressed by a combination with a SOS1i (Thatikonda, et al. Nat Cancer 2024, 5, 1352-1370). In another aspect the combined treatment of compound of formula (I), and a KRAS G12C inhibitor is administered following treatment with a KRAS G12C inhibitor. Preferably, the patients were treated with adagrasib (or MRTX 849) or sotorasib (or AMG 510), but also including next generation inhibitors such as Divarisib.

[0251] Any disease / condition / cancer, medical use, use, method of treatment and / or prevention as disclosed or defined herein (including molecular / genetic features) may be treated / performed with any compound of formula (I) as disclosed or defined herein (including all individual embodiments or generic subsets of compounds (I)).

[0252] Therapeutic Use

[0253] Due to their biological properties the compounds of the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above- mentioned forms may be suitable for treating diseases characterised by excessive or abnormal cell proliferation such as cancer.

[0254] For example, the following cancers, tumors and other proliferative diseases may be treated with compounds of the invention, without being restricted thereto:

[0255] 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, 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,

[0256] 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);

[0257] 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.

[0258] All cancers / tumors / carcinomas mentioned above may be further differentiated by their histopathological classification:

[0259] 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;

[0260] Nonepithelial 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;

[0261] The compounds of the invention may be used in therapeutic regimens in the context of first line, second line, or any further line treatments.

[0262] The compounds of the invention may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy and / or surgery.

[0263] Of course, the above also includes the use of the compounds of the invention in various methods of treating the above diseases by administering a therapeutically effective dose to a patient in need thereof, as well as the use of these compounds for the manufacture of medicaments for the treatment of such diseases, as well as pharmaceutical compositions including such compounds of the invention, as well as the preparation and / or manufacture of medicaments including such compounds of the invention, and the like.

[0264] Preparation of the compounds according to the invention

[0265] The compounds according to the invention and intermediates are prepared by the methods of synthesis described hereinafter in which the substituents of the general formula have the meanings given hereinbefore. These methods are intended as an illustration of the invention without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein, i.e. it is within the skills of an organic chemist to synthesize these compounds. Substances described in the literature can be prepared according to the published methods of synthesis.

[0266] 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. Starting materials may be either commercially available or may be prepared by methods that are described in the literature or herein or may be prepared in an analogous or similar manner. 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.

[0267] The scheme below (Scheme 1) illustrates the possible synthesis of the compounds of general formula (I) and its intermediates. The first step can be an amide coupling using carboxylic acid derivatives of structure B and benzylic amines of structure A as reaction partners to form bicyclic intermediates of structure C containing an aromatic bicyclic 5-6 fused ring system with an attached functional group 1 (FG1). The functional group 1 enables use of cross coupling reactions such as Suzuki reactions, Buchwald couplings, or alike in the next reaction step the. This allows either to form directly compounds of general formula (I) or the intermediate structures D. The functional group 2 (FG2) in intermediate D can be further derivatized using for example reductive amination reactions, nucleophilic substitution reactions or alike with reagents known to the people skilled in the art to form compounds of general formula (I).

[0268] Scheme 1 : Schematic synthesis of compounds of general formula (I).

[0269] As described for some exemplified compounds, a reaction called Dimroth rearrangement (described for example herein: ACS Med. Chem. Lett. 2017, 8, 12, 1320-1325) can also be used to form intermediates of structure C, which can be used in the synthesis of compound of general formula (I). Abbreviations

[0270] Experimental part - Chemical synthesis

[0271] Other features and advantages of the present invention will become apparent from the following more detailed examples which exemplarily illustrate the principles of the invention without restricting its scope. General

[0272] The terms "cis" and "trans" are used in accordance with the IIIPAC Gold Book's guidelines to denote the stereochemical information of the substituents, which varies based on the positions of atoms (or groups) relative to a reference plane in a ring system. In the cisisomer, the atoms are located on the same side, while in the trans-isomer, they are on opposing sides. This follows the traditional order of priority for substituents / ligands. (PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IIIPAC Recommendations 1996)) on page 2203).

[0273] Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatuses 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 inert gas (nitrogen or argon).

[0274] Room temperature in the following schemes means the temperature ranging from 19 °C to 24 °C.

[0275] If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive.

[0276] Some compounds according to the exemplified preparation are filtered through carbonate functionalized MP resin (carbonate cartridge) by Agilent Technologies (PL-HCO3 MP SPE; Part. No. PL3540-C603) as indicated.

[0277] Some compounds according to the exemplified preparation are filtered through thiol functionalized SPEmedia (thiol resin) by Agilent Technologies (PL-Thiol MP SPE Part. No. 3582-CM89) prior to chromatography, if indicated.

[0278] The following catalyst, termed catalyst I, is used for some exemplified coupling reactions of this invention [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-yl]-dichloro-(2- methyl-1-pyridyl)palladium (catalyst I; CAS: 1612891-29-8).

[0279] The following catalyst, termed catalyst II, is used for some exemplified coupling reactions of this invention [1,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (CAS: 95464-05-4). NMR method

[0280] NMR spectra were recorded on a BrukerAVANCE IIIHD 400 MHz instrument using TopSpin 3.2 pl6 software. Chemical shifts are given in parts per million (ppm) downfield from an internal reference like trimethylsilane and / or water and / or solvent (eg. d6-DMSO) in 5 units. Selected data are reported in the following manner: chemical shift (number of hydrogens).

[0281] Chromatography

[0282] Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.

[0283] Prep. RP-HPLC is carried out with columns made by Waters (Sunfire C18, 10 pm, 30x100 mm Part. No. 186003971 or X-Bridge C18, 10 pm, 30x100 mm Part. No. 186003930). The compounds are eluted using either different gradients of H2O / ACN or H2O / MeOH, where 0.1% TFA is added to the water, or with different gradients utilizing a basic aqueous buffer solution (1 L water contains 5 mL of an ammonium hydrogencarbonate solution (158 g per 1 L H2O) and 2 mL NH3 (7 mol / L solution in MeOH)) instead of the water-TFA-mixture.

[0284] Mass spectroscopy

[0285] Low resolution mass spectra are obtained using a high performance liquid chromatography coupled to a quadrupole mass spectrometer (HPLC-MS; electrospray positive ionization). The reported mass spectrometry (MS) data correspond to the observed mass peaks of the monoisotopic masses of the respective compound ([M+H]+) or a fragment thereof (e.g., [M-Boc+H ]+, [M-NH3+H ]+).Analytical HPLC Methods (A.M.)

[0286] Mobile phase preparations

[0287] Examples:

[0288] The mobile phase “Water 0.1% TFA (v / v)” is prepared by adding 1 mL of a commercially available TFA solution to 999 mL water.

[0289] The mobile phase “Water0.1 % NH3” is prepared by adding 4 mL of a commercially available concentrated ammonium hydroxide solution (25 wt%) to 996 mL water.

[0290] Analytical SFC Methods (A.M.)

[0291] Mobile phase preparations

[0292] The mobile phase “MEOH 20 mM NH3” is prepared by adding 3 ml of a commercially available solution of ammonia (7 M in methanol) to 997 ml methanol.

[0293] The mobile phase “I PA 20 mM NH3” is prepared by adding 3 ml of a commercially available solution of ammonia (7 M in methanol) to 997 ml isopropyl alcohol.

[0294] The mobile phase “ETOH 20 mM NH3” is prepared by adding 3 ml of a commercially available solution of ammonia (7 M in methanol) to 997 ml ethanol. Preparations

[0295] Synthesis scheme of intermediate 9

[0296] Synthesis of intermediate 2 Methyl 6-amino-5-bromonicotinate 1 (14.8 g, 61 mmol) and / V, / V-dimethylformamide dimethyl acetal (17.2 mL, 122 mmol) in DMF (141 mL) is stirred for 4 h at 100 °C. The solvents are evaporated under reduced pressure to obtain intermediate 2. The intermediate is used without further purification.

[0297] Synthesis of intermediate 3

[0298] Intermediate 2 (17.5 g, 61 mmol), sodium acetate (11 g, 134 mmol) and hydroxylamine hydrochloride (6.4 g, 91 mmol) in ethanol (249 mL) are stirred for 3 h at 50 °C. The mixture is poured into water and is further stirred for 1 h at rt. The solids are filtered off, washed with water and dried in vacuo at 55 °C to obtain intermediate 3. The intermediate 3 is used without further purification.

[0299] Intermediate 3

[0300] Analytical HPLC-MS Method: D

[0301] Rt [min]: 0.83 MS [m / z]: 274 [M+H]+

[0302] Synthesis of intermediate 4

[0303] Intermediate 3 (16.7 g, 61 mmol) in THF (201 mL) is cooled to 0 °C. Trifluoroacetic anhydride (11 mL, 79 pmol) is added dropwise. After complete addition, the mixture is allowed to reach rt and stirring is continued for 16 h. The mixture is basified with NaHCOs solution under ice cooling, diluted with water and stirred for 2 h. The solvent is reduced under reduced pressure and the precipitate is filtered off, washed with water and dried in vacuo at 55 °C to obtain intermediate 4. The intermediate 4 is used without further purification.

[0304] Intermediate 4

[0305] Analytical HPLC-MS Method: D

[0306] Rt [min]: 0.75 MS [m / z]: 256 [M+H]+

[0307] Synthesis of intermediate 5 4 5

[0308] An aqueous NaOH solution (4 M; 14.5 mL, 68 mmol) is added to intermediate 4 (13.5 g, 53 mmol) in MeOH (149 mL) and stirred for 1 h at 50 °C. The mixture is further stirred at rt for 16 h. MeOH is evaporated under reduced pressure before the mixture is diluted with water and filtered. The aqueous mixture is acidified with aqueous 4 M HCI solution. The mixture is stirred for 1 h. The precipitate is filtered off, washed with water and dried in vacuo at 55 °C to obtain intermediate 5. The intermediate 5 is used without further purification.

[0309] Intermediate 5

[0310] Analytical HPLC-MS Method: E

[0311] Rt [min]: 0.66 MS [m / z]: 242 [M+H]+

[0312] Synthesis of intermediate 7 Intermediate 5 (140 mg, 578 pmol) in DMF (9.4 mL) is treated with HATU (330 mg, 868 12-0516-WO-1 µmol) and triethylamine (325 µL, 2.3 mmol) and stirred for 15 h at rt. Benzylamine 6 (CAS:1389852-29-2; 131 mg, 578 µmol) is added and the mixture is stirred for 16 h. MeOH / THF is added, solids are filtered off and the mixture is purified by prep. RP-HPLC (acidic conditions) to obtain intermediate 7. Intermediate 7 Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 413 [M+H]+5 Synthesis of intermediate 9 Amixture of intermediate 7 (7.0 g, 16 mmol), piperidin-4-one hydrochloride 8 (2.5 g, 18mmol), K3PO4(10.4 g, 48 mmol), and catalyst I (406 mg, 483 µmol) in 1,4-dioxane (70 mL) 10 is stirred under argon for 16 h at 110 °C. The mixture is diluted with EtOAc and filtered. The solvent is removed under reduced pressure. The material is taken up in EtOAc and extracted with water and saturated aqueous NaCl solution. The separated organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The material is purified by column chromatography (SiO2; EtOAc / petroleum ether: 1:3 ^ 1:0) to15 obtain intermediate 9. Intermediate 9 Analytical HPLC-MS Method: D Rt[min]: 0.91 MS [m / z]: 432 [M+H]+1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.57 (3 H), 2.51 - 2.57 (4 H), 3.97 - 4.07(4 H), 5.37 - 5.47 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.57 (1 H), 7.65 - 7.74 (1 H), 8.50 - 8.59(1 H), 9.05 - 9.14 (2 H). Scheme of alternative synthesis of intermediate 7

[0313] 13 7

[0314] Synthesis of intermediate 11 10 11

[0315] Hydrazine hydrate (45 ml, 603 mmol, 64-65%) is added to a mixture of 5-bromo-6- chloronicotinic acid 10 (50 g, 201 mmol) in ethanol (410 mL). The mixture is refluxed for 16 h. After cooling to rt, the solids are filtered off, washed with ethanol, and dried in vacuo to obtain intermediate 11. The material is used without further purification.

[0316] Intermediate 11

[0317] Analytical HPLC-MS Method: E

[0318] Rt[min]: 0.16 MS [m / z]: 232 [M+H]+ Synthesis of intermediate 12

[0319] Intermediate 11 (16.9 g, 73 mmol) is treated with formic acid (40 mL, 1.1 mmol) and stirred at 100 °C for 2 h. The mixture is cooled to 0 °C. The solid material is filtered off and dried under reduced pressure to obtain the intermediate 12. The material is used without further purification.

[0320] Intermediate 12

[0321] Analytical HPLC-MS Method: E

[0322] Rt [min]: 0.56 MS [m / z]: 242 [M+H]+

[0323] Synthesis of intermediate 13 12 6 13

[0324] A mixture of intermediate 12 (6.3 g, 25 mmol), benzylamine 6 (CAS: 1389852-29-2; 6.0 g, 26 mmol) and 4-methylmorpholine (11 mL, 99 mmol) in ACN (60 mL) is cooled down to 0 °C. 1-Propanephosphonic acid anhydride (37 mL, 62 mmol) is added dropwise. The mixture is allowed to reach rt before it is poured into water and stirred for 20 min. The solids are filtered and washed with ACN / water (1 :1). The material is dried in vacuo (55 °C) to obtain intermediate 13. The material is used without further purification.

[0325] Intermediate 13

[0326] Analytical HPLC-MS Method: E

[0327] Rt [min]: 0.92 MS [m / z]: 413 [M+H]+ 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.72 (9 H), 1.85 - 1.94 (2 H), 2.43 - 2.48(1 H), 2.62 - 2.72 (1 H), 2.80 - 2.92 (4 H), 3.02 - 3.10 (1 H), 4.28 - 4.41 (3 H), 5.36 - 5.46(1 H), 7.07 - 7.37 (3 H), 7.49 - 7.56 (1 H), 7.65 - 7.72 (1 H), 8.47 - 8.53 (1 H), 9.02 - 9.10(2 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of intermediate 7 Amixture of intermediate 13 (710 mg, 1.7 mmol), Cs2CO3 (280 mg, 859 µmol), piperidine5 (85 µL, 859 µmol) in 1,4-dioxane (10 mL) is stirred 6 h at 100 °C. EtOAc and water are added. The aqueous layer is separated and extracted with EtOAc. The combined organic layers are dried over Na2SO4. The solids are filtered, and the solvent is evaporated under reduced pressure. The material is purified by column chromatography (SiO2; obtain intermediate 7.Intermediate 7Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 413 [M+H]+10 Amixture of Intermediate 9 (34.5 mg, 80 µmol), D-prolinol 14 (12.1 mg, 120 µmol), AcOH 12-0516-WO-1 (30.0 µL, 51 µmol), and 2-picoline-borane complex (8.6 mg, 80 µmol) in MeOH (2.0 mL) is stirred for 12 h at rt. The mixture was diluted with DMF und purified by prep. RP-HPLC (basic conditions) to obtain the example E1. Example E1 HPLC-MS Method: A Rt[min]: 0.73 MS [m / z]: 517 [M+H]+Analytical SFC method: AU Rt [min]: 1.66 d.e. > 95%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.72 (9 H), 1.85 - 1.94 (2 H), 2.43 - 2.48(1 H), 2.62 - 2.72 (1 H), 2.80 - 2.92 (4 H), 3.02 - 3.10 (1 H), 4.28 - 4.41 (3 H), 5.36 - 5.46(1 H), 7.07 - 7.37 (3 H), 7.49 - 7.56 (1 H), 7.65 - 7.72 (1 H), 8.47 - 8.53 (1 H), 9.02 - 9.10(2 H), missing proton(s) presumably hidden by / overlapping with solvent signals Example E2 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (R)-3-hydroxypyrrolidine hydrochloride 15 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-boranecomplex (80 µmol), 2 mL MeOH. Example E2 Analytical HPLC-MS Method: D Rt[min]: 0.91 MS [m / z]: 503 [M+H]+Analytical SFC method: L Rt [min]: 6.60 d.e. > 98% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 - 1.61 (6 H), 1.88 - 2.02 (3 H), 2.17 - 2.27(1 H), 2.35 - 2.42 (1 H), 2.60 - 2.69 (1 H), 2.74 - 2.83 (1 H), 2.92 - 3.03 (2 H), 4.13 - 4.25(3 H), 4.58 - 4.70 (1 H), 5.36 - 5.46 (1 H), 7.06 - 7.38 (3 H), 7.49 - 7.56 (1 H), 7.65 - 7.73(1 H), 8.50 (1 H), 9.01 - 9.11 (2 H), missing proton(s) presumably hidden by / overlappingwith solvent signals 5 Example E3 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (7R)-5-azaspiro[2.4]heptan-7-ol 16 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-boranecomplex (80 µmol), 2 mL MeOH. Example E3 Analytical HPLC-MS Method: A Rt[min]: 0.76 MS [m / z]: 529 [M+H]+Analytical SFC method: L Rt [min]: 2.26 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.30 - 0.40 (1 H), 0.45 - 0.58 (2 H), 0.77 - 0.86(1 H), 1.45 - 1.61 (5 H), 1.87 - 1.98 (2 H), 2.18 - 2.27 (1 H), 2.41 - 2.48 (1 H), 2.60 - 2.66(1 H), 2.93 - 3.04 (2 H), 3.04 - 3.12 (1 H), 3.68 - 3.77 (1 H), 4.16 - 4.26 (2 H), 4.47 - 4.56(1 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.56 (1 H), 7.64 - 7.72 (1 H), 8.47 - 8.52(1 H), 9.02 - 9.11 (2 H), missing proton(s) presumably hidden by / overlapping with solventsignals 12-0516-WO-1 Synthesis of example E4 917 E4Example E4 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (3S)-3-5 methylpyrrolidin-3-ol hydrochloride 17 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E4 Analytical HPLC-MS Method: A Rt [min]: 0.75 MS [m / z]: 517 [M+H]+Analytical SFC method: F Rt [min]: 1.56 d.e. > 90%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.21 - 1.27 (3 H), 1.48 - 1.61 (5 H), 1.62 - 1.77(2 H), 1.87 - 1.98 (2 H), 2.18 - 2.29 (1 H), 2.52 - 2.61 (3 H), 2.65 - 2.74 (1 H), 2.94 - 3.05(2 H), 4.14 - 4.25 (2 H), 4.41 - 4.50 (1 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.48 - 7.57(1 H), 7.64 - 7.72 (1 H), 8.48 - 8.53 (1 H), 9.02 - 9.10 (2 H). 10 Example E5 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (3R)-3-methylpyrrolidin-3-ol hydrochloride 18 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline- 12-0516-WO-1 borane complex (80 µmol), 2 mL MeOH. Example E5 Analytical HPLC-MS Method: A Rt[min]: 0.75 MS [m / z]: 517 [M+H]+Analytical SFC method: L Rt [min]: 2.02 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.19 - 1.28 (3 H), 1.46 - 1.60 (5 H), 1.62 - 1.77(2 H), 1.87 - 1.97 (2 H), 2.19 - 2.29 (1 H), 2.52 - 2.62 (3 H), 2.65 - 2.74 (1 H), 2.95 - 3.05(2 H), 4.14 - 4.26 (2 H), 4.41 - 4.49 (1 H), 5.36 - 5.46 (1 H), 7.06 - 7.38 (3 H), 7.48 - 7.56(1 H), 7.64 - 7.72 (1 H), 8.47 - 8.52 (1 H), 9.02 - 9.12 (2 H). 5 Example E6 is prepared in analogy to example E1: Intermediate 9 (80 µmol), L-prolinol 19(0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH.Example E6 Analytical HPLC-MS Method: A Rt[min]: 0.76 MS [m / z]: 517 [M+H]+Analytical SFC method: AP Rt [min]: 1.91 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.72 (9 H), 1.85 - 1.94 (2 H), 2.62 - 2.71(1 H), 2.79 - 2.93 (4 H), 3.01 - 3.11 (1 H), 4.27 - 4.41 (3 H), 5.36 - 5.47 (1 H), 7.07 - 7.37(3 H), 7.49 - 7.56 (1 H), 7.65 - 7.72 (1 H), 8.48 - 8.53 (1 H), 9.02 - 9.11 (2 H), missing 12-0516-WO-1 proton(s) presumably hidden by / overlapping with solvent signals 5 Example E7 is prepared in analogy to example E1: Intermediate 9 (80 µmol), 2-methyl-1-(methylamino)propan-2-ol 20 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-boranecomplex (80 µmol), 2 mL MeOH. Example E7 Analytical HPLC-MS Method: A Rt[min]: 0.84 MS [m / z]: 519 [M+H]+Analytical SFC method: AR Rt [min]: 5.33 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.04 - 1.11 (6 H), 1.49 - 1.54 (3 H), 1.55 - 1.65(2 H), 1.77 - 1.86 (2 H), 2.26 - 2.31 (2 H), 2.31 - 2.35 (3 H), 2.53 - 2.62 (1 H), 2.73 - 2.83(2 H), 3.92 - 3.99 (1 H), 4.36 - 4.46 (2 H), 5.36 - 5.46 (1 H), 7.08 - 7.38 (3 H), 7.49 - 7.56(1 H), 7.64 - 7.72 (1 H), 8.49 - 8.53 (1 H), 9.02 - 9.11 (2 H).

[0328] 12-0516-WO-1 Synthesis of example E8 Example E8 is prepared in analogy to example E1: Intermediate 9 (80 µmol), 5-5 azaspiro[2.4]heptane hydrochloride 21 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E8 Analytical HPLC-MS Method: A Rt [min]: 0.94 MS [m / z]: 513 [M+H]+Analytical SFC method: AF Rt [min]: 0.98 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.44 - 0.55 (4 H), 1.49 - 1.62 (5 H), 1.68 - 1.75(2 H), 1.89 - 1.98 (2 H), 2.17 - 2.26 (1 H), 2.68 - 2.75 (2 H), 2.93 - 3.03 (2 H), 4.17 - 4.26(2 H), 5.36 - 5.45 (1 H), 7.08 - 7.38 (3 H), 7.50 - 7.56 (1 H), 7.65 - 7.72 (1 H), 8.49 - 8.52(1 H), 9.04 - 9.09 (2 H), missing proton(s) presumably hidden by / overlapping with solventsignals 10 Example E10 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (S)-3- 12-0516-WO-1 methoxypyrrolidine hydrochloride 22 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E10 Analytical HPLC-MS Method: A Rt [min]: 0.81 MS [m / z]: 531 [M+H]+Analytical SFC method: AP Rt [min]: 1.07 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.49 - 1.69 (6 H), 1.89 - 2.01 (3 H), 2.17 - 2.27(1 H), 2.58 - 2.66 (1 H), 2.73 - 2.80 (1 H), 2.92 - 3.03 (2 H), 3.15 - 3.19 (3 H), 3.81 - 3.89(1 H), 4.15 - 4.26 (2 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.56 (1 H), 7.65 - 7.73(1 H), 8.47 - 8.54 (1 H), 9.02 - 9.10 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals Synthesis of examples cis-E11a and cis-E11b 59 cis-23 cis-E11a cis-E11bA mixture of Intermediate 9 (250 mg, 579 µmol), (1r,2s,5s)-rel-3-azabicyclo[3.1.0]hexan-2-ylmethanol hydrochloride cis-23 (134 mg, 869 µmol), AcOH (68 µL, 1.16 mmol),triethylamine (117 µL, 1.16 mmol) in DMF (2.9 mL) is stirred for 4 h at rt, before sodium triacetoxyborohydride (246 mg, 1.16 mmol) is added at rt. The mixture is stirred for 2 h at10 rt. Water, MeOH, THF are added, the mixture filtered, and directly purified by prep. RP- HPLC (basic conditions) and chiral SFC to obtain examples cis-E11a and cis-E11b assingle stereoisomers. The absolute configuration of the hydroxymethyl substituent and[3.1.0] ring system is not known; their relative configuration is cis. 12-0516-WO-1 Example cis-E11a Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 529 [M+H]+Analytical SFC method: N Rt [min]: 4.47 d.e. > 96%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.14 - 0.25 (1 H), 0.48 - 0.56 (1 H), 1.29 - 1.37(1 H), 1.47 - 1.73 (7 H), 1.78 - 1.86 (1 H), 2.69 - 2.88 (5 H), 2.98 - 3.06 (1 H), 3.18 - 3.26(1 H), 3.54 - 3.62 (1 H), 4.34 - 4.48 (3 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.57(1 H), 7.64 - 7.73 (1 H), 8.46 - 8.54 (1 H), 9.02 - 9.10 (2 H).Example cis-E11b Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 529 [M+H]+Analytical SFC method: N Rt [min]: 3.53 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.15 - 0.24 (1 H), 0.48 - 0.56 (1 H), 1.28 - 1.38(1 H), 1.48 - 1.72 (7 H), 1.77 - 1.86 (1 H), 2.69 - 2.89 (5 H), 2.99 - 3.07 (1 H), 3.19 - 3.27(1 H), 3.54 - 3.62 (1 H), 4.34 - 4.49 (3 H), 5.36 - 5.46 (1 H), 7.06 - 7.38 (3 H), 7.49 - 7.57(1 H), 7.64 - 7.72 (1 H), 8.46 - 8.54 (1 H), 9.00 - 9.10 (2 H) 5 Example E12 is prepared in analogy to example E1: Intermediate 9 (80 µmol), (3S,5S)-5- 12-0516-WO-1 methylpyrrolidin-3-ol hydrochloride 24 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E12 Analytical HPLC-MS Method: A Rt[min]: 0.72 MS [m / z]: 517 [M+H]+Analytical SFC method: AL Rt [min]: 2.30 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.69 (6 H), 1.89 - 2.00 (3 H), 2.17 - 2.26(1 H), 2.58 - 2.66 (1 H), 2.73 - 2.80 (1 H), 2.92 - 3.03 (2 H), 3.15 - 3.19 (3 H), 3.81 - 3.90(1 H), 4.15 - 4.26 (2 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.48 - 7.56 (1 H), 7.64 - 7.72(1 H), 8.47 - 8.53 (1 H), 9.00 - 9.12 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals 5 Amixture of Intermediate 9 (200 mg, 464 µmol), 1-[(methylamino)methyl]cyclopropan-1-olhydrochloride 25 (101 mg, 695 µmol), AcOH (54 µL, 927 µmol), triethylamine (94 mg, 927µmol) in DMF (2.9 mL) is stirred for 4 h at rt, before sodium triacetoxyborohydride (197 mg, 927 µmol) is added at rt. The mixture is stirred for 2 h at rt. Water, MeOH, THF are added, 10 the mixture is filtered, and directly purified by prep. RP-HPLC (basic conditions) to obtain example E13. Example E13 Analytical HPLC-MS Method: D 12-0516-WO-1 Rt [min]: 0.97 MS [m / z]: 517 [M+H]+Analytical SFC method: T Rt [min]: 4.34 e.e. = 90%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.35 - 0.42 (2 H), 0.52 - 0.58 (2 H), 1.48 - 1.66(5 H), 1.78 - 1.89 (2 H), 2.25 - 2.35 (3 H), 2.52 - 2.55 (2 H), 2.60 - 2.70 (1 H), 2.77 - 2.86(2 H), 4.33 - 4.46 (2 H), 4.78 - 4.81 (1 H), 5.37 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.56(1 H), 7.66 - 7.72 (1 H), 8.48 - 8.55 (1 H), 9.03 - 9.10 (2 H). Amixture of Intermediate 9 (90 mg, 209 µmol), (S)-morpholin-2-ylmethanol hydrochloride5 26 (67 mg, 417 µmol) is stirred in MeOH (2 mL) for 2 h at 35 °C. AcOH (18 µL, 313 µmol)and sodium cyanoborohydride (26 mg, 417 µmol) are added and stirred for 16 h at rt. The mixture is diluted with water and MeOH, filtered and basified with triethylamine. The mixture is purified by prep. RP-HPLC (acidic conditions) to obtain the desired compound. The compound is dissolved in MeOH und filtered through a carbonate cartridge, the solvent is10 evaporated, dissolved in ACN / H2O and lyophilized to obtain example E14. Example E14 Analytical HPLC-MS Method: D Rt [min]: 0.73 MS [m / z]: 533 [M+H]+Analytical SFC method: Y Rt [min]: 5.10 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.64 (5 H), 1.87 - 1.97 (3 H), 2.16 - 2.25(1 H), 2.34 - 2.46 (1 H), 2.70 - 2.77 (1 H), 2.81 - 2.92 (3 H), 3.35 - 3.52 (3 H), 3.74 - 3.81 12-0516-WO-1 (1 H), 4.31 - 4.43 (2 H), 4.56 - 4.63 (1 H), 5.36 - 5.46 (1 H), 7.08 - 7.38 (3 H), 7.49 - 7.56(1 H), 7.63 - 7.73 (1 H), 8.48 - 8.53 (1 H), 9.03 - 9.10 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals Example E15 is prepared in analogy to example E14: Intermediate 9 (209 µmol), (R)-5 morpholin-2-ylmethanol hydrochloride 27 (417 µmol), AcOH (313 µmol), and sodiumcyanoborohydride (417 µmol), 2 mL MeOH. Example E15 Analytical HPLC-MS Method: D Rt [min]: 0.79 MS [m / z]: 533 [M+H]+Analytical SFC method: Y Rt [min]: 4.57 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 - 1.65 (5 H), 1.87 - 2.00 (3 H), 2.14 - 2.26(1 H), 2.34 - 2.46 (1 H), 2.69 - 2.77 (1 H), 2.82 - 2.93 (3 H), 3.35 - 3.52 (3 H), 3.72 - 3.82(1 H), 4.31 - 4.44 (2 H), 4.54 - 4.64 (1 H), 5.35 - 5.47 (1 H), 7.06 - 7.38 (3 H), 7.47 - 7.57(1 H), 7.64 - 7.72 (1 H), 8.47 - 8.54 (1 H), 9.00 - 9.12 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals 12-0516-WO-1 Synthesis of examples cis-E16a and cis-E16b 9cis-28 cis-E16a cis-E16bA mixture of intermediate 9 (100 mg, 232 µmol), cis-4-aminotetrahydrofuran-3-ol cis-28 (275 mg, 255 µmol) and AcOH (15 µL, 255 µmol) in DCM (1 mL) is stirred for 15 min at rt before sodium triacetoxyborohydride (76 mg, 348 µmol) is added. The mixture is stirred for 3 h at rt. Saturated aqueous sodium bicarbonate solution and DCM are added. The separated aqueous layer is extracted with DCM and the combined organic layers are concentrated in vacuo. The material is purified by prep. RP-HPLC (acidic conditions) and by chiral SFC to10 obtain examples cis-E16a and cis-E16b as single stereoisomers. The absoluteconfiguration of the amino and hydroxy substituents at the THF ring is not known; theirrelative configuration is cis. Example cis-E16a HPLC-MS Method: D Rt [min]: 0.87 MS [m / z]: 519 [M+H]+Analytical SFC method: J Rt [min]: 4.38 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.34 - 1.56 (5 H), 1.90 - 2.03 (2 H), 2.67 - 2.77(1 H), 2.91 - 3.02 (2 H), 3.56 - 3.63 (1 H), 3.77 - 3.86 (2 H), 4.02 - 4.09 (1 H), 4.18 - 4.30(2 H), 4.74 - 5.07 (1 H), 5.36 - 5.46 (1 H), 7.07 - 7.38 (3 H), 7.48 - 7.56 (1 H), 7.64 - 7.72(1 H), 8.47 - 8.54 (1 H), 9.02 - 9.11 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals 12-0516-WO-1 Example cis-E16b HPLC-MS Method: D Rt [min]: 0.87 MS [m / z]: 519 [M+H]+Analytical SFC method: J Rt [min]: 5.00 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.37 - 1.56 (5 H), 1.90 - 2.01 (2 H), 2.65 - 2.77(1 H), 2.90 - 3.03 (2 H), 3.54 - 3.63 (1 H), 3.76 - 3.87 (2 H), 4.01 - 4.09 (1 H), 4.17 - 4.30(2 H), 4.79 - 5.00 (1 H), 5.36 - 5.47 (1 H), 7.07 - 7.39 (3 H), 7.48 - 7.57 (1 H), 7.64 - 7.72(1 H), 8.45 - 8.54 (1 H), 9.01 - 9.11 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals Synthesis of examples E17a and E17b Amixture of Intermediate 9 (200 mg, 464 µmol), azepin-4-ol 29 (111 mg, 695 µmol), AcOH5 (53 µL, 927 µmol), triethylamine (130 µL, 927 µmol) in DMF (2 mL) is stirred for 4 h at rt, before sodium triacetoxyborohydride (197 mg, 927 µmol) is added at rt. The mixture is stirred for 2 h at rt. Water, MeOH, THF are added, the mixture is filtered and directly purified by prep. RP-HPLC (basic conditions) and chiral SFC to obtain examples E17a andE17b assingle stereoisomers. The absolute configuration of the hydroxy substituent is not known. Example E17a Analytical HPLC-MS Method: D Rt [min]: 0.93 MS [m / z]: 531 [M+H]+Analytical SFC method: AC Rt [min]: 5.73 d.e. > 98% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.36 - 1.85 (13 H), 2.57 - 2.73 (4 H), 2.77 - 2.88(2 H), 3.63 - 3.74 (1 H), 4.25 - 4.43 (3 H), 5.36 - 5.47 (1 H), 7.07 - 7.38 (3 H), 7.49 - 7.56(1 H), 7.65 - 7.72 (1 H), 8.47 - 8.53 (1 H), 9.01 - 9.10 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals Example E17b Analytical HPLC-MS Method: D Rt [min]: 0.93 MS [m / z]: 531 [M+H]+Analytical SFC method: AC Rt [min]: 4.48 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.37 - 1.86 (13 H), 2.58 - 2.73 (4 H), 2.77 - 2.87(2 H), 3.63 - 3.74 (1 H), 4.28 - 4.44 (3 H), 5.36 - 5.46 (1 H), 7.08 - 7.40 (3 H), 7.50 - 7.57(1 H), 7.65 - 7.73 (1 H), 8.50 - 8.53 (1 H), 9.03 - 9.09 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals 5A mixture of Intermediate 9 (40 mg, 93 µmol), (S)-3-hydroxypiperidine hydrochloride 30 (20mg, 139 µmol) and AcOH (5.3 µL, 93 µmol) in DMF (0.8 mL) is stirred at rt for 1 h before sodium triacetoxyborohydride (79 mg, 371 µmol) is added. The mixture is stirred for 4 h at rt. Water is added and the mixture is basified with aqueous NH3solution (10 %). The mixture is further diluted with THF / MeOH, filtered and directly purified by prep. RP-HPLC (basic 10 conditions) to obtain example E18. 12-0516-WO-1 Example E18 Analytical HPLC-MS Method: D Rt [min]: 0.93 MS [m / z]: 517 [M+H]+Analytical SFC method: S Rt [min]: 7.84 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.99 - 1.15 (1 H), 1.32 - 1.45 (1 H), 1.47 - 1.69(6 H), 1.75 - 1.90 (3 H), 1.90 - 2.01 (1 H), 2.01 - 2.15 (1 H), 2.69 - 2.77 (1 H), 2.78 - 2.93(3 H), 3.38 - 3.51 (1 H), 4.34 - 4.47 (2 H), 4.48 - 4.59 (1 H), 5.36 - 5.47 (1 H), 7.07 - 7.39(3 H), 7.49 - 7.58 (1 H), 7.65 - 7.74 (1 H), 8.49 - 8.55 (1 H), 9.00 - 9.14 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals Amixture of bromide 7 (80 mg, 194 µmol), tert-butyl 1,9-diazaspiro[5.5]undecane-1-5 carboxylate 32 (78 mg, 290 µmol) and catalyst I (7 mg, 8 µmol) in 1,4-dioxane (3 mL) isdegassed with argon. K3PO4 (126 mg, 581 µmol) is added, and the mixture is heated for 3.5 h at 95 °C. The mixture is filtered, rinsed with EtOAc, and concentrated in vacuo. Intermediate 33 is used directly for the next step.Intermediate 33 Analytical HPLC-MS Method: D Rt [min]: 1.19 MS [m / z]: 587 [M+H]+ 12-0516-WO-1 Synthesis of example E19 Amixture of intermediate 33 (140 mg, 167 µmol) and TFA (0.4 mL) in DCM (2 mL) is stirred5 for 1.5 h at rt. The mixture is concentrated in vacuo and the residue is dissolved in ACN.Cs2CO3is added, and the resulting suspension is filtered. The filtrate is purified by prep. RP-HPLC (basic conditions) to obtain example E19. Example E19 Analytical HPLC-MS Method: D Rt [min]: 1.01 MS [m / z]: 487 [M+H]+Chiral SFC Method: H Rt [min]: 3.67 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 - 1.79 (13 H), 2.52 - 2.80 (3 H), 3.40 - 3.48(2 H), 3.64 - 3.80 (2 H), 5.42 (1 H), 7.08 - 7.38 (3 H), 7.52 (1 H), 7.69 (1 H), 8.49 (1 H),9.03 (1 H), 9.07 (1 H). Synthesis of example E2010 Amixture of intermediate 7 (100 mg, 230 µmol), 1-methyl-1,8-diazaspiro[4.5]decane 12-0516-WO-1 dihydrochloride 52 (60 mg, 253 µmol) and Cs2CO3 (300 mg, 920 µmol) in 1,4-dioxane (2mL) is degassed with argon. Then catalyst I (19 mg, 23 µmol) is added, and the mixture is heated under argon for 16 h at 120°C. Aqueous NaHCO3 solution is added, the aqueous layer is extracted with EtOAc and the combined organic layers are dried with MgSO4. After 5 filtration and evaporation of the solvent the material is purified by prep. RP-HPLC (basic conditions) to obtain example E20. Example E20 Analytical HPLC-MS Method: D Rt [min]: 1.02 MS [m / z]: 487 [M+H]+Analytical SFC method: AD Rt [min]: 1.55 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.57 (3 H), 1.64 - 1.85 (6 H), 2.04 - 2.09(1 H), 2.16 - 2.24 (3 H), 2.65 - 2.74 (2 H), 2.78 - 2.91 (2 H), 4.29 - 4.41 (2 H), 5.36 - 5.48(1 H), 7.05 - 7.39 (3 H), 7.49 - 7.57 (1 H), 7.64 - 7.73 (1 H), 8.45 - 8.55 (1 H), 8.99 - 9.11(2 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of examples cis-E21a and cis-E21b 10 Intermediate 9 (200 mg, 464 µmol) is dissolved in THF (7.5 mL). Then rac-cisazabicyclo[3.1.0]hexan-1-ylmethanole hydrochloride cis-34 (347 mg, 2.32 mmol), andmolecular sieves 4 Å are added and stirring is continued for 1 h at 60°C. After cooling to rt, sodium triacetoxyborohydride (202 mg, 927 µmol) is added and the reaction mixture stirred for 1 h at rt. The crude mixture is filtered through Celite and directly purified by prep. RP-15 HPLC (basic conditions) and by chiral SFC to obtain example cis-E21a and example cis-E21b as single stereoisomers. The absolute configuration of the bridged carbon atoms is 12-0516-WO-1 not known; the relative configuration of the [3.1.0] ring system is cis. Example cis-E21a Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 529 [M+H]+Analytical SFC method: T Rt[min]: 4.58 d.e. = 98% 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.33 - 0.41 (1 H), 0.69 - 0.76 (1 H), 1.17 - 1.25(1 H), 1.44 - 1.57 (5 H), 1.82 - 1.94 (2 H), 2.24 - 2.38 (3 H), 2.93 - 3.08 (4 H), 3.39 - 3.53(2 H), 4.09 - 4.20 (2 H), 4.44 - 4.50 (1 H), 5.35 - 5.45 (1 H), 7.08 - 7.38 (3 H), 7.49 - 7.56(1 H), 7.65 - 7.72 (1 H), 8.46 - 8.53 (1 H), 9.01 - 9.10 (2 H).Example cis-E21b Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 529 [M+H]+Analytical SFC method: T Rt [min]: 4.95 d.e. = 94% 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.34 - 0.40 (1 H), 0.70 - 0.77 (1 H), 1.17 - 1.26(1 H), 1.42 - 1.58 (5 H), 1.82 - 1.94 (2 H), 2.25 - 2.39 (3 H), 2.94 - 3.08 (4 H), 3.40 - 3.54(2 H), 4.09 - 4.20 (2 H), 4.38 - 4.54 (1 H), 5.35 - 5.46 (1 H), 7.07 - 7.39 (3 H), 7.49 - 7.57(1 H), 7.64 - 7.74 (1 H), 8.47 - 8.54 (1 H), 9.00 - 9.13 (2 H). 12-0516-WO-1 (R)-3-Hydroxypiperidine hydrochloride 35 (130 mg, 927 µmol) is dissolved in MeOH (5 mL)and filtered through a carbonate cartridge. Intermediate 9 (200 mg, 464 µmol) is added andthe mixture is stirred for 2 h at 35 °C. AcOH (41 µl, 695 µmol) and sodium cyanoborohydride (58 mg, 927 µmol) are added and the mixture stirred for 16 h at rt. Water is added, filtered5 and the filtrate is directly purified by prep. RP-HPLC (acidic conditions). After lyophilization,the material is redissolved in MeOH and filtered through a carbonate cartridge to obtain example E22. Example E22 Analytical HPLC-MS Method: D Rt [min]: 0.80 MS [m / z]: 517 [M+H]+Analytical SFC method: Z Rt [min]: 4.85 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.00 - 1.14 (1 H), 1.30 - 1.47 (1 H), 1.49 - 1.67(6 H), 1.74 - 1.89 (3 H), 1.89 - 1.98 (1 H), 2.03 - 2.13 (1 H), 2.65 - 2.77 (1 H), 2.77 - 2.92(3 H), 3.37 - 3.49 (1 H), 4.32 - 4.46 (2 H), 4.49 - 4.56 (1 H), 5.36 - 5.47 (1 H), 7.07 - 7.40(3 H), 7.48 - 7.57 (1 H), 7.66 - 7.73 (1 H), 8.46 - 8.53 (1 H), 9.02 - 9.09 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals Synthesis scheme of intermediate 38 Synthesis of intermediate 37

[0329] To a mixture of intermediate 5 (12.5 g, 51.6 mmol), (1 R)-1-[2-fluoro-3- (trifluoromethyl)phenyl]ethan-1 -amine hydrochloride 36 (CAS: 2230840-52-3; 13.8 g, 51.6 mmol) and N-methyl morpholine (20.1 mL, 181 mmol) in ACN (152 mL) is added 1- propanephosphonic anhydride (50%; 36.9 mL, 62.0 mmol) at 0 °C dropwise. The mixture is allowed to reach rt and is stirred for 3 h. ACN is evaporated under reduced pressure. Water and EtOAc are added to the remaining material. The organic layer is separated and extracted with 0.5 M KHSO4 solution and water sequentially. The organic layer is dried with MgSCL, filtered, and the solvent is evaporated. The remaining material is dissolved in warm EtOAc and is allowed to cool down over night. The solids are filtered to obtain intermediate 37. The liquid layer is separated, and the solvent evaporated. The remaining solid is stirred in MTBE. The solids are filtered to obtain intermediate 37, and the two batches are combined.

[0330] Intermediate 37

[0331] HPLC-MS Method: E

[0332] Rt [min]: 1.04 MS [m / z]: 431 [M+H]+

[0333] Synthesis of intermediate 38 12-0516-WO-1 Amixture of intermediate 37 (1.3 g, 3.1 mmol), piperidin-4-one hydrochloride 8 (881 mg,6.2 mmol) and Cs2CO3 (3.5 g, 10.8 mmol) in 1,4-dioxane (18 mL) is degassed with argon. Catalyst I (78 mg, 93 µmol) is added, and the mixture is heated under argon for 3.5 h at 95 °C. The mixture is filtered, the solids are washed with EtOAc, and the combined solvents 5 are evaporated under reduced pressure. The material is purified by column chromatography (SiO2; EtOAc / cyclohexane: 80:20 100:0) to obtain intermediate 38.Intermediate 38Analytical HPLC-MS Method: D Rt[min]: 1.00 MS [m / z]: 450 [M+H]+Scheme of alternative synthesis of intermediate 37 Synthesis of intermediate 39 10 HATU (189 mg, 496 µmol) and triethylamine (232 µL, 1.7 µmol) are added to intermediate 12 (100 mg, 413 µmol) in DMF (1.6 mL). The mixture is stirred for 15 min at rt before (1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride 36 (CAS: 2230840-52-3;15 112 mg, 454 µmol) is added. The mixture is stirred for 16 h at rt before it is diluted with MeOH, filtered, and purified by prep. RP-HPLC (acidic conditions) to obtain intermediate 39.

[0334] Intermediate 39

[0335] HPLC-MS Method: E

[0336] Rt [min]: 0.98 MS [m / z]: 431 [M+H]+

[0337] Synthesis of intermediate 37

[0338] A mixture of intermediate 39 (12.0 g, 19.5 mmol), CS2CO3 (6.3 g, 19.5 mmol), piperidine (1.9 mL, 19.5 mmol) in 1 ,4-dioxane (90 mL) is stirred at 100 °C for 16 h. EtOAc and water are added. The aqueous layer is separated and extracted with EtOAc. The combined organic layers are dried over Na2SO4. The solids are filtered, and the solvent is evaporated under reduced pressure. The material is purified by column chromatography (SiO2;

[0339] EtOAc / petroleum ether: 30:70) to obtain intermediate 37.

[0340] Intermediate 37

[0341] Analytical HPLC-MS Method: D

[0342] Rt [min]: 1.00 MS [m / z]: 431 [M+H]+

[0343] 12-0516-WO-1 Synthesis of example E24 Example E24 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (3R,5S)-5-5 methylpyrrolidin-3-ol hydrochloride 40 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E24 HPLC-MS Method: A Rt [min]: 0.80 MS [m / z]: 535 [M+H]+Analytical SFC method: L Rt [min]: 2.25 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 - 1.49 (3 H), 1.50 - 1.56 (3 H), 1.62 - 1.70(1 H), 1.77 - 1.92 (2 H), 2.04 - 2.12 (1 H), 2.18 - 2.27 (1 H), 2.37 - 2.45 (1 H), 2.80 - 2.90(2 H), 3.82 - 3.93 (1 H), 4.36 - 4.43 (1 H), 4.43 - 4.57 (2 H), 5.38 - 5.47 (1 H), 7.14 - 7.20(1 H), 7.36 - 7.45 (1 H), 7.63 - 7.73 (1 H), 7.80 - 7.86 (1 H), 8.52 - 8.59 (1 H), 9.09 - 9.19(2 H), 9.45 - 9.58 (1 H), missing proton(s) presumably hidden by / overlapping with solventsignals. 12-0516-WO-1 Example E25 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (2R,3R)-2-methylazetidin-3-ol hydrochloride 41 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH. Example E25 HPLC-MS Method: A Rt[min]: 0.77 MS [m / z]: 521 [M+H]+Analytical SFC method: Q Rt [min]: 1.76 d.e. > 97%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.02 - 1.09 (3 H), 1.24 - 1.43 (2 H), 1.49 - 1.55(3 H), 1.65 - 1.83 (2 H), 2.27 - 2.37 (1 H), 2.93 - 3.04 (3 H), 4.05 - 4.19 (3 H), 5.35 - 5.43(1 H), 7.08 - 7.14 (1 H), 7.35 - 7.44 (1 H), 7.63 - 7.70 (1 H), 7.77 - 7.84 (1 H), 8.45 - 8.52(1 H), 9.00 - 9.05 (1 H), missing proton(s) presumably hidden by / overlapping with solventsignals. Example E26 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (S)-pyrrolidin-3-ylmethanol 42 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex(80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E26 HPLC-MS Method: A Rt[min]: 0.78 MS [m / z]: 535 [M+H]+Analytical SFC method: AP 12-0516-WO-1 Rt [min]: 1.67 e.e. / d.e. >98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.49 - 1.88 (6 H), 1.90 - 2.24 (3 H), 2.35 - 2.46(0.5 H), 2.82 - 2.93 (2.5 H), 3.07 - 3.23 (1 H), 4.42 - 4.55 (2 H), 5.36 - 5.47 (1 H), 7.15 -7.21 (1 H), 7.38 - 7.45 (1 H), 7.64 - 7.72 (1 H), 7.80 - 7.88 (1 H), 8.52 - 8.58 (1 H), 9.09- 9.20 (2 H), 9.50 - 9.76 (1 H), missing proton(s) presumably hidden by / overlapping withsolvent signals Example E27 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (R)-5 pyrrolidin-3-ylmethanol 43 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex(80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E27 HPLC-MS Method: A Rt[min]: 0.78 MS [m / z]: 535 [M+H]+Analytical SFC method: L Rt [min]: 2.11 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.89 (6 H), 1.89 - 2.24 (3 H), 2.35 - 2.46(0.5 H), 2.80 - 2.95 (2.5 H), 3.07 - 3.22 (1 H), 4.42 - 4.55 (2 H), 5.37 - 5.47 (1 H), 7.15 -7.22 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.72 (1 H), 7.79 - 7.88 (1 H), 8.51 - 8.59 (1 H), 9.08- 9.22 (2 H), 9.47 - 9.76 (1 H), missing proton(s) presumably hidden by / overlapping withsolvent signals 12-0516-WO-1 Synthesis of example E28 Example E28 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (7R)-5-5 azaspiro[2.4]heptan-7-ol 16 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-boranecomplex (80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E28 HPLC-MS Method: A Rt[min]: 0.80 MS [m / z]: 547 [M+H]+Analytical SFC method: L Rt [min]: 2.16 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.63 - 0.82 (3 H), 0.89 - 0.98 (1 H), 1.48 - 1.59(3 H), 1.65 - 1.89 (2 H), 2.07 - 2.29 (2 H), 2.78 - 2.95 (2 H), 3.18 - 3.31 (1 H), 3.86 - 3.94(1 H), 4.44 - 4.55 (2 H), 5.37 - 5.47 (1 H), 7.15 - 7.20 (1 H), 7.37 - 7.45 (1 H), 7.65 - 7.72(1 H), 7.79 - 7.87 (1 H), 8.55 (1 H), 9.09 - 9.20 (2 H), 9.97 - 10.29 (1 H), missing proton(s)presumably hidden by / overlapping with solvent signals

[0344] 12-0516-WO-1 Synthesis of example cis-E29 38 cis-44 cis-E295 Example cis-E29 is prepared in analogy to example E1: Intermediate 38 (80 µmol), diol cis-44 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH;purification by prep. RP-HPLC (acidic conditions) and is obtained as a mixture of cis-diastereomers. Example cis-E29 HPLC-MS Method: A Rt [min]: 0.76 MS [m / z]: 565 [M+H]+1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.15 - 1.21 (3 H), 1.49 - 1.58 (3 H), 1.68 - 2.03(4 H), 2.04 - 2.13 (1 H), 2.16 - 2.25 (1 H), 2.81 - 2.99 (3 H), 3.01 - 3.12 (1 H), 4.44 - 4.61(2 H), 5.12 - 5.31 (1 H), 5.37 - 5.47 (1 H), 7.14 - 7.20 (1 H), 7.38 - 7.45 (1 H), 7.64 - 7.73(1 H), 7.79 - 7.87 (1 H), 8.53 - 8.58 (1 H), 8.74 - 8.87 (1 H), 9.08 - 9.18 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals 10 ple E1: Intermediate 38 (80 µmol), (7S)-5- 12-0516-WO-1 azaspiro[2.4]heptan-7-ol 45 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-boranecomplex (80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E30 HPLC-MS Method: A Rt [min]: 0.80 MS [m / z]: 547 [M+H]+Analytical SFC method: F Rt [min]: 1.49 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.61 - 0.82 (3 H), 0.88 - 0.98 (1 H), 1.48 - 1.59(3 H), 1.66 - 1.90 (2 H), 2.06 - 2.28 (2 H), 2.78 - 2.94 (2 H), 3.17 - 3.31 (1 H), 3.86 - 3.95(1 H), 4.40 - 4.55 (2 H), 5.38 - 5.47 (1 H), 7.14 - 7.21 (1 H), 7.37 - 7.46 (1 H), 7.64 - 7.72(1 H), 7.78 - 7.87 (1 H), 8.51 - 8.58 (1 H), 9.09 - 9.20 (2 H), 9.94 - 10.28 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Example E31 is prepared in analogy to example E1: Intermediate 38 (80 µmol), L-prolinol19 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH;purification by prep. RP-HPLC (acidic conditions). Example E31 HPLC-MS Method: A Rt [min]: 0.80 MS [m / z]: 535 [M+H]+Analytical SFC method: L Rt [min]: 2.06 d.e. > 98% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.49 - 1.57 (3 H), 1.73 - 2.00 (5 H), 2.00 - 2.10(1 H), 2.10 - 2.26 (2 H), 2.82 - 2.93 (2 H), 3.23 - 3.34 (1 H), 3.38 - 3.47 (1 H), 4.48 - 4.57(2 H), 5.38 - 5.47 (1 H), 7.14 - 7.20 (1 H), 7.37 - 7.45 (1 H), 7.65 - 7.72 (1 H), 7.81 - 7.87(1 H), 8.52 - 8.57 (1 H), 9.10 - 9.17 (2 H), 9.17 - 9.24 (1 H), missing proton(s) presumablyhidden by / overlapping with solvent signals Example E32 is prepared in analogy to example E1: Intermediate 38 (80 µmol), (2S,3R)-2-5 methylazetidin-3-ol hydrochloride 46 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E32 HPLC-MS Method: A Rt [min]: 0.73 MS [m / z]: 521 [M+H]+Analytical SFC method: L Rt [min]: 1.83 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.12 - 1.20 (3 H), 1.26 - 1.45 (2 H), 1.48 - 1.55(3 H), 1.69 - 1.78 (1 H), 1.80 - 1.89 (1 H), 2.24 - 2.31 (1 H), 2.86 - 2.93 (1 H), 2.93 - 3.02(2 H), 4.07 - 4.21 (2 H), 5.35 - 5.43 (1 H), 7.07 - 7.13 (1 H), 7.36 - 7.43 (1 H), 7.63 - 7.69(1 H), 7.77 - 7.83 (1 H), 8.45 - 8.50 (1 H), 9.00 - 9.03 (1 H), missing proton(s) presumablyhidden by / overlapping with solvent signals 12-0516-WO-1 Synthesis of example E33 Example E33 is prepared in analogy to example E1: Intermediate 38 (80 µmol), 5-5 azaspiro[2.4]heptane hydrochloride 21 (0.12 mmol), AcOH (0.51 mmol), and 2-picoline-borane complex (80 µmol), 2 mL MeOH; purification by prep. RP-HPLC (acidic conditions). Example E33 HPLC-MS Method: A Rt [min]: 0.98 MS [m / z]: 531 [M+H]+Analytical SFC method: L Rt [min]: 2.02 d.e. >98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.58 - 0.79 (4 H), 1.50 - 1.60 (3 H), 1.68 - 1.90(3 H), 2.01 - 2.18 (2 H), 2.18 - 2.26 (1 H), 2.81 - 2.93 (2 H), 3.25 - 3.33 (2 H), 3.34 - 3.47(2 H), 4.44 - 4.54 (2 H), 5.37 - 5.47 (1 H), 7.16 - 7.21 (1 H), 7.37 - 7.45 (1 H), 7.65 - 7.72(1 H), 7.80 - 7.87 (1 H), 8.52 - 8.59 (1 H), 9.09 - 9.20 (2 H), 9.85 - 10.00 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals Synthesis of intermediate 48 10 A mixture of bromide 37 (200 mg, 464 µmol), tert-butyl 1,8-diazaspiro[4.5]decane-1- 12-0516-WO-1 carboxylate hydrochloride 47 (149 mg, 510 µmol) and Cs2CO3 (382 mg, 1.16 mmol) andcatalyst I (19 mg, 23 µmol) in degassed 1,4-dioxane (2 mL) is stirred under argon for 16 h at 95 °C. The mixture is diluted with 1,4-dioxane, filtered through a thiol resin, and washed with DMF / MeOH. The material is purified by prep. RP-HPLC (acidic conditions) to obtain 5 intermediate 48. Intermediate 48 Analytical HPLC-MS Method: D Rt [min]: 1.17 MS [m / z]: 591 [M+H]+ Intermediate 48 (134 mg, 227 µmol) in DCM (3 mL) is treated with 4 N HCl in 1,4-dioxane10 (142 µL) at 0 °C and stirred for 3 h at 0 °C. The solvent is evaporated under reduced pressure and the material is purified by prep. RP-HPLC (basic conditions) to obtain example E34. Example E34 Analytical HPLC-MS Method: D Rt [min]: 1.06 MS [m / z]: 491 [M+H]+Analytical SFC method: X Rt [min]: 4.10 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.76 (11 H), 1.90 - 2.16 (1 H), 2.78 - 2.88(2 H), 3.55 - 3.67 (4 H), 5.36 - 5.47 (1 H), 7.11 - 7.16 (1 H), 7.38 - 7.45 (1 H), 7.64 - 7.71(1 H), 7.79 - 7.86 (1 H), 8.47 - 8.53 (1 H), 9.02 - 9.06 (1 H), 9.06 - 9.13 (1 H). 12-0516-WO-1 Synthesis of example E35 Amixture of bromide 38 (80 mg, 186 µmol), N,N-dimethylpiperidine-4-amine 49 (29 mg,5 223 µmol) and Cs2CO3 (121 mg, 371 µmol) and catalyst I (16 mg, 19 µmol) in degassed1,4-dioxane is stirred under argon for 18 h at 105 °C. The mixture is diluted with THF and ACN / water and filtered. The material is purified by prep. RP-HPLC (basic conditions) to obtain example E35. Example E35 Analytical HPLC-MS Method: A Rt [min]: 0.83 MS [m / z]: 479 [M+H]+Analytical SFC method: X Rt [min]: 4.14 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.46 - 1.61 (5 H), 1.84 - 1.93 (2 H), 2.17 - 2.22(6 H), 2.23 - 2.35 (1 H), 2.80 - 2.91 (2 H), 4.30 - 4.37 (2 H), 5.36 - 5.47 (1 H), 7.14 - 7.19(1 H), 7.36 - 7.44 (1 H), 7.63 - 7.70 (1 H), 7.82 - 7.90 (1 H), 8.47 - 8.52 (1 H), 9.04 - 9.39(2 H), missing proton(s) presumably hidden by / overlapping with solvent signalsSynthesis of intermediate 51 10 12-0516-WO-1 Amixture of bromide 37 (300 mg, 647 µmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride 50 (246 mg, 971 µmol) and Cs2CO3 (532 mg, 1.62 mmol) andcatalyst I (27 mg, 32 µmol) in degassed 1,4-dioxane (2 mL) is stirred under argon for 18 h at 105 °C. The mixture is diluted with 1,4-dioxane, filtered through a thiol resin and washed 5 with MeOH. The material is purified by prep. RP-HPLC (basic conditions) to obtain intermediate 51. Intermediate 51 Analytical HPLC-MS Method: D Rt [min]: 1.15 MS [m / z]: 591 [M+H]+ 10 Intermediate 51 (370 mg, 626 µmol) in 1,4-dioxane (1 mL) is treated with 4 N HCl in 1,4-dioxane (2 mL) and stirred for 16 h at rt. The mixture is filtered through a carbonate cartridge, the solids are washed with MeOH and the combined solvents are evaporated under reduced pressure. The material is purified by prep. RP-HPLC (basic conditions) to obtain example E36. Example E36 Analytical HPLC-MS Method: D Rt [min]: 1.06 MS [m / z]: 491 [M+H]+Analytical SFC method: H Rt [min]: 4.02 e.e. = 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.49 - 1.58 (5 H), 1.60 - 1.71 (4 H), 2.59 - 2.64(2 H), 2.78 - 2.85 (2 H), 3.48 - 3.63 (4 H), 5.37 - 5.47 (1 H), 7.11 - 7.20 (1 H), 7.38 - 7.44 12-0516-WO-1 (1 H), 7.64 - 7.71 (1 H), 7.80 - 7.86 (1 H), 8.48 - 8.53 (1 H), 9.04 - 9.07 (1 H), 9.07 - 9.14(1 H), missing proton(s) presumably hidden by / overlapping with solvent signals Synthesis of example E37 37 52 E37A mixture of bromide 37 (200 mg, 464 µmol), 1-methyl-1,8-diazaspiro[4.5]decane5 dihydrochloride 52 (122 mg, 510 µmol) and Cs2CO3 (534 mg, 1.62 mmol) and catalyst I (19mg, 23 µmol) in degassed 1,4-dioxane (2 mL) is stirred under argon for 16 h at 90 °C. The mixture is diluted with 1,4-dioxane, filtered through thiol resin, and washed with MeOH. The material is purified by prep. RP-HPLC (basic conditions) to obtain example E37. Example E37 Analytical HPLC-MS Method: D Rt [min]: 1.06 MS [m / z]: 505 [M+H]+Analytical SFC method: AB Rt [min]: 3.63 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.28 - 1.37 (2 H), 1.49 - 1.57 (3 H), 1.65 - 1.84(6 H), 2.17 - 2.23 (3 H), 2.65 - 2.74 (2 H), 2.80 - 2.91 (2 H), 4.30 - 4.40 (2 H), 5.37 - 5.48(1 H), 7.13 - 7.21 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87 (1 H), 8.47 - 8.56(1 H), 9.04 - 9.13 (2 H).Synthesis of intermediate 54 10 12-0516-WO-1 Amixture of intermediate 53 (WO2016147011; 188 mg, 465 µmol), Pd / C (5 wt.%, 50 mg)and 2 drops aqueous NH3 solution (7 N) in MeOH (10 mL) is stirred under 1 bar hydrogen for 16 h at rt. The mixture is filtered and the solids are washed with MeOH. The solvent is removed under reduced pressure and intermediate 54 is used in the next reaction step5 without further purification. Intermediate 54 Analytical HPLC-MS Method: D Rt [min]: 0.98 MS [m / z]: 271 [M+H]+Synthesis of intermediate 55 Amixture of bromide 7 (80 mg, 194 µmol), intermediate 54 (60 mg, 222 µmol) and10 potassium phosphate (84 mg, 387 µmol) and catalyst I (8 mg, 10 µmol) in degassed 1,4-dioxane (3 mL) is stirred under argon for 18 h at 105 °C. The mixture is diluted with DCM, filtered through Celite, and washed with MeOH. The solvent is removed under reduced pressure and the material is used in the next reaction step without further purification. Intermediate 55 Analytical HPLC-MS Method: D Rt [min]: 1.10 MS [m / z]: 603 [M+H]+ 12-0516-WO-1 Synthesis of examples E38a and E38b Intermediate 55 (117 mg, 194 µmol) in 1,4-dioxane (2 mL) is treated with HCl in 1,4-dioxane5 (4 M; 242 µL) and stirred for 6 h at rt, then aqueous HCl solution (4 M; 300 µL) is added, and the mixture stirred for 18 h before aqueous HCl solution (6 M; 500 µL) is added and the mixture is stirred for 16 h at rt. The mixture is neutralized with NaOH solution (4 M), basified with aqueous NH3solution and extracted with DCM. The organic solvent is evaporated under reduced pressure and the material is purified by prep. RP-HPLC (basic conditions)10 and chiral SFC to obtain examples E38a and E38b as single stereoisomers. The absoluteconfiguration at the pyrrolidine is not known.Example E38a Analytical HPLC-MS Method: D Rt [min]: 0.98 MS [m / z]: 503 [M+H]+Analytical SFC method: AI Rt [min]: 2.02 d.e.: > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.74 (10 H), 2.74 - 2.88 (2 H), 2.89 - 2.95(1 H), 3.13 - 3.24 (2 H), 3.54 - 3.59 (1 H), 4.01 - 4.29 (3 H), 5.35 - 5.47 (1 H), 7.06 - 7.38(3 H), 7.48 - 7.56 (1 H), 7.64 - 7.74 (1 H), 8.47 - 8.53 (1 H), 9.01 - 9.11 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals Example E38b Analytical HPLC-MS Method: D Rt [min]: 0.98 MS [m / z]: 503 [M+H]+ 12-0516-WO-1 Analytical SFC method: AI Rt [min]: 1.38 d.e. = 96%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.74 (11 H), 2.72 - 2.86 (2 H), 2.86 - 2.92(1 H), 3.12 - 3.22 (2 H), 3.83 - 4.34 (3 H), 5.36 - 5.47 (1 H), 7.06 - 7.38 (3 H), 7.49 - 7.57(1 H), 7.64 - 7.74 (1 H), 8.46 - 8.53 (1 H), 9.01 - 9.10 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals. Amixture of intermediate 38 (50 mg, 111 µmol), (2R)-1-aminopropan-2-ol 56 (13 mg, 1675 µmol) and AcOH (9.6 µL, 167 µmol) in DCM (0.5 mL) is stirred for 15 min at rt before sodiumtriacetoxyborohydride (36 mg, 167 µmmol) is added. The mixture is stirred for 3 h at rt, diluted with DCM, and extracted with aqueous saturated NaHCO3 solution. The volume of the separated organic layer is decreased under reduced pressure. The material is purified by prep. RP-HPLC (acidic conditions). After lyophilization, the material is redissolved in10 MeOH and filtered through a carbonate cartridge to obtain example E39.Example E39 Analytical HPLC-MS Method: D Rt [min]: 0.97 MS [m / z]: 509 [M+H]+Analytical SFC method: AO Rt [min]: 5.90 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.02 - 1.09 (3 H), 1.36 - 1.48 (2 H), 1.51 - 1.57(4 H), 1.89 - 2.00 (2 H), 2.41 - 2.49 (1 H), 2.58 - 2.70 (1 H), 2.92 - 3.04 (2 H), 3.60 - 3.70(1 H), 4.16 - 4.29 (2 H), 4.37 - 4.57 (1 H), 5.36 - 5.47 (1 H), 7.10 - 7.18 (1 H), 7.38 - 7.46 12-0516-WO-1 (1 H), 7.64 - 7.72 (1 H), 7.80 - 7.87 (1 H), 8.49 - 8.54 (1 H), 9.05 - 9.16 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Example E40 is prepared in analogy to example E39: Intermediate 38 (111 µmol), (2S)-1-5 aminopropan-2-ol 57 (167 µmol), AcOH (167 µmol), and sodium triacetoxyborohydride (167µmol), 0.5 mL DCM. Example E40 Analytical HPLC-MS Method: D Rt [min]: 0.97 MS [m / z]: 509 [M+H]+Analytical SFC method: AG Rt [min]: 5.00 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.00 - 1.09 (3 H), 1.31 - 1.48 (2 H), 1.48 - 1.67(4 H), 1.88 - 1.99 (2 H), 2.42 - 2.48 (1 H), 2.56 - 2.65 (1 H), 2.93 - 3.04 (2 H), 3.58 - 3.69(1 H), 4.14 - 4.27 (2 H), 4.39 - 4.44 (1 H), 5.36 - 5.47 (1 H), 7.10 - 7.16 (1 H), 7.37 - 7.45(1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87 (1 H), 8.48 - 8.53 (1 H), 9.04 - 9.13 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis of examples cis-E41a and cis-E41b 38 cis-28 cis-E41a cis-E41bExamples cis-E41 and cis-E41b are prepared in analogy to example E39: Intermediate 385 (223 µmol), cis-4-aminotetrahydrofuran-3-ol cis-28 (245 µmol), AcOH (245 µmol), andsodium triacetoxyborohydride (334 µmol), 1 mL DCM; in addition: chiral SFC separation (basic conditions). Cis-E41a and cis-E41b are isolated as single stereoisomers. Theabsolute configuration of the amino and hydroxy substituents at the THF ring is not known;their relative configuration is cis. Example cis-E41a Analytical HPLC-MS Method: D Rt [min]: 0.83 MS [m / z]: 537 [M+H]+Analytical SFC method: J Rt [min]: 3.22 d.e. = 97 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.36 - 1.58 (5 H), 1.89 - 2.03 (2 H), 2.67 - 2.77(1 H), 2.92 - 3.03 (2 H), 3.57 - 3.64 (1 H), 3.76 - 3.87 (2 H), 4.03 - 4.09 (1 H), 4.20 - 4.30(2 H), 4.68 - 5.11 (1 H), 5.37 - 5.48 (1 H), 7.12 - 7.17 (1 H), 7.38 - 7.45 (1 H), 7.64 - 7.72(1 H), 7.80 - 7.87 (1 H), 8.48 - 8.55 (1 H), 9.04 - 9.16 (2 H), missing proton(s) presumablyhidden by / overlapping with solvent signals. 10 Example cis-E41b Analytical HPLC-MS Method: D Rt [min]: 0.83 MS [m / z]: 537 [M+H]+Analytical SFC method: J 12-0516-WO-1 Rt [min]: 3.61 d.e. = 84 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.38 - 1.58 (5 H), 1.90 - 2.03 (2 H), 2.69 - 2.79(1 H), 2.92 - 3.03 (2 H), 3.56 - 3.63 (1 H), 3.76 - 3.87 (2 H), 4.04 - 4.10 (1 H), 4.20 - 4.31(2 H), 5.37 - 5.47 (1 H), 7.12 - 7.16 (1 H), 7.39 - 7.45 (1 H), 7.64 - 7.72 (1 H), 7.80 - 7.87(1 H), 8.47 - 8.54 (1 H), 9.05 - 9.15 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of examples trans-E42a and trans-E42b Examples trans-E42 and trans-E42b are prepared in analogy to example E39:5 Intermediate 38 (445 µmol), trans-4-aminotetrahydrofuran-3-ol trans-28 (668 µmol), AcOH(668 µmol), and sodium triacetoxyborohydride (668 µmol), 2 mL DCM; in addition: chiral SFC separation (basic conditions). Trans-E42a and trans-E42b are isolated as singlestereoisomers. The absolute configuration of the amino and hydroxy substituents at the THF ring is not known; their relative configuration is trans.Example trans-E42a HPLC-MS Method: E Rt [min]: 0.83 MS [m / z]: 537 [M+H]+Analytical SFC method: G Rt [min]: 3.64 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.33 - 1.48 (2 H), 1.49 - 1.57 (3 H), 1.91 - 2.03(2 H), 2.69 - 2.79 (1 H), 2.90 - 3.01 (2 H), 3.15 - 3.22 (1 H), 3.37 - 3.43 (1 H), 3.43 - 3.50(1 H), 3.77 - 3.84 (1 H), 3.86 - 3.92 (1 H), 3.94 - 3.99 (1 H), 4.20 - 4.30 (2 H), 4.87 - 4.96(1 H), 5.37 - 5.47 (1 H), 7.10 - 7.15 (1 H), 7.37 - 7.44 (1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87(1 H), 8.49 - 8.53 (1 H), 9.03 - 9.14 (2 H), missing proton(s) presumably hidden by / 12-0516-WO-1 overlapping with solvent signals. Example trans-E42b Analytical HPLC-MS Method: C Rt [min]: 0.83 MS [m / z]: 537 [M+H]+Analytical SFC method: G Rt [min]: 5.52 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.33 - 1.48 (2 H), 1.49 - 1.58 (3 H), 1.92 - 2.03(2 H), 2.68 - 2.79 (1 H), 2.90 - 3.02 (2 H), 3.15 - 3.22 (1 H), 3.37 - 3.44 (1 H), 3.44 - 3.50(1 H), 3.77 - 3.84 (1 H), 3.86 - 3.93 (1 H), 3.93 - 4.01 (1 H), 4.20 - 4.31 (2 H), 4.85 - 4.96(1 H), 5.36 - 5.47 (1 H), 7.10 - 7.17 (1 H), 7.38 - 7.45 (1 H), 7.64 - 7.71 (1 H), 7.79 - 7.86(1 H), 8.48 - 8.54 (1 H), 9.03 - 9.14 (2 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of examples E43a and E43b 5 Examples E43a and E43b are prepared in analogy to example E39: Intermediate 38 (556µmol), azepin-4-ol 29 (834 µmol), AcOH (834 µmol), and sodium triacetoxyborohydride(1.11 mmol), 2 mL DCM; in addition: chiral SFC separation (basic conditions). E43a andE43b are isolated as single stereoisomers. The absolute configuration of the hydroxysubstituent is not known. Example E43a HPLC-MS Method: E 12-0516-WO-1 Rt [min]: 0.83 MS [m / z]: 549 [M+H]+Analytical SFC method: AC Rt [min]: 4.46 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.36 - 1.85 (13 H), 2.58 - 2.73 (4 H), 2.77 - 2.88(2 H), 3.63 - 3.74 (1 H), 4.17 - 4.47 (3 H), 5.35 - 5.46 (1 H), 7.10 - 7.15 (1 H), 7.38 - 7.44(1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87 (1 H), 8.48 - 8.52 (1 H), 9.03 - 9.14 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Example E43b HPLC-MS Method: E Rt[min]: 0.83 MS [m / z]: 549 [M+H]+Analytical SFC method: AC Rt [min]: 3.51 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.35 - 1.90 (13 H), 2.56 - 2.75 (4 H), 2.75 - 2.89(2 H), 3.61 - 3.76 (1 H), 4.16 - 4.47 (3 H), 5.37 - 5.48 (1 H), 7.08 - 7.16 (1 H), 7.36 - 7.45(1 H), 7.60 - 7.73 (1 H), 7.78 - 7.88 (1 H), 8.44 - 8.59 (1 H), 9.00 - 9.18 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals. 5 2-Picoline-borane complex (6.2 mg, 60 µmol) is added to a mixture of intermediate 38 (26mg, 158 µmol), (S)-3-hydroxypiperidine hydrochloride 30 (17 mg, 116 µmol) and AcOH (10µL, 514 µM) in MeOH (0.5 mL). The mixture is stirred for 16 h at rt. The mixture is neutralized with AcOH, diluted with MeOH and purified by prep. RP-HPLC (acidic conditions) to obtain 12-0516-WO-1 example E44. Example E44 Analytical HPLC-MS Method: E Rt [min]: 0.79 MS [m / z]: 535 [M+H]+Analytical SFC method: AE Rt [min]: 1.48 d.e. > 98 %1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.50 - 2.25 (11 H), 2.80 - 2.94 (3 H), 2.98 - 3.14(2 H), 4.53 (2 H), 5.42 (1 H), 7.18 (1 H), 7.41 (1 H), 7.64 - 7.72 (1 H), 7.83 (1 H), 8.55 (1H), 8.90 - 9.34 (3 H), missing proton(s) presumably hidden by / overlapping with solventsignals. Synthesis of intermediate 58 5 Amixture of bromide 37 (120 mg, 278 µmol), tert-butyl 1,9-diazaspiro[5.5]undecane-1-carboxylate 32 (112 mg, 418 µmol) and Cs2CO3 (272 mg, 835 µmol) in 1,4-dioxane (4 mL)is degassed with argon. Catalyst I (14 mg, 17 µmol) is added, and the mixture is heated under argon for 3 h at 90 °C. The mixture is diluted with ACN, filtered, and the solvent is 10 evaporated under reduced pressure. The desired material is used directly for the next step without further purification. Intermediate 58 Analytical HPLC-MS Method: D Rt [min]: 1.23 MS [m / z]: 605 [M+H]+ 12-0516-WO-1 Synthesis of example E45 Amixture of intermediate 58 (168 mg, 278 µmol) and TFA (0.4 mL) in DCM (1.5 mL) is5 stirred for 1.5 h at rt. The mixture is concentrated under reduced pressure, saturated aqueous Na2CO3solution is added, and the mixture is extracted with EtOAc. The combined organic layers are washed with saturated NaCl solution, dried over MgSO4,and concentrated under reduced pressure. The residue is purified by prep. RP-HPLC (basic conditions) to give example E45. Example E45 HPLC-MS Method: E Rt [min]: 0.89 MS [m / z]: 505 [M+H]+Analytical SFC method: AL Rt [min]: 2.75 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.38 (4 H), 1.51 - 1.78 (10 H), 2.64 - 2.70 (2 H),3.40 - 3.48 (2 H), 3.70 - 3.81 (2 H), 5.39 - 5.46 (1 H), 7.12 - 7.16 (1 H), 7.39 - 7.43 (1 H),7.66 - 7.69 (1 H), 7.81 - 7.84 (1 H), 8.49 (1 H), 9.02 - 9.04 (1 H), 9.08 - 9.10 (1 H).10 12-0516-WO-1 Example E46 is prepared in analogy to example E39: E45 (142 µmol), aqueousformaldehyde solution (37 %, 213 µmol), AcOH (142 µmol), and sodium triacetoxyborohydride (213 µmol), 3 mL DCE; purification by prep. RP-HPLC (acidic conditions). Example E46 Analytical HPLC-MS Method: D Rt [min]: 1.09 MS [m / z]: 519 [M+H]+Analytical SFC method: AL Rt[min]: 2.57 e.e. > 98% 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.53 - 1.55 (3 H), 1.58 - 1.71 (3 H), 1.74 - 1.97(3 H), 1.99 - 2.21 (4 H), 2.80 - 2.82 (3 H), 2.95 - 3.24 (3 H), 3.32 - 3.48 (1 H), 5.39 - 5.46(1 H), 7.17 - 7.20 (1 H), 7.39 - 7.43 (1 H), 7.66 - 7.70 (1 H), 7.82 - 7.85 (1 H), 8.55 (1 H),9.13 - 9.15 (2 H), 9.41 (1 H), missing proton(s) presumably hidden by / overlapping withsolvent signals. 5Synthesis of examples E47a and E47b Examples E47a and E47b are prepared in analogy to example E1: Intermediate 38 (223µmol), 3-methylpiperidin-3-ol 59 (334 µmol), AcOH (445 µmol), and 2-picoline-borane10 complex (445 µmol), 2 mL MeOH; reaction time: 16 h and in addition: purification by chiral SFC (basic conditions). E47a and E47b are isolated as single stereoisomers. The absoluteconfiguration of the hydroxy substituent is not known. Example E47a Analytical HPLC-MS Method: D 12-0516-WO-1 Rt [min]: 1.08 MS [m / z]: 549 [M+H]+Analytical SFC method: P Rt [min]: 4.80d.e. > 96%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.08 - 1.12 (3 H), 1.28 - 1.48 (3 H), 1.50 - 1.68 (6 H),1.78 - 1.88 (2 H), 2.21 - 2.34 (2 H), 2.37 - 2.46 (2 H), 2.79 - 2.91 (2 H), 3.97 - 4.06 (1 H), 4.31 -4.44 (2 H), 5.36 - 5.48 (1 H), 7.10 - 7.15 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.71 (1 H), 7.80 - 7.86(1 H), 8.48 - 8.54 (1 H), 9.05 - 9.14 (2 H), missing proton(s) presumably hidden by / overlappingwith solvent signals. Example E47b Analytical HPLC-MS Method: D Rt[min]: 1.08 MS [m / z]: 549 [M+H]+Analytical SFC method: P Rt[min]: 5.40d.e. > 93%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.08 - 1.12 (3 H), 1.29 - 1.49 (3 H), 1.50 - 1.66 (6 H),1.76 - 1.88 (2 H), 2.21 - 2.35 (2 H), 2.37 - 2.46 (2 H), 2.79 - 2.90 (2 H), 3.98 - 4.05 (1 H), 4.31 -4.44 (2 H), 5.37 - 5.47 (1 H), 7.10 - 7.16 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87(1 H), 8.48 - 8.53 (1 H), 9.05 - 9.13 (2 H), missing proton(s) presumably hidden by / overlappingwith solvent signals. Synthesis of example E48 Amixture of intermediate 37 (50 mg, 116 µmol), 4-(1-pyrrolidinyl)piperidine 60 (36 mg, 232 12-0516-WO-1 µmol), Cs2CO3 (94 mg, 290 µmol) in 1,4-dioxane (4 mL) is degassed with argon. Catalyst I (4 mg, 5 µmol) is added, and the mixture is stirred under argon at 90 °C for 16 h. The mixture is filtered and purified by prep. RP-HPLC (basic conditions) to obtain example E48. Example E48 HPLC-MS Method: E Rt[min]: 0.90 MS [m / z]: 505 [M+H]+Analytical SFC method: S Rt[min]: 7.15e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.49 - 1.76 (9 H), 1.92 - 2.02 (2 H), 2.15 - 2.25 (1 H),2.93 - 3.04 (2 H), 4.14 - 4.27 (2 H), 5.35 - 5.47 (1 H), 7.11 - 7.17 (1 H), 7.37 - 7.45 (1 H), 7.63 -7.71 (1 H), 7.79 - 7.87 (1 H), 8.48 - 8.52 (1 H), 9.04 - 9.08 (1 H), 9.08 - 9.16 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Synthesis of example E49 Example E49 is prepared in analogy to example E48: Intermediate 37 (116 µmol), 4-piperidinopiperidine 61 (232 µmol), Cs2CO3 (290 µmol), and catalyst I (5 µmol), 2 mL 1,4-dioxane. Example E49 HPLC-MS Method: E Rt [min]: 0.92 MS [m / z]: 519 [M+H]+Analytical SFC method: S Rt [min]: 7.55 e.e. > 98% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.32 - 1.71 (11 H), 1.81 - 1.89 (2 H), 2.38 - 2.49(4 H), 2.75 - 2.87 (2 H), 4.33 - 4.45 (2 H), 5.37 - 5.47 (1 H), 7.10 - 7.14 (1 H), 7.37 - 7.44(1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87 (1 H), 8.47 - 8.55 (1 H), 9.04 - 9.08 (1 H), 9.08 - 9.16(1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. 2-Picoline borane complex (12 mg, 111 µmol) is added to a mixture of intermediate 38 (505 mg, 111 µmol), 1-amino-2-methyl-propan-2-ol 62 (21 mg, 223 µmol) and AcOH (60 µL, 1.03mmol) in MeOH (1 mL) and the resulting mixture is stirred for 16 h at rt. The mixture is neutralized with aqueous NaOH solution (4 N), diluted with MeOH, and purified by prep. RP-HPLC (basic conditions) to obtain example E50. Example E50 HPLC-MS Method: E Rt [min]: 0.89 MS [m / z]: 523 [M+H]+Analytical SFC method: V Rt [min]: 6.91 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.02 - 1.15 (6 H), 1.35 - 1.57 (6 H), 1.89 - 2.00(2 H), 2.42 - 2.48 (2 H), 2.55 - 2.64 (1 H), 2.94 - 3.05 (2 H), 4.09 - 4.17 (1 H), 4.17 - 4.29(2 H), 5.37 - 5.48 (1 H), 7.07 - 7.17 (1 H), 7.38 - 7.44 (1 H), 7.64 - 7.72 (1 H), 7.79 - 7.87(1 H), 8.49 - 8.57 (1 H), 9.03 - 9.08 (1 H), 9.08 - 9.16 (1 H). 12-0516-WO-1 Synthesis of intermediate cis-64 s-64A mixture of intermediate 37 (130 mg, 271 µmol), tert-butyl octahydro-1H-pyrrolo[2,3-5 c]pyridine-1-carboxylate cis-63 (84 mg, 353 µmol) is degassed with argon. Cs2CO3 (354mg, 1.1 mmol) in 1,4-dioxane (2.3 mL) and catalyst I (22.8 mg, 27 µmol) are added, and the mixture is heated under argon for 16 h at 120°C. The mixture is diluted with MeOH, filtered, and purified by prep. RP-HPLC (basic conditions) to give intermediate cis-64 as mixture ofstereoisomers. Intermediate cis-64 Analytical HPLC-MS Method: D Rt [min]: 1.15 MS [m / z]: 577 [M+H]+10 Synthesis of examples cis-E52a and cis-E52b Amixture of intermediate cis-64 (100 mg, 173 µmol) in 1,4-dioxane (0.3 mL) is treated withHCl in 1,4-dioxane (4 M; 434 µL) and stirring is continued for 2 h at rt. The mixture is diluted 15 with MeOH, neutralized with aqueous NH3 solution, and purified by prep. RP-HPLC (basic conditions) and chiral SFC to obtain example cis-E52a and example cis-E52b as singlestereoisomers. The absolute configuration of the bridgehead carbon atoms is not known; 12-0516-WO-1 their relative configuration is cis. Example cis-E52a Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 477 [M+H]+Analytical SFC method: AJ Rt [min]: 2.93 d.e. > 97%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.40 - 1.57 (4 H), 1.68 - 1.94 (3 H), 2.19 - 2.30(1 H), 2.75 - 2.84 (1 H), 2.91 - 3.02 (1 H), 3.10 - 3.16 (1 H), 3.38 - 3.47 (1 H), 3.67 - 3.77(1 H), 3.93 - 4.03 (1 H), 5.36 - 5.47 (1 H), 7.05 - 7.09 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.72(1 H), 7.79 - 7.86 (1 H), 8.47 - 8.51 (1 H), 8.98 - 9.03 (1 H), 9.04 - 9.12 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Example cis-E52b Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 477 [M+H]+Analytical SFC method: AJ Rt [min]: 3.30 d.e. > 89%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.38 - 1.58 (4 H), 1.66 - 1.95 (3 H), 2.19 - 2.30(1 H), 2.73 - 2.84 (1 H), 2.91 - 3.00 (1 H), 3.09 - 3.15 (1 H), 3.37 - 3.47 (1 H), 3.70 - 3.79(1 H), 3.93 - 4.02 (1 H), 5.34 - 5.47 (1 H), 7.05 - 7.08 (1 H), 7.37 - 7.46 (1 H), 7.63 - 7.71(1 H), 7.77 - 7.87 (1 H), 8.47 - 8.51 (1 H), 8.98 - 9.01 (1 H), 9.05 - 9.10 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis of examples trans-E53a and trans-E53b Intermediate 38 (200 mg, 445 µmol) is dissolved in THF (7.2 mL) and 2-amino-1-5 methylcyclopentan-1-ol trans-65 (103 mg, 890 µmol), AcOH (51 µL, 890 µmol) andmolecular sieves 4 Å are added and the mixture is stirred for 1 h at 60 °C. After cooling to rt, sodium triacetoxyborohydride (194 mg, 890 µmol) is added and the reaction mixture is stirred 1 h at rt. The reaction mixture is filtered through Celite, the solvent is evaporated, and the mixture is purified by prep. RP-HPLC (basic conditions) and by chiral SFC to obtain10 example trans-E53a and example trans-E53b as single stereoisomers. The absoluteconfiguration of the amino and hydroxy substituents is not known; their relative configurationis trans. Example trans-E53a Analytical HPLC-MS Method: D Rt [min]: 1.01 MS [m / z]: 549 [M+H]+Analytical SFC method: AE Rt [min]: 0.85 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.03 - 1.13 (3 H), 1.17 - 1.64 (11 H), 1.86 - 2.02(3 H), 2.68 - 2.79 (1 H), 2.84 - 2.92 (1 H), 2.92 - 3.02 (2 H), 4.13 - 4.32 (3 H), 5.35 - 5.47(1 H), 7.10 - 7.16 (1 H), 7.37 - 7.44 (1 H), 7.64 - 7.72 (1 H), 7.79 - 7.88 (1 H), 8.46 - 8.55(1 H), 9.03 - 9.07 (1 H), 9.07 - 9.15 (1 H).Example trans-E53b Analytical HPLC-MS Method: D Rt [min]: 1.01 MS [m / z]: 549 [M+H]+ 12-0516-WO-1 Analytical SFC method: AE Rt [min]: 1.17 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.02 - 1.11 (3 H), 1.17 - 1.61 (11 H), 1.83 - 2.02(3 H), 2.68 - 2.79 (1 H), 2.84 - 2.91 (1 H), 2.91 - 3.02 (2 H), 4.17 - 4.29 (3 H), 5.37 - 5.47(1 H), 7.08 - 7.17 (1 H), 7.37 - 7.45 (1 H), 7.64 - 7.72 (1 H), 7.79 - 7.87 (1 H), 8.48 - 8.53(1 H), 9.03 - 9.07 (1 H), 9.07 - 9.13 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Example E54 is prepared in analogy to example E1: Intermediate 38 (111 µmol), D-alaninol5 66 (223 µmol), AcOH (1.03 mmol), and 2-picoline-borane complex (200 µmol), 2 mL MeOH;purification prep. RP-HPLC (basic conditions). Example E54 Analytical HPLC-MS Method: D Rt[min]: 0.96 MS [m / z]: 509 [M+H]+Analytical SFC method: AH Rt [min]: 5.51 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.90 - 0.98 (3 H), 1.28 - 1.48 (2 H), 1.50 - 1.57(3 H), 1.87 - 2.01 (2 H), 2.71 - 2.85 (2 H), 2.92 - 3.03 (2 H), 3.22 - 3.26 (2 H), 4.16 - 4.30(2 H), 4.33 - 4.57 (1 H), 5.37 - 5.48 (1 H), 7.11 - 7.17 (1 H), 7.39 - 7.45 (1 H), 7.64 - 7.73(1 H), 7.80 - 7.87 (1 H), 8.48 - 8.55 (1 H), 9.03 - 9.08 (1 H), 9.09 - 9.13 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis of example E55 Example E55 is prepared in analogy to example E1: Intermediate 38 (49 µmol), 2-5 (methylamino)ethanol 67 (98 µmol), AcOH (514 µmol), and 2-picoline-borane complex (49µmol), 0.5 mL MeOH; reaction time: 16 h; purification by prep. RP-HPLC (acidic conditions). Example E55 HPLC-MS Method: E Rt [min]: 0.79 MS [m / z]: 509 [M+H]+Analytical SFC method: X Rt [min]: 4.62 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.46 - 1.59 (3 H), 1.76 - 1.90 (2 H), 2.08 - 2.21(2 H), 2.76 - 2.82 (3 H), 2.83 - 2.95 (2 H), 3.04 - 3.13 (1 H), 3.32 - 3.37 (1 H), 4.48 - 4.59(2 H), 5.38 - 5.47 (1 H), 7.15 - 7.20 (1 H), 7.37 - 7.46 (1 H), 7.64 - 7.71 (1 H), 7.79 - 7.87(1 H), 8.50 - 8.58 (1 H), 9.09 - 9.17 (2 H), 9.20 - 9.29 (1 H), missing proton(s) presumablyhidden by / overlapping with solvent signals. 10 Example E57 is prepared in analogy to example E1: Intermediate 38 (89 µmol), (R)-3- 12-0516-WO-1 hydroxypyrrolidine 11 (178 µmol), AcOH (1.03 µmol), and 2-picoline-borane complex (89µmol), 0.6 mL MeOH; purification by prep. RP-HPLC (basic conditions).Example E57 HPLC-MS Method: E Rt[min]: 0.79 MS [m / z]: 521 [M+H]+Analytical SFC method: AN Rt [min]: 1.14 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 - 1.60 (6 H), 1.89 - 2.01 (3 H), 2.17 - 2.26(1 H), 2.35 - 2.41 (1 H), 2.60 - 2.69 (1 H), 2.74 - 2.82 (1 H), 2.93 - 3.03 (2 H), 4.13 - 4.27(3 H), 4.43 - 4.86 (1 H), 5.36 - 5.48 (1 H), 7.10 - 7.18 (1 H), 7.38 - 7.45 (1 H), 7.63 - 7.71(1 H), 7.79 - 7.87 (1 H), 8.47 - 8.54 (1 H), 9.04 - 9.08 (1 H), 9.08 - 9.16 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals. Synthesis scheme of intermediate 71 12-0516-WO-1 Synthesis of intermediate 69 An aqueous Na2CO3 solution (2 M; 7.7 mL, 15 mmol), intermediate 7 (2.0 g, 4.8 mmol) and5 borane 68 (1.6 g, 5.8 mmol) in 1,4-dioxane (24 mL) is stirred under argon atmosphere.Catalyst II (198 mg, 242 µmol) is added, and the mixture is stirred at 95 °C for 1.5 h. Aqueous NaCl solution is added. The layers are separated, and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with saturated NaCl solution, dried over Na2SO4, filtered and the solvent is evaporated. The residue is purified10 by column chromatography (SiO2; EtOAc / cyclohexane: 60:40 100:0) to obtainintermediate 69. Intermediate 69 Analytical HPLC-MS Method: D Rt [min]: 0.99 MS [m / z]: 473 [M+H]+ 15 A mixture of intermediate 69 (1.6 g, 3.4 mmol) and Pd / C (10%w / w, 200 mg) in MeOH (30mL) is stirred under H2atmosphere (50 psi) for 18 h at rt. The mixture is filtered, and the solvent evaporated to obtain intermediate 70. The material is used in the next reaction step 12-0516-WO-1 without further purification. Intermediate 70 HPLC-MS Method: E Rt[min]: 1.02 MS [m / z]: 475 [M+H]+ 5Intermediate 70 (1.5 g, 3.2 mmol) in THF (20 mL) is treated with aqueous HCl solution (4M; 5 mL, 20 mmol). The mixture is stirred for 24 h at rt. An aqueous NaOH solution (4 M; 5 mL) and saturated NaHCO3 solution are added, and the mixture is extracted with EtOAc. The separated organic layers are extracted with aqueous saturated NaCl solution. The solvents are evaporated under reduced pressure. The desired material is treated with MTBE10 and the solvent evaporated to obtain intermediate 71. The material is used in the next reaction step without further purification. Intermediate 71 Analytical HPLC-MS Method: D Rt [min]: 0.93 MS [m / z]: 431 [M+H]+

[0345] 12-0516-WO-1 Synthesis of example E58 71 35 E58A mixture of intermediate 71 (160 mg, 372 µmol) and (R)-3-hydroxypiperidine hydrochloride5 35 (104 mg, 743 µmol) in MeOH (3 mL) is prepared and AcOH (150 µL, 2.6 mmol) addedfollowed by 2-picoline-borane complex (49 mg, 446 µmol). The mixture is stirred for 1.5 h at rt. An aqueous NaOH solution (4 M) and MeOH are added. The mixture is filtered and directly purified by prep. RP-HPLC (basic conditions) to obtain example E58. Example E58 Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 516 [M+H]+Chiral SFC Method: Y Rt [min]: 5.21 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.99 - 1.11 (1 H), 1.32 - 1.51 (3 H), 1.51 - 1.56(3 H), 1.56 - 1.84 (4 H), 1.84 - 1.93 (2 H), 1.94 - 2.06 (3 H), 2.08 - 2.18 (1 H), 2.38 - 2.48(1 H), 2.65 - 2.73 (1 H), 2.83 - 2.92 (1 H), 3.02 - 3.14 (1 H), 3.38 - 3.48 (1 H), 4.47 - 4.55(1 H), 5.37 - 5.47 (1 H), 7.07 - 7.39 (2 H), 7.49 - 7.57 (1 H), 7.66 - 7.74 (1 H), 7.80 - 7.86(1 H), 8.55 - 8.62 (1 H), 9.06 - 9.15 (1 H), 9.37 - 9.43 (1 H).10 12-0516-WO-1 AcOH (11 µL, 186 µmol) is added to a mixture of intermediate 71 (80 mg, 186 µmol) and(3S)-3-methylpyrrolidin-3-ol 13 (40 mg, 279 µmol) in THF (1.5 mL) and the mixture is stirredfor 16 h at rt. Sodium triacetoxyborohydride (158 mg, 744 µmol) is added and stirring is continued for 2 h at rt. The crude mixture is directly purified by prep. RP-HPLC (basic 5 conditions) to give example E59. Example E59 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 516 [M+H]+Chiral SFC Method: AT Rt [min]: 0.65 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.21 - 1.41 (5 H), 1.53 (3 H), 1.61 - 1.79 (4 H),1.93 - 2.19 (5 H), 2.67- 2.75 (1 H) , 3.05 - 3.15 (1 H), 4.44 (1 H), 5.42 (1 H), 7.03 - 7.41(2 H), 7.53 (1 H), 7.70 (1 H), 7.84 (1 H), 8.58 (1 H), 9.11 (1 H), 9.40 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. AcOH (13 µL, 232 µmol) is added to a mixture of intermediate 71 (100 mg, 232 µmol) and10 [(2R,4R)-4-fluoropyrrolidin-2-yl]methanol hydrochloride 72 (56 mg, 349 µmol) in THF (1.9mL) and the mixture is stirred for 16 h at rt. Sodium triacetoxyborohydride (197 mg, 929 µmol) is added and stirring is continued for 2 h at rt. The crude mixture is directly purified by prep. RP-HPLC to give example E60. Example E60 Analytical HPLC-MS Method: D 12-0516-WO-1 Rt [min]: 0.94 MS [m / z]: 534 [M+H]+Chiral SFC Method: AK Rt [min]: 1.06 d.e. > 98% 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.31 - 1.56 (5 H), 1.64 - 2.19 (8 H), 2.62 - 2.88(2 H), 2.95 (1 H), 3.04 - 3.23 (3 H), 3.41 - 3.50 (1 H), 4.41 (1 H), 5.02 - 5.26 (1 H), 5.42(1 H), 7.08 - 7.39 (2 H), 7.53 (1 H), 7.70 (1 H), 7.84 (1 H), 8.58 (1 H), 9.12 (1 H), 9.41 (1H). Synthesis of examples trans-E61a and trans-E61b Amixture of intermediate 71 (150 mg, 348 µmol) and trans-4-fluoropiperidin-3-ol5 hydrochloride trans-73 (114 mg, 697 µmol) in AcOH (100 µL, 1.75 mmol) and isopropanol(2 mL) is stirred for 10 min at rt.2-Picoline-borane complex (58 mg, 523 µmol) is added, and the reaction mixture is stirred for 2 days at rt. An aqueous NaOH solution (4 M) is added, and the mixture is diluted with MeOH, filtered, and directly purified via RP-HPLC (basic conditions) and chiral SFC to obtain examples trans-E61a and trans-61b as single10 stereoisomers. The absolute configuration of the fluorine and hydroxy substituents is notknown; their relative configuration is trans. Example trans-E61a Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 534 [M+H]+Analytical SFC method: R Rt [min]: 3.49 d.e. > 89%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.37 - 1.61 (6 H), 1.65 - 1.79 (2 H), 1.84 - 1.93(2 H), 1.94 - 2.15 (4 H), 2.26 (1 H), 2.38 - 2.49 (1 H), 2.74 - 2.84 (1 H), 2.86 - 2.95 (1 H), 12-0516-WO-1 3.03 - 3.13 (1 H), 3.41 - 3.54 (1 H), 4.00 - 4.32 (1 H), 5.11 (1 H), 5.42 (1 H), 7.07 - 7.37(2 H), 7.53 (1 H), 7.70 (1 H), 7.83 (1 H), 8.58 (1 H), 9.11 (1 H), 9.41 (1 H). Example trans-E61b Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 534 [M+H]+Analytical SFC method: R Rt [min]: 4.40 d.e. > 94%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.35 - 1.62 (6 H), 1.64 - 1.79 (2 H), 1.83 - 1.92(2 H), 1.94 - 2.14 (4 H), 2.26 (1 H), 2.39 - 2.49 (1 H), 2.75 - 2.83 (1 H), 2.85 - 2.94 (1 H),3.03 - 3.14 (1 H), 3.41 - 3.54 (1 H), 4.07 - 4.33 (1 H), 5.11 (1 H), 5.42 (1 H), 7.07 - 7.38(2 H), 7.55 (1 H), 7.70 (1 H), 7.83 (1 H), 8.58 (1 H), 9.11 (1 H), 9.41 (1 H). 5 A mixture of intermediate 71 (140 mg, 325 µmol), (3R,5R)-5-methylpyrrolidin-3-oltrifluoroacetate 74 (119 mg, 553 µmol), AcOH (38 µL, 651 µmol), and 2-picoline-boranecomplex (45 mg, 423 µmol) in MeOH (4 mL) is stirred for 3 days at rt. The mixture is neutralized with aqueous NaOH solution (1 N) and diluted with MeOH. The mixture is separated via prep. RP-HPLC (basic conditions) to give example E62. Example E62 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 516 [M+H]+ 12-0516-WO-1 Analytical SFC method: AJ Rt [min]: 4.83 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.98 (3 H), 1.32 - 1.56 (6 H), 1.64 - 2.07 (7 H),2.41 - 2.47 (1 H), 2.60 - 2.70 (1 H), 2.98 - 3.14 (3 H), 4.10 - 4.18 (1 H), 4.59 (1 H), 5.43(1 H), 7.09 - 7.38 (2 H), 7.53 (1 H), 7.70 (1 H), 7.83 - 7.87 (1 H), 8.58 (1 H), 9.12 (1 H),9.40 (1 H). An aqueous HCl solution (4 M; 2 mL, 8 mmol) is added to intermediate 70 (690 mg, 1.465 mmol) in THF (10 mL) and the mixture is stirred at rt for 16 h. An aqueous NaOH solution (4 M; 1.8 mL) and saturated NaHCO3solution is added, and the mixture is extracted with EtOAc. The combined organic layers are washed with aqueous saturated NaCl solution, and the solvent is evaporated under reduced pressure. The material is purified by column chromatography (SiO2; EtOAc / cyclohexane: 80:20) to obtain intermediate 75.Intermediate 75 HPLC-MS Method: E Rt [min]: 0.97 MS [m / z]: 429 [M+H]+10 12-0516-WO-1 Synthesis of example E63 AcOH (100 µL, 1.7 mmol) and 2-picoline-borane complex (39 mg, 350 µmol) are added to5 a mixture of intermediate 75 (100 mg, 233 µmol) and (S)-3-hydroxypiperidine hydrochloride30 (66 mg, 467 µmol) in MeOH (3 mL). The resulting mixture is stirred for 16 h at rt.Additional 2-picoline-borane complex (20 mg) is added, and the reaction mixture is stirred for 2 days at rt. An aqueous NaOH solution (4 M, 400 µL) is added, and the mixture is diluted with MeOH, filtered, and directly purified by prep. RP-HPLC (basic conditions) to obtain10 example E63. Separation of the diastereomers is possible by standard purification methods. Example E63 Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 514 [M+H]+1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.01 - 1.15 (1 H), 1.32 - 1.47 (1 H), 1.49 - 1.68(5 H), 1.76 - 1.87 (1 H), 1.90 - 2.19 (3 H), 2.24 - 2.46 (2 H), 2.55 - 2.81 (4 H), 2.85 - 2.98(1 H), 3.39 - 3.52 (1 H), 4.51 - 4.56 (1 H), 5.38 - 5.48 (1 H), 7.08 - 7.40 (3 H), 7.50 - 7.57(1 H), 7.67 - 7.74 (1 H), 7.88 - 7.93 (1 H), 8.59 - 8.65 (1 H), 9.12 - 9.20 (1 H), 9.38 - 9.44(1 H). Synthesis of examples E64a and E64b AcOH (49 µl, 836 µmol) is added to a mixture of intermediate 71 (120 mg, 279 µmol) and 12-0516-WO-1 3-azabicyclo[3.1.0]hexan-1-ol hydrochloride 76 (76 mg, 558 µmol) in dimethyl sulfoxide (1mL) and the mixture is stirred for 10 min at rt.2-Picoline-borane complex (49 mg, 446 µmol) is added, and the reaction mixture is stirred at rt for 16 h. The mixture is neutralized with aqueous NaOH solution (1 N), diluted with ACN, filtered, and directly purified by prep. RP-5 HPLC (basic conditions) and chiral SFC to obtain example E64a and E64b as singlestereoisomers. The absolute configuration of bridged carbon atoms is not known; the relative configuration of the [3.1.0] ring system is cis. Example E64a Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 514 [M+H]+Analytical SFC method: AE Rt [min]: 1.11 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.66 (1 H), 0.79 (1 H), 1.17 - 1.35 (3 H), 1.53 (3H), 1.63 - 1.79 (2 H), 1.92 - 2.06 (4 H), 2.15 - 2.25 (1 H), 2.82 (1 H), 3.01 - 3.13 (2 H),5.42 (1 H), 5.55 (1 H), 7.09 - 7.38 (2 H), 7.53 (1 H), 7.70 (1 H), 7.83 (1 H), 8.58 (1 H),9.12 (1 H), 9.40 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Example E64b Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 514 [M+H]+Analytical SFC method: AE Rt [min]: 1.37 d.e. > 96%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.66 (1 H), 0.79 (1 H), 1.17 - 1.34 (3 H), 1.53 (3H), 1.64 - 1.79 (2 H), 1.91 - 2.05 (4 H), 2.14 - 2.24 (1 H), 2.45 - 2.49 (2 H), 2.82 (1 H),3.01 - 3.14 (2 H), 5.42 (1 H), 5.54 (1 H), 7.08 - 7.38 (2 H), 7.53 (1 H), 7.70 (1 H), 7.83 (1H), 8.58 (1 H), 9.12 (1 H), 9.40 (1 H). 12-0516-WO-1 Synthesis scheme of intermediate 795 Tert-butanole (103 mL) is added to AD-Mix beta (43 g, 55 mmol) in water (80 mL) and the mixture is stirred 20 min at rt. The mixture is cooled to 0°C. Methanesulfonamide (1.05 g, 11.1 mmol) and a solution of intermediate 69 (5.2 g, 11.1 mmol) in THF (45 mL) are addedand stirring is continued for 3 days at rt. An aqueous Na2S2O3 solution (10%; 100 mL) is 10 added and stirring continued for 30 min at rt. EtOAc and saturated aqueous NaHCO3solution are added, the organic layer is washed with saturated aqueous NaHCO3 solution and dried over MgSO4. After filtering and evaporation of the solvents, intermediate 77 isused for the next step without further purification. Intermediate 77

[0346] Analytical HPLC-MS Method: D

[0347] Rt [min]: 0.89 MS [m / z]: 507 [M+H]+

[0348] Aqueous HCI (4 M; 19 mL) is added to a solution of intermediate 77 (5.6 g, 11.1 mmol) in THF (27 mL) and stirring continued for 48 h at rt. THF is evaporated and the solution is basified with aqueous NH3 solution. EtOAc and water are added, the organic layer is separated and dried over MgSCL. After filtration and evaporation, the material is purified by prep. RP-HPLC (acidic conditions) to obtain intermediate 78.

[0349] Intermediate 78

[0350] HPLC-MS Method: E

[0351] Rt [min]: 0.92 MS [m / z]: 445 [M+H]+

[0352] A mixture of intermediate 78 (2.6 g, 5.74 mmol) and Pd / C (10%w / w, 200 mg) in EtOAc (168 mL) is stirred under H2 atmosphere (30 psi) for 2 h at rt. The mixture is filtered, the solvent evaporated, and the residue purified by prep. RP-HPLC (acidic conditions) to obtain 12-0516-WO-1 intermediate 79. Intermediate 79HPLC-MS Method: E Rt [min]: 0.93 MS [m / z]: 447 [M+H]+ 5 Intermediate 79 (100 mg, 224 µmol) is dissolved in 1.8 mL THF. Then (R)-3-fluoropyrrolidinehydrochloride 80 (42 mg, 336 µmol) and AcOH (13 µL, 224 µmol) are added and stirring iscontinued for 2 h at rt. Then sodium triacetoxyborohydride (189 mg, 896 µmol) is added and the reaction mixture stirred for additional 2 h at rt. Water is added, filtered and the filtrate is directly purified by prep. RP-HPLC (basic conditions) to give example E65. Example E65 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 520 [M+H]+Analytical SFC method: K Rt [min]: 5.78 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.44 - 1.59 (5 H), 1.64 - 1.95 (5 H), 1.99 - 2.17(1 H), 2.19 - 2.30 (1 H), 2.35 - 2.46 (1 H), 2.61 - 2.99 (5 H), 5.06 - 5.33 (2 H), 5.35 - 5.55(1 H), 7.06 - 7.41 (2 H), 7.46 - 7.60 (1 H), 7.64 - 7.82 (1 H), 8.13 - 8.29 (1 H), 8.60 (1 H),9.06 - 9.26 (1 H), 9.39 - 9.54 (1 H). 12-0516-WO-1 Intermediate 79 (100 mg, 224 µmol) is dissolved in THF (1.8 mL). Then (S)-3-5 fluoropyrrolidine hydrochloride 81 (42.2 mg, 336 µmol) and AcOH (12.8 µL, 224 µmol) areadded and stirring is continued for 2 h at rt. Then sodium triacetoxyborohydride (190 mg, 896 µmol) is added and the reaction mixture stirred for additional 2 h at rt. The mixture is filtered and directly purified by prep. RP-HPLC (basic conditions) to give example E66. Example E66 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 520 [M+H]+Analytical SFC method: K Rt [min]: 6.06 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 - 1.63 (5 H), 1.64 - 2.34 (7 H), 2.59 - 3.03(5 H), 5.01 - 5.54 (3 H), 7.03 - 7.39 (2 H), 7.45 - 7.81 (2 H), 8.18 - 8.29 (1 H), 8.51 - 8.71(1 H), 9.07 - 9.24 (1 H), 9.42 - 9.56 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals.

[0353] 12-0516-WO-1 Synthesis scheme of intermediate 845 Amixture of an aqueous Na2CO3 solution (2 M, 7.0 mL, 14 mmol), intermediate 37 (2.0 g,4.6 mmol) and borane 68 (1.4 g, 5.1 mmol) in 1,4-dioxane (15 mL) is stirred under argonatmosphere. Catalyst II (227 mg, 0.28 mmol) is added, and the mixture is stirred under argon for 1.5 h at 95 °C. Aqueous saturated NaCl solution is added, and the mixture is 10 extracted with EtOAc. The combined organic layers are washed with saturated NaCl solution, dried over Na2SO4, filtered and the solvent is evaporated. The remaining material is purified by column chromatography (SiO2; EtOAc / cyclohexane: 100:0) to obtainintermediate 82. Intermediate 82

[0354] Analytical HPLC-MS Method: D

[0355] Rt [min]: 1.04 MS [m / z]: 491 [M+H]+

[0356] Intermediate 82 (2.1 g, 4.3 mmol) in MeOH (50 mL) and Pd / C (10%w / w, 200 mg) is stirred under H2 atmosphere (50 psi) for 18 h at rt. The mixture is filtered, and the solvent evaporated to obtain intermediate 83. The material is used in the next reaction step without further purification.

[0357] Intermediate 83

[0358] Analytical HPLC-MS Method: D

[0359] Rt [min]: 1 .04 MS [m / z]: 493 [M+H]+

[0360] Intermediate 83 (2.1 g, 4.3 mmol) in THF (20 mL) is treated with aqueous HCI solution (4 M; 5.3 mL). The mixture is stirred for 16 h at rt. Aqueous NaOH solution and aqueous saturated NaHCCh solution are added, and the mixture is extracted with EtOAc. The 12-0516-WO-1 separated organic layer is washed with aqueous saturated NaCl solution. The organic layer is evaporated under reduced pressure. The remaining material is purified by column chromatography (SiO2; EtOAc / MeOH: 80:20) to obtain intermediate 84.Intermediate 84 HPLC-MS Method: E Rt[min]: 1.01 MS [m / z]: 449 [M+H]+5 Amixture of intermediate 84 (60 mg, 134 µmol) and (S)-3-hydroxypiperidine hydrochloride30 (50 mg, 352 µmol) in MeOH (2 mL) is prepared. AcOH (16 µL, 268 µmol) and 2-picoline-borane complex (15 mg, 134 µmol) are added. The mixture is stirred for 16 h at rt. Additional10 AcOH (30 µL) and 2-picoline-borane complex (15 mg, 134 µmol) are added and the mixtureis stirred for 24 h at rt. (S)-3-Hydroxypiperidine hydrochloride 30 (20 mg, 141 µmol) and 2-picoline-borane complex (20 mg, 179 µmol) are added, and the mixture is stirred for 24 h at rt. An aqueous NaOH solution (4 M; 230 µL) and MeOH are added. The mixture is filtered and directly purified by reversed phase (basic conditions) to obtain example E67. Example E67 Analytical HPLC-MS Method: D Rt[min]: 1.00 MS [m / z]: 534 [M+H]+Analytical SFC method: Y Rt [min]: 3.28 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.99 - 1.12 (1 H), 1.31 - 1.52 (3 H), 1.52 - 1.58(3 H), 1.58 - 1.85 (4 H), 1.85 - 1.94 (2 H), 1.94 - 2.07 (3 H), 2.09 - 2.19 (1 H), 2.39 - 2.47 12-0516-WO-1 (1 H), 2.64 - 2.73 (1 H), 2.84 - 2.91 (1 H), 3.03 - 3.13 (1 H), 3.40 - 3.48 (1 H), 4.33 - 4.71(1 H), 5.39 - 5.48 (1 H), 7.37 - 7.45 (1 H), 7.65 - 7.72 (1 H), 7.80 - 7.88 (2 H), 8.56 - 8.61(1 H), 9.13 - 9.22 (1 H), 9.38 - 9.44 (1 H). To a mixture of intermediate 84 (95 mg, 212 µmol) and (R)-3-hydroxypiperidine5 hydrochloride 35 (59 mg, 424 µmol) in MeOH (2 mL), AcOH (100 µL, 1.72 mmol) and 2-picoline-borane complex (25 mg, 222 µmol) are added. The mixture is stirred for 16 h at rt. (R)-3-Hydroxypiperidine hydrochloride 35 (20 mg, 141 µmol) and 2-picoline-boranecomplex (20 mg, 179 µmol) are added, and the mixture is stirred for 24 h at rt. The mixture is neutralized with an aqueous NaOH solution (4 M; 400 µL) and MeOH is added. The solids 10 are filtered off and the filtrate is purified by prep. RP-HPLC (basic conditions) to obtain example E68. Example E68 Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 534 [M+H]+Analytical SFC method: S Rt [min]: 7.04 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.98 - 1.13 (1 H), 1.30 - 1.51 (3 H), 1.51 - 1.58(3 H), 1.58 - 1.84 (4 H), 1.84 - 1.93 (2 H), 1.93 - 2.06 (3 H), 2.09 - 2.18 (1 H), 2.39 - 2.48(1 H), 2.64 - 2.74 (1 H), 2.82 - 2.90 (1 H), 3.03 - 3.14 (1 H), 3.41 - 3.48 (1 H), 4.40 - 4.61(1 H), 5.37 - 5.49 (1 H), 7.36 - 7.47 (1 H), 7.63 - 7.74 (1 H), 7.81 - 7.88 (2 H), 8.56 - 8.61(1 H), 9.14 - 9.21 (1 H), 9.37 - 9.44 (1 H). 12-0516-WO-1 To a mixture of intermediate 84 (95 mg, 212 µmol) and (S)-3-hydroxypyrrolidine 85 (37 mg,5 424 µmol) in MeOH (2 mL), AcOH (100 µL, 1.7 mmol) and 2-picoline-borane complex (25 mg, 222 µmol) are added. The mixture is stirred for 16 h at rt. The mixture is neutralized with an aqueous NaOH solution (4 M) and MeOH is added. The solids are filtered off and the filtrate is purified by prep. RP-HPLC (basic conditions) to obtain example E69.Example E69 Analytical HPLC-MS Method: D Rt [min]: 0.98 MS [m / z]: 520 [M+H]+Analytical SFC method: T Rt [min]: 3.74 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.24 - 1.40 (2 H), 1.47 - 1.58 (4 H), 1.65 - 1.79(2 H), 1.90 - 2.02 (3 H), 2.02 - 2.15 (3 H), 2.36 - 2.42 (1 H), 2.61 - 2.69 (1 H), 2.75 - 2.82(1 H), 3.03 - 3.15 (1 H), 4.12 - 4.22 (1 H), 4.45 - 4.82 (1 H), 5.37 - 5.48 (1 H), 7.37 - 7.45(1 H), 7.63 - 7.72 (1 H), 7.82 - 7.88 (2 H), 8.56 - 8.60 (1 H), 9.13 - 9.22 (1 H), 9.40 - 9.44(1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of example trans-E70a and trans-E70b 10 Sodium triacetoxyborohydride (180 mg, 849 µmol) is added to a mixture of intermediate 84 12-0516-WO-1 (200 mg, 446 µmol) and trans-4-fluoropiperidin-3-ol hydrochloride trans-73 (88 mg, 535µmol) in DCM. The reaction mixture is stirred for 18 h at rt. The solvent is evaporated, aqueous NaHCO3solution is added, and the mixture is extracted with DCM. The combined extracts are purified via prep. RP-HPLC (basic conditions) and by chiral SFC to obtain5 example trans-E70a and trans-E70b as single stereoisomers. The absolute configurationof the fluorine and hydroxy substituent is not known; their relative configuration is trans. Example trans-E70a Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 552 [M+H]+Analytical SFC method: AA Rt[min]: 0.88d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.35 - 1.61 (6 H), 1.65 - 1.78 (2 H), 1.89 (2 H),1.94 - 2.12 (4 H), 2.26 (1 H), 2.73 - 2.83 (1 H), 2.86 - 2.96 (1 H), 3.01 - 3.15 (1 H), 3.42 -3.54 (1 H), 4.07 - 4.29 (1 H), 5.11 (1 H), 5.43 (1 H), 7.41 (1 H), 7.68 (1 H), 7.81 - 7.87 (2H), 8.58 (1 H), 9.15 (1 H), 9.42 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Example trans-E70b Analytical HPLC-MS Method: D Rt[min]: 1.00 MS [m / z]: 552 [M+H]+Analytical SFC method: AA Rt[min]: 1.81d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.36 - 1.62 (6 H), 1.64 - 1.79 (2 H), 1.88 (2 H),1.94 - 2.13 (4 H), 2.26 (1 H), 2.73 - 2.84 (1 H), 2.86 - 2.96 (1 H), 3.02 - 3.14 (1 H), 3.43 -3.54 (1 H), 4.06 - 4.30 (1 H), 5.11 (1 H), 5.43 (1 H), 7.41 (1 H), 7.68 (1 H), 7.81 - 7.87 (2H), 8.58 (1 H), 9.16 (1 H), 9.42 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis scheme of intermediate 885 Tert-butanol (95 mL, 1019 mmol) is added to a mixture of AD-Mix beta (39.7 g, 51 mmol) in water (83 mL) and the mixture is stirred for 20 min at rt. The mixture is cooled to 0°C. Methanesulfonamide (970 mg, 10.2 mmol) and a solution of intermediate 82 (5.0 g, 10.2mol) in THF (83 mL) are added and stirring is continued at rt for 16 h. An aqueous Na2S2O3 10 solution (10%, 100 mL) is added and stirring continued for 30 min at rt. EtOAc is added, the organic layer washed with saturated aqueous NaHCO3 solution and dried over MgSO4. After filtering and evaporation of the solvents, the remaining mixture is purified via column chromatography (SiO2; EtOAc / petroleum ether: 0:100) to obtain intermediate 86. 12-0516-WO-1 Intermediate 86 Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 525 [M+H]+Synthesis of intermediate 87 86 87A mixture of intermediate 86 (4.7 g, 9.0 mmol) in THF (22 mL) is treated with aqueous HCl5 solution (4 M; 16 mL) and stirring is continued at rt for 24 h. THF is evaporated, and the aqueous layer is extracted with EtOAc. The combined organic layers are dried with MgSO4, filtered and concentrated. The intermediate 87 is used for the next reaction step withoutfurther purification. Intermediate 87 HPLC-MS Method: E Rt [min]: 0.97 MS [m / z]: 463 [M+H]+10 Amixture of intermediate 87 (4.8 g, 10 mmol) in 1,4-dioxane (85 mL) is treated with HCl in1,4-dioxane (4 M; 25 mL) and Pd / C (10% wt / wt 500 mg). The mixture is stirred under H2atmosphere (50 psi) for 24 h at rt. The mixture is filtered, the solvents are evaporated, and 12-0516-WO-1 the residue purified by prep. RP-HPLC (acidic conditions) to obtain intermediate 88. Intermediate 88 HPLC-MS Method: E Rt [min]: 0.99 MS [m / z]: 465 [M+H]+Synthesis of example E71 5Intermediate 88 (123 mg, 265 µmol) in THF (2.1 mL) is treated with (S)-3-fluoropyrrolidinehydrochloride 81 (50 mg, 397 µmol), AcOH (30 µL, 530 µmol) and molecular sieves 4 Å andis stirred at 55°C for 2 h. After cooling to rt, sodium triacetoxyborohydride (225 mg, 1.06 mmol) is added and the reaction mixture stirred for 1 h at rt. The crude mixture is filtered through Celite and directly purified by prep. RP-HPLC (basic conditions) to give example10 E71. Example E71 Analytical HPLC-MS Method: D Rt [min]: 1.01 MS [m / z]: 538 [M+H]+Analytical SFC method: I Rt [min]: 1.91 d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.50 - 1.97 (10 H), 2.02 - 2.21 (1 H), 2.24 - 2.37(1 H), 2.61 - 3.04 (5 H), 5.08 - 5.32 (2 H), 5.37 - 5.50 (1 H), 7.37 - 7.45 (1 H), 7.65 - 7.73(1 H), 7.80 - 7.90 (1 H), 8.20 - 8.25 (1 H), 8.58 - 8.62 (1 H), 9.16 - 9.24 (1 H), 9.47 - 9.52(1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis scheme of intermediate 92 Synthesis of intermediate 90 5 HATU (1.56 g, 4.09 mmol) and triethylamine (2.09 mL, 14.9 mmol) are added to intermediate 12 (1.00 g, 3.72 mmol) in DMF (5 mL) and the mixture is stirred for 10 min atrt. (R)-1-(3-(1,1-Difluoroethyl)-2-fluorophenyl)ethanamine hydrochloride 89 (CAS:2569698-48-0; 949 mg, 3.90 mmol) is added and the mixture is stirred for 16 h at rt. The 10 mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with aqueous saturated NaCl solution, dried over MgSO4and concentrated in vacuo. The material is purified by column chromatography (SiO2; EtOAc / MeOH: 96:4 ^ 80:20) to obtain intermediate 90. 12-0516-WO-1 Intermediate 90 Analytical HPLC-MS Method: D Rt [min]: 0.92 MS [m / z]: 427 [M+H]+Synthesis of intermediate 91 Amixture of intermediate 90 (1.00 g, 2.34 mmol), Cs2CO3 (385 mg, 1.17 mmol), piperidine5 (116 µL, 1.17 mmol) in 1,4-dioxane (10 mL) is stirred for 4 h at 80 °C. The mixture is diluted with EtOAc, filtered over a pad of silica gel, rinsed with EtOAc, and concentrated in vacuo. The residue is dissolved in EtOAc and washed with water. The organic layer is concentrated under reduced pressure and purified by prep. RP-HPLC (basic conditions) to obtain intermediate 91. Intermediate 91 HPLC-MS Method: E Rt [min]: 1.03 MS [m / z]: 427 [M+H]+10 Synthesis of intermediate 92 Amixture of intermediate 91 (330 mg, 772 µmol), piperidin-4-one hydrochloride 8 (220 mg,1.55 mmol) and Cs2CO3(1.01 g, 3.09 mmol) in 1,4-dioxane (6 mL) is degassed with argon. 12-0516-WO-1 Catalyst I (26 mg, 31 µmol) is added, and the mixture is stirred under argon for 3 h at 95 °C. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with aqueous saturated NaCl solution, dried over MgSO4 and the solvent is evaporated under reduced pressure. The material is purified by prep. RP-HPLC (basic 5 conditions) to obtain intermediate 92. Intermediate 92 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 446 [M+H]+ 2-Picoline borane complex (16 mg, 146 µmol) is added to a mixture of intermediate 92 (5010 mg, 112 µmol), L-prolinol 19 (23 mg, 224 µmol), and AcOH (20 µL, 337 µmol) in MeOH (2mL) and the resulting mixture is stirred for 16 h at rt. The reaction mixture is neutralized with aqueous NaOH solution (1 N), diluted with MeOH, filtered, and purified by prep. RP-HPLC (basic conditions) to obtain example E72. Example E72 Analytical HPLC-MS Method: D Rt[min]: 0.99 MS [m / z]: 531 [M+H]+Analytical SFC method: Y Rt[min]: 5.24d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 - 1.72 (9 H), 1.85 - 1.95 (2 H), 1.95 - 2.10 (3H), 2.62 - 2.73 (1 H), 2.80 - 2.94 (4 H), 3.02 - 3.11 (1 H), 4.30 - 4.40 (3 H), 5.37 - 5.47 (1H), 7.10 - 7.18 (1 H), 7.26 - 7.33 (1 H), 7.42 - 7.51 (1 H), 7.60 - 7.69 (1 H), 8.47 - 8.53 (1 12-0516-WO-1 H), 9.01 - 9.08 (2 H), missing proton(s) presumably hidden by / overlapping with solventsignals. 2-Picoline borane complex (16 mg, 146 µmol) is added to a mixture of intermediate 92 (505 mg, 112 µmol), (R)-pyrrolidin-3-ylmethanol 43 (23 mg, 224 µmol) and AcOH (20 µL, 337µmol) in MeOH (2 mL) and the resulting mixture is stirred at rt for 16 h. The reaction mixture is neutralized with aqueous NaOH solution (1 N), diluted with MeOH, and purified by prep. RP-HPLC (basic conditions) to obtain example E73. Example E73Analytical HPLC-MS Method: D Rt[min]: 0.96 MS [m / z]: 531 [M+H]+Analytical SFC method: Y Rt[min]: 3.74d.e. > 97%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 - 1.42 (1 H), 1.48 - 1.63 (5 H), 1.73 - 1.85 (1H), 1.90 - 2.11 (5 H), 2.12 - 2.26 (2 H), 2.30 - 2.37 (1 H), 2.61 - 2.69 (1 H), 2.95 - 3.06 (2H), 4.14 - 4.30 (2 H), 4.38 - 4.61 (1 H), 5.37 - 5.48 (1 H), 7.13 - 7.18 (1 H), 7.26 - 7.33 (1H), 7.43 - 7.51 (1 H), 7.61 - 7.69 (1 H), 8.49 - 8.53 (1 H), 9.03 - 9.11 (2 H), missingproton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis scheme of intermediate 95 Synthesis of intermediate 93 512 93A mixture of intermediate 12 (1.00 g, 4.13 mmol) in DCM (7 mL) and MeOH (1.5 mL) istreated dropwise with trimethysilyldiazomethane (0.6 M in hexane; 8.26 mL, 4.96 mmol)whereby the temperature in the reaction mixture is kept below 25°C. After complete addition, stirring is continued for 1 h at rt. AcOH (0.28 mL, 4.96 mmol) is added and stirring 10 is continued for 15 min at rt. Aqueous 2 M NaHCO3 solution is added, the aqueous layer extracted with DCM, and the combined organic layers dried with MgSO4. The mixture is filtered, and the solvent is evaporated to obtain intermediate 93, which is used in the next reaction step without further purification. Intermediate 93 HPLC-MS Method: E Rt [min]: 0.69 MS [m / z]: 256 [M+H]+ 12-0516-WO-1 Synthesis of intermediate 94 Amixture of intermediate 93 (400 mg, 1.48 mmol), 1-methyl-1,8-diazaspiro[4.5]decane5 dihydrochloride 52 (390 mg, 1.63 mmol) and Cs2CO3 (1.93 g, 5.94 mmol) in 1,4-dioxane(13 mL) is degassed with argon. Catalyst I (125 mg, 148 µmol) is added, and the mixture is stirred under argon at 90°C for 16 h. The solvent is evaporated, water is added and the aqueous layer extracted with EtOAc. The organic layer is dried with MgSO4. After filtration and evaporation of the solvent, the material is purified by prep. RP-HPLC (basic conditions)10 to obtain intermediate 94. Intermediate 94 Analytical HPLC-MS Method: D Rt [min]: 0.91 MS [m / z]: 330 [M+H]+ Amixture of intermediate 94 (107 mg, 325 µmol) in MeOH (1.3 mL) is treated with aqueous15 NaOH solution (4 M; 0.24 mL, 975 µmol) and stirring is continued for 16 h at rt. After evaporation of the solvents, water and aqueous HCl solution (4 M; 0.24 mL, 975 µmol) are added and stirring is continued for 30 min at 0°C. The reaction mixture is filtered and purified by prep. RP-HPLC (acidic conditions) to obtain the desired intermediate 95. Intermediate 95 HPLC-MS Method: E 12-0516-WO-1 Rt [min]: 0.61 MS [m / z]: 314 [M+H]+Synthesis of example E74 Amixture of intermediate 95 (65 mg, 206 µmol) in THF (3.3 mL) is treated with HATU (945 mg, 247 µmol) and triethylamine (116 µL, 824 µmol) and the mixture is stirred for 15 min at rt. (R)-1-(3-(1,1-Difluoroethyl)-2-fluorophenyl)ethanamine hydrochloride 89 (54 mg, 227µmol) is added and stirring is continued for 16 h at rt. The mixture is diluted with MeOH, filtered, and the mixture is purified by prep. RP-HPLC (acidic conditions) and filtered through a carbonate cartridge. The solvent is evaporated to obtain example E74. Example E74 HPLC-MS Method: E Rt [min]: 0.84 MS [m / z]: 501 [M+H]+Analytical SFC method: F Rt [min]: 1.74 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.28 - 1.38 (2 H), 1.46 - 1.56 (3 H), 1.65 - 1.86(6 H), 1.96 - 2.10 (3 H), 2.18 - 2.24 (3 H), 2.65 - 2.74 (2 H), 2.80 - 2.91 (2 H), 4.29 - 4.40(2 H), 5.37 - 5.48 (1 H), 7.13 - 7.19 (1 H), 7.26 - 7.34 (1 H), 7.43 - 7.50 (1 H), 7.60 - 7.68(1 H), 8.48 - 8.53 (1 H), 9.02 - 9.09 (2 H).10 12-0516-WO-1 Synthesis of intermediate 96 39 8 96A mixture of intermediate 39 (1.5 g, 3.5 mmol), piperidin-4-one hydrochloride 8 (1.0 g, 7.05 mmol) and K3PO4 (2.7 g, 12.2 mmol) in 1,4-dioxane (50 mL) is degassed with argon. Catalyst I (88 mg, 104 µmol) is added, and the mixture is stirred for 3 h at 95 °C under an argon atmosphere. The mixture is filtered, and the filter is rinsed with EtOAc. The organic solvents are evaporated under reduced pressure. The material is purified by columnchromatography (SiO2; 80:20) to obtain intermediate 96.Intermediate 96Analytical HPLC-MS Method: D Rt [min]: 0.94 MS [m / z]: 450 [M+H]+10 Synthesis of example E75 Amixture of intermediate 96 (31 mg, 70 µmol), (3R)-3-methoxypyrrolidine trifluoroacetate15 97 (24 mg, 0.11 mmol), AcOH (30.0 µL, 0.51 mmol), and 2-picoline borane complex (7.5mg, 70 µmol) in MeOH (1.5 mL) is stirred for 12 h at rt. The mixture is diluted with DMF und purified by prep. RP-HPLC (basic conditions) to obtain example E75. 12-0516-WO-1 Example E75 HPLC-MS Method: A Rt[min]: 0.80 MS [m / z]: 535 [M+H]+Analytical SFC method: AH Rt [min]: 7.22 d.e. > 98%1H NMR (400 MHz, DMSO-d6 + ND4OD) δ (ppm): 1.43 - 1.58 (5 H), 1.58 - 1.69 (1 H), 1.85- 1.98 (3 H), 2.12 - 2.29 (1 H), 2.39 - 2.47 (1 H), 2.52 - 2.58 (2 H), 2.79 - 2.90 (3 H), 3.11- 3.17 (3 H), 5.28 - 5.37 (1 H), 6.66 - 6.80 (1 H), 7.29 - 7.39 (1 H), 7.59 - 7.66 (1 H), 7.68- 7.75 (1 H), 8.46 - 8.56 (1 H), 9.14 - 9.25 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of example E76 Amixture of bromide 39 (70 mg, 154 µmol), intermediate 98 (36 mg, 170 µmol), Cs2CO35 (201 mg, 617 µmol) and catalyst I (13 mg, 15 µmol) in degassed 1,4-dioxane (1.3 mL) isstirred under argon for 16 h at 90 °C. Water and MeOH are added, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by prep. RP-HPLC (basic conditions) to obtain example E76. Example E76 Analytical HPLC-MS Method: D Rt [min]: 0.96 MS [m / z]: 477 [M+H]+Analytical SFC method: T Rt [min]: 4.92 e.e. > 94% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 - 1.58 (3 H), 1.71 - 1.83 (2 H), 1.92 - 2.04 (2H), 2.19 - 2.29 (3 H), 2.97 - 3.07 (2 H), 3.18 - 3.27 (2 H), 4.11 - 4.26 (2 H), 5.34 - 5.49 (1H), 6.58 - 6.68 (1 H), 7.35 - 7.47 (1 H), 7.64 - 7.73 (1 H), 7.75 - 7.86 (1 H), 8.58 - 8.66 (1H), 8.97 - 9.10 (1 H), 9.26 - 9.35 (1 H).Synthesis of example E77 39 52 E77A mixture of intermediate 39 (125 mg, 0.275 mmol) and 1-methyl-1,8-diazaspiro[4.5]decane5 dihydrochloride 52 (72 mg, 303 µmol) in 1,4-dioxane (2.4 mL) is degassed with argon.Cs2CO3 (359 mg, 1.10 mmol) and catalyst I (23 mg, 28 µmol) is added, and the mixture is heated for 16 h at 120°C. Aqueous NaHCO3 solution is added and the mixture is extracted with EtOAc. The organic layer is dried with MgSO4. After filtration and evaporation of the solvent, the mixture is purified by prep. RP-HPLC (basic conditions) to obtain example E77. Example E77 Analytical HPLC-MS Method: D Rt [min]: 1.01 MS [m / z]: 505 [M+H]+Analytical SFC method: AB Rt [min]: 6.31 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.58 (3 H), 1.65 - 1.88 (6 H), 2.18 - 2.26(3 H), 2.59 - 2.77 (2 H), 2.82 - 2.93 (2 H), 4.39 - 4.52 (2 H), 5.35 - 5.47 (1 H), 6.77 - 6.84(1 H), 7.37 - 7.48 (1 H), 7.64 - 7.73 (1 H), 7.77 - 7.86 (1 H), 8.63 - 8.69 (1 H), 9.02 - 9.11(1 H), 9.27 - 9.34 (1 H), missing proton(s) presumably hidden by / overlapping with solventsignals. 10 12-0516-WO-1 Synthesis scheme of intermediate 102 Amixture of intermediate 11 (460 mg, 2.0 mmol) in AcOH (1.7 mL, 30 mmol) is stirred at140 °C for 5 h. The mixture is cooled to rt and poured into ice-water. The solid material is filtered off, washed with water and dried under reduced pressure at 55 °C to obtain the intermediate 99. The material is used without further purification. Intermediate 99 HPLC-MS Method: E Rt[min]: 0.60 MS [m / z]: 256 [M+H]+ 12-0516-WO-1 Synthesis of intermediate 100 Intermediate 99 is synthesized in analogy to intermediate 39: Intermediate 99 (27 mmol),5 (1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride 36 (27 mmol), 1-propanephosphonic anhydride (53 mmol), N-methylmorpholine (80 mmol), 70 mL ACN. Intermediate 100 HPLC-MS Method: E Rt [min]: 0.99 MS [m / z]: 445 [M+H]+Synthesis of intermediate 101 10 A mixture of intermediate 100 (150 mg, 337 µmol), Cs2CO3 (220 mg, 674 µmol), piperidine(57 mg, 674 µmol) in 1,4-dioxane (3 mL) is stirred for 2.5 h at 90 °C. The mixture is poured into aqueous 0.5 M KHSO4solution and is extracted with EtOAc. The solvent is evaporated under reduced pressure and the material is used in the next reaction step without purification. Intermediate 101 Analytical HPLC-MS Method: D 12-0516-WO-1 Rt [min]: 1.01 MS [m / z]: 445 [M+H]+Synthesis of intermediate 102 5A mixture of bromide 101 (60 mg, 135 µmol), tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate hydrochloride 47 (47 mg, 162 µmol) and Cs2CO3 (154 mg, 472 µmol) andcatalyst I (11 mg, 13 µmol) in degassed 1,4-dioxane (2 mL) is stirred under argon for 16 h at 90 °C. The mixture is diluted with DMF / MeOH, filtered, and washed with DMF / MeOH. The material is purified by prep. RP-HPLC (basic conditions) to obtain intermediate 102. Intermediate 102 Analytical HPLC-MS Method: D Rt[min]: 1.18 10 Intermediate 102 (68 mg, 112 µmol) in 1,4-dioxane (2 mL) is treated with 4 N HCl in 1,4-dioxane (2 mL) and stirred for 3 h at rt. The solvent is evaporated under reduced pressure15 and the material is purified by prep. RP-HPLC (basic conditions) to obtain example E78. 12-0516-WO-1 Example E78 Analytical HPLC-MS Method: D Rt [min]: 1.04 MS [m / z]: 505 [M+H]+Analytical SFC method: H Rt [min]: 3.16 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.48 - 1.77 (11 H), 2.81 - 2.89 (2 H), 3.50 - 3.65(4 H), 5.34 - 5.47 (1 H), 7.08 - 7.15 (1 H), 7.37 - 7.45 (1 H), 7.63 - 7.72 (1 H), 7.78 - 7.86(1 H), 8.88 - 8.95 (1 H), 9.03 - 9.10 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. Synthesis of example E79 Amixture of bromide 100 (200 mg, 449 µmol), 1-methyl-1,8-diazaspiro[4.5]decane5 dihydrochloride 52 (161 mg, 674 µmol) and Cs2CO3 (585 g, 1.8 mmol) in 1,4-dioxane (8 mL)is degassed with argon. Catalyst I (15 mg, 18 µmol) is added, and the mixture is heated under argon for 3 h at 110 °C. The mixture is filtered, washed with EtOAc, and the solvent is evaporated under reduced pressure. The material is purified by prep. RP-HPLC (basic conditions) to obtain example E79.Example E79 Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 519 [M+H]+Analytical SFC method: U Rt [min]: 3.15 e.e. > 98% 12-0516-WO-1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.29 - 1.37 (2 H), 1.49 - 1.61 (3 H), 1.66 - 1.86 (6H), 2.16 - 2.26 (3 H), 2.65 - 2.76 (5 H), 2.79 - 2.93 (2 H), 4.32 - 4.53 (2 H), 5.34 - 5.49 (1H), 6.74 - 6.86 (1 H), 7.34 - 7.48 (1 H), 7.64 - 7.74 (1 H), 7.77 - 7.86 (1 H), 8.36 - 8.49 (1H), 8.93 - 9.09 (1 H).Synthesis of intermediate 104 Amixture of intermediate 99 (7.0 g, 27 mmol), (R)-1-(2-methyl-3-5 (trifluoromethyl)phenyl)ethanamine 103 (CAS: 2230840-58-9; 7.4 g, 27 mmol) and 4-methylmorpholine (8.8 mL, 80 mmol) in ACN (70 mL) is cooled to 0°C. PPA (50%, 32 mL, 53 mmol) is added dropwise and the mixture is allowed to reach rt. The mixture is poured into ice-water, ACN is evaporated under reduced pressure and water is added to the suspension. The solids are filtered, washed with water and tert-butylmethyl ether and dried10 to obtain intermediate 104. The material is used without further purification. Intermediate 104 HPLC-MS Method: E Rt [min]: 0.99 MS [m / z]: 445 [M+H]+Synthesis of example E80 12-0516-WO-1 Amixture of bromide 104 (60 mg, 136 µmol), 1-methyl-1,8-diazaspiro[4.5]decanedihydrochloride 52 (49 mg, 204 µmol) and potassium phosphate (133 g, 612 µmol) in 1,4-dioxane (1 mL) is degassed with argon. Catalyst I (6 mg, 7 µmol) is added and the mixture is heated under argon for 16 h at 110 °C. The mixture is diluted with 1,4-dioxane, filtered 5 through a thiol resin, and washed with DMF / MeOH (9:1). The mixture is directly purified by prep. RP-HPLC (basic conditions) to obtain example E80. Example E80Analytical HPLC-MS Method: D Rt [min]: 1.03 MS [m / z]: 515 [M+H]+Analytical SFC method: AL Rt [min]: 2.13 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.27 - 1.40 (2 H), 1.45 - 1.55 (3 H), 1.66 - 1.87 (6H), 2.15 - 2.24 (3 H), 2.62 - 2.76 (5 H), 2.79 - 2.92 (2 H), 4.33 - 4.50 (2 H), 5.35 - 5.48 (1H), 6.74 - 6.84 (1 H), 7.37 - 7.46 (1 H), 7.53 - 7.63 (1 H), 7.70 - 7.79 (1 H), 8.36 - 8.46 (1H), 8.92 - 9.02 (1 H), missing proton(s) presumably hidden by / overlapping with solventsignals.

[0361] 12-0516-WO-1 Synthesis scheme of intermediate 111 Synthesis of intermediate 106 5 105 30 106A mixture of 1,4-dioxaspiro[4.5]decan-8-one 105 (3.0 g, 18.8 mmol) and (S)-3-hydroxypiperidine hydrochloride 30 (2.9 g, 20.7 mmol) in THF (30 mL) is stirred at rt for 1h. Sodium triacetoxyborohydride (5.2 g, 24.5 mmol) is added and the reaction mixture is stirred at rt for 16 h. The mixture is concentrated in vacuo and the residue is submitted to 12-0516-WO-1 column chromatography (SiO2; (DCM / MeOH / 7 N NH3 in MeOH = 50:48:2) / DCM: 10:90 ^ 60:40) to obtain intermediate 106. Intermediate 106 Analytical HPLC-MS Method: D Rt [min]: 0.70 MS [m / z]: 242 [M+H]+Synthesis of intermediate 107 5106 107A mixture of intermediate 106 (2.66 g, 11.0 mmol) and aqueous HCl (4 N; 10 mL, 40 mmol)in acetone (20 mL) is stirred at rt for 16 h. Aqueous NaOH solution (4 N; 10 mL, 40 mmol) and saturated aqueous NaHCO3 solution (10 mL) are added, and the mixture is extracted with EtOAc. The organic layers are washed with aqueous saturated NaCl solution, dried10 over MgSO4, and concentrated in vacuo. The intermediate 107 is used for the next stepwithout further purification. Intermediate 107 Analytical HPLC-MS Method: D Rt [min]: 0.61 MS [m / z]: 198 [M+H]+Synthesis of intermediate 108 107 10815 A mixture of intermediate 107 (2.1 g, 10.8 mmol), imidazole (1.8 g, 27.0 mmol) and tert-butyldimethylsilyl chloride (2.4 g, 16.2 mmol) in DMF (20 mL) is stirred for 16 h at rt. Themixture is diluted with water and extracted with EtOAc. The combined organic layers arewashed with aqueous saturated NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue is purified by column chromatography (SiO2; (DCM / MeOH / 7 N NH3 in 12-0516-WO-1 MeOH 30:70) to give intermediate 108.Intermediate 108 Analytical HPLC-MS Method: D Rt [min]: 1.23 MS [m / z]: 312 [M+H]+Synthesis of intermediate 109 108 1095 LDA (1 N solution in THF; 16.3 mL, 16.3 mmol) is added to intermediate 108 (2.54 g, 8.15mmol) in THF (30 mL) at -75°C under argon atmosphere and the resulting mixture is stirred for 2 h. A solution of N,N-bis(trifluoromethylsulfonyl)aniline (4.08 g, 11.4 mmol) in THF (30 mL) is slowly added at -75°C and the reaction mixture is stirred for 16 h, being allowed to warm to rt. The reaction mixture is quenched with a saturated aqueous solution of NH4Cl 10 (50 mL) and extracted with EtOAc. The combined organic layers are washed with aqueous saturated NaCl solution, dried over MgSO4,and concentrated in vacuo. The residue is purified by column chromatography (SiO2; cyclohexane / EtOAc: 98:2 70:30) to giveintermediate 109. Intermediate 109 Analytical HPLC-MS Method: D Rt [min]: 1.35 MS [m / z]: 444 [M+H]+Synthesis of intermediate 110 15 109 110A mixture of intermediate 109 (2.64 g, 5.95 mmol), bis(pinacolato)diboron (1.51 g, 5.95 12-0516-WO-1 mmol) and the potassium acetate (1.46 g, 14.9 mmol) in 1,4-dioxane (30 mL) is degassed with argon. Catalyst II (218 mg, 298 µmol) is added, and the mixture is stirred for 1 h at80°C under an argon atmosphere. The solvent is evaporated, and EtOAc is added. The organic layer is washed with water and aqueous saturated NaCl solution, dried over MgSO4, 5 and concentrated in vacuo. The residue is dissolved in DCM and purified by column chromatography 85:15). The product is dissolved in ACN / water,filtered, and purified via prep. RP-HPLC (basic conditions) to give intermediate 110. Intermediate 110HPLC-MS Method: M Rt [min]: 1.25 MS [m / z]: 422 [M+H]+Synthesis of intermediate 11110 An aqueous Na2CO3solution (2 M; 0.77 mL, 1.55 mmol) is added to a mixture of intermediate 13 (200 mg, 484 µmol) and borane 110 (245 mg, 581 µmol) in 1,4-dioxane (6mL) and the mixture is degassed with argon. Catalyst II (20 mg, 24 µmol) is added, and the mixture is stirred for 12 h at 95 °C under an argon atmosphere. The mixture is diluted with 15 aqueous saturated NaCl solution and extracted with EtOAc. The combined organic phases are washed with aqueous saturated NaCl solution, dried over MgSO4, and concentrated in vacuo. The material is dissolved in ACN / MeOH / water, filtered, and purified by prep. RP- HPLC (basic conditions) to give intermediate 111. Intermediate 111 Analytical HPLC-MS Method: D Rt [min]: 1.28 MS [m / z]: 628 [M+H]+ 12-0516-WO-1 Synthesis of example E82 111 E82Tetrabutylammonium fluoride (573 µl, 573 µmol) is added to intermediate 111 (120 mg, 1915 µmol) in THF (3 mL) under an argon atmosphere and the resulting mixture is stirred at rt for 20 h. The mixture is diluted with water / ACN and purified via RP-HPLC (basic conditions) to obtain example E82. Example E82 Analytical HPLC-MS Method: D Rt [min]: 0.91 MS [m / z]: 514 [M+H]+1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.01 - 1.21 (1 H), 1.31 - 1.49 (1 H), 1.49 - 1.71 (5H), 1.75 - 1.88 (1 H), 1.90 - 2.23 (3 H), 2.25 - 2.48 (2 H), 2.54 - 2.86 (4 H), 2.86 - 3.02 (1H), 3.39 - 3.55 (1 H), 4.43 - 4.64 (1 H), 5.38 - 5.48 (1 H), 7.07 - 7.39 (2 H), 7.48 - 7.58 (2H), 7.59 - 7.65 (1 H), 7.65 - 7.72 (1 H), 8.98 - 9.07 (1 H), 9.12 - 9.19 (1 H), 9.34 - 9.41 (1H).10 Example E82 (55 mg, 107 µmol) in MeOH (3 mL) is stirred in the presence of Pd / C(10%w / w, 10 mg) under an H2 atmosphere (50 psi) for 5 h at rt. The mixture is filtered andconcentrated in vacuo. The residue is dissolved in MeOH, filtered, and purified by prep. RP- 12-0516-WO-1 HPLC (basic conditions) to obtain example E81. Example E81 Analytical HPLC-MS Method: D: Rt[min]: 0.91 MS [m / z]: 516 [M+H]+Analytical SFC method: Z Rt[min]: 2.93d.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.99 - 1.14 (1 H), 1.33 - 1.55 (6 H), 1.58 - 1.84 (4H), 1.86 - 2.19 (6 H), 2.39 - 2.48 (1 H), 2.64 - 2.73 (1 H), 2.84 - 2.92 (1 H), 3.04 - 3.16 (1H), 3.39 - 3.48 (1 H), 4.51 (1 H), 5.42 (1 H), 7.08 - 7.38 (2 H), 7.51 - 7.57 (2 H), 7.68 (1H), 9.00 (1 H), 9.08 (1 H), 9.34 (1 H). Synthesis of intermediate 113 5A mixture of intermediate 39 (150 mg, 348 µmol) and borane 112 (170 mg, 522 µmol) in1,4-dioxane (3 mL), MeOH (1.1 mL) and aqueous Na2CO3solution (2 M; 0.55 mL, 1.11 mmol) is degassed with argon. Catalyst II (28 mg, 35 µmol) is added, and the mixture is heated 3 h under argon at 110°C. To the reaction mixture water is added, the aqueous layer is extracted with EtOAc, and the combined organic layers dried with MgSO4. After filtration 10 and evaporation of the solvent, the mixture is purified by prep. RP-HPLC (basic conditions) to obtain intermediate 113. Intermediate 113 Analytical HPLC-MS Method: D Rt [min]: 1.08 MS [m / z]: 534 [M+H]+ 12-0516-WO-1 Synthesis of intermediate 114 113 114Intermediate 113 (135 mg, 253 µmol) in 1,4-dioxane (2.2 mL) is treated with HCl solution (45 M in 1,4-dioxane; 1.26 mL, 5.06 mmol). The mixture is stirred for 16 h at rt. The solvent is evaporated, the residue co-evaporated with toluene to give intermediate 114, which is used in the next reaction step without further purification. Intermediate 114 Analytical HPLC-MS Method: D Rt [min]: 0.91 MS [m / z]: 434 [M+H]+Synthesis of example E83 10 114 E83A mixture of intermediate 114 (135 mg, 287 µmol) in DMF (1.2 mL) is treated with acetone(73 µL, 1.01 mmol), AcOH (16 µL, 287 µmol), and sodium triacetoxyborohydride (244 mg, 1.15 mmol). The mixture is stirred for 2 h at rt. Additional acetone (73 µL, 1.01 mmol) is added and stirring is continued for 1 h at rt. Water is added, the mixture is neutralized with 15 10% aqueous NH3 solution, diluted with THF and MeOH and filtered. The mixture is purified by prep. RP-HPLC (basic conditions) to obtain example E83. 12-0516-WO-1 Example E83 Analytical HPLC-MS Method: DRt [min]: 1.02 MS [m / z]: 476 [M+H]+Analytical SFC method: AHRt [min]: 6.68 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.97 - 1.12 (6 H), 1.49 - 1.59 (3 H), 2.57 - 2.85(5 H), 5.37 - 5.49 (1 H), 7.37 - 7.46 (1 H), 7.59 - 7.73 (3 H), 7.78 - 7.87 (1 H), 9.00 - 9.08(1 H), 9.13 - 9.22 (1 H), 9.36 - 9.42 (1 H), missing proton(s) presumably hidden by / overlapping with solvent signals.

[0362] Synthesis scheme of intermediate 119

[0363] 12-0516-WO-1 Synthesis of intermediate 115 Amixture of intermediate 99 (2.0 g, 7.6 mmol), benzylamine 6 (CAS: 1389852-29-2; 1.8 g,5 8.0 mmol), 4-methylmorpholine (2.7 g, 27 mmol) in ACN (20 mL) is cooled to 0 °C. 1- Propanephosphonic anhydride (50%, 5.0 mL, 8.4 mmol) is added dropwise and the mixture is stirred for 16 h at rt. The mixture is poured into ice-water and treated with aqueous HCl solution. The solid material is filtered off, washed with water and dried in vacuo at 55 °C toobtain intermediate 115. Intermediate 115 Analytical HPLC-MS Method: D Rt[min]: 0.90 MS [m / z]: 427 [M+H]+10 Synthesis of intermediate 116 Amixture of intermediate 115 (2.6 g, 6.1 mmol), Cs2CO3 (2.0 g, 6.1 mmol), piperidine (603µL, 6.1 mmol) in 1,4-dioxane (16 mL) is stirred for 7 h at 120 °C and for 48 h at rt. The 15 solvent is evaporated under reduced pressure. EtOAc and water are added. The aqueous layer is separated and extracted with EtOAc. The combined organic layers are dried over MgSO4. The solids are filtered, and the solvent is evaporated under reduced pressure. The 12-0516-WO-1 material is purified by prep. RP-HPLC (basic conditions) to obtain intermediate 116. Intermediate 116 Analytical HPLC-MS Method: D Rt [min]: 0.95 MS [m / z]: 427 [M+H]+Synthesis of intermediate 117 5A mixture of intermediate 116 (800 mg, 1.8 mmol), aqueous Na2CO3 solution (2 M; 2.8 mL,5.7 mmol), and borane 68 (575 mg, 2.1 mmol) in 1,4-dioxane (10 mL) is stirred under argonatmosphere. Catalyst II (87 mg, 107 µmol) is added, and the mixture is stirred at 95 °C for 2 h. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with aqueous saturated NaCl solution, dried over Na2SO4, filtered and 10 the solvents are evaporated. The material is purified by column chromatography (SiO2; EtOAc / cyclohexane: 100:0) to obtain intermediate 117.Intermediate 117 HPLC-MS Method: E Rt[min]: 1.03 MS [m / z]: 487 [M+H]+

[0364] 12-0516-WO-1 Synthesis of intermediate 118 117 118Intermediate 117 (940 mg, 1.9 mmol) in MeOH (10 mL) is stirred under H2 atmosphere (505 psi) in the presence of Pd / C (10 %w / w, 100 mg) for 18 h at rt. The mixture is filtered, and the solvent is evaporated to obtain intermediate 118. The material is used in the next reaction step without further purification. Intermediate 118 HPLC-MS Method: E Rt [min]: 1.02 MS [m / z]: 489 [M+H]+10 Intermediate 118 (783 mg, 1.6 mmol) in THF (10 mL) is treated with aqueous HCl solution(4 M; 2.0 mL). The mixture is stirred for 24 h at rt. A saturated NaHCO3solution is added, and the mixture is extracted with EtOAc. The separated organic layer is extracted with aqueous saturated NaCl solution. The solvent of the combined organic layers is evaporated 15 under reduced pressure to obtain intermediate 119. The material is used in the next reaction step without further purification. 12-0516-WO-1 Intermediate 119 HPLC-MS Method: E Rt[min]: 0.97 MS [m / z]: 445 [M+H]+ Amixture of intermediate 119 (50 mg, 112 µmol) and pyrrolidine 120 (19 µL, 225 µmol) in5 MeOH (1 mL) is prepared and AcOH (60 µL, 1.03 mmol) is added followed by 2-picoline- borane complex (12 mg, 112 µmol). The mixture is stirred for 60 h at rt. An aqueous NaOH solution is added and directly purified by prep. RP-HPLC (basic conditions) to obtain example E84. Example E84 Analytical HPLC-MS Method: D Rt [min]: 1.07 MS [m / z]: 500 [M+H]+Analytical SFC method: Y Rt [min]: 5.57 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.27 - 1.41 (2 H), 1.49 - 1.56 (3 H), 1.62 - 1.77(6 H), 1.92 - 2.02 (2 H), 2.03 - 2.14 (3 H), 2.99 - 3.11 (1 H), 5.37 - 5.47 (1 H), 7.07 - 7.37(2 H), 7.49 - 7.56 (1 H), 7.65 - 7.72 (1 H), 7.79 - 7.83 (1 H), 9.04 - 9.09 (1 H), 9.22 - 9.28(1 H), missing proton(s) presumably hidden by / overlapping with solvent signals. 12-0516-WO-1 Synthesis of example E85 Amixture of intermediate 119 (180 mg, 405 µmol) and (S)-3-hydroxypiperidine5 hydrochloride 30 (115 mg, 810 µmol) in iPrOH (3 mL) is prepared and AcOH (500 µL, 8.6mmol) is added followed by 2-picoline-borane complex (45 mg, 405 µmol). The mixture is stirred for 18 h at rt. An aqueous NaOH solution (4 M; 2 mL) is added and directly purified by prep. RP-HPLC (basic conditions) to obtain example E85. Example E85 Analytical HPLC-MS Method: D Rt [min]: 0.97 MS [m / z]: 530 [M+H]+Analytical SFC method: N Rt [min]: 3.05 d.e. >98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.99 - 1.12 (1 H), 1.30 - 1.92 (13 H), 1.93 - 2.05(3 H), 2.08 - 2.17 (1 H), 2.38 - 2.47 (1 H), 2.64 - 2.73 (1 H), 2.83 - 2.90 (1 H), 2.98 - 3.08(1 H), 3.38 - 3.48 (1 H), 4.47 - 4.52 (1 H), 5.37 - 5.46 (1 H), 7.06 - 7.37 (2 H), 7.49 - 7.56(1 H), 7.65 - 7.72 (1 H), 7.78 - 7.82 (1 H), 9.03 - 9.10 (1 H), 9.24 - 9.28 (1 H), missingproton(s) presumably hidden by / overlapping with solvent signals.

[0365] 12-0516-WO-1 Synthesis of intermediate 122 HATU (864 mg, 2.27 mmol) and triethylamine (0.87 mL, 6.20 mmol) are added to 5intermediate 121 (500 mg, 2.07 mmol) in THF (33 mL). The mixture is stirred for 15 min atrt then (1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride 36 (CAS:2230840-52-3; 503 mg, 2.07 mmol) is added. Stirring is continued for 16 h at rt. Semi- saturated aqueous NaHCO3 solution is added, and the aqueous layer extracted with EtOAc. The combined organic layers are dried with MgSO4. After filtration and evaporation of the 10 solvent, the material is purified by prep. RP-HPLC (basic conditions) to obtain intermediate 122. Intermediate 122 Analytical HPLC-MS Method: D Rt [min]: 1.00 MS [m / z]: 431 [M+H]+Synthesis of example E8615 Amixture of intermediate 122 (70 mg, 154 µmol) and 1-methyl-1,8-diazaspiro[4.5]decanedihydrochloride 52 (41 mg, 170 µmol) in 1,4-dioxane (1.3 mL) is degassed with argon. 12-0516-WO-1 Cs2CO3 (201 mg, 617 µmol) and catalyst I (8 mg, 9 µmol) are added, and the mixture is stirred at 120 °C for 16 h. The reaction mixture is diluted with DMF / MeOH / THF, filtered, concentrated, and purified by prep. RP-HPLC (basic conditions) to obtain example E86. Example E86 Analytical HPLC-MS Method: D Rt [min]: 1.05 MS [m / z]: 505 [M+H]+Analytical SFC method: L Rt [min]: 1.91 e.e. > 98%1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.37 - 1.48 (2 H), 1.50 - 1.58 (3 H), 1.66 - 1.94(6 H), 2.24 - 2.35 (3 H), 2.69 - 2.99 (4 H), 4.01 - 4.15 (2 H), 5.39 - 5.49 (1 H), 6.86 - 6.95(1 H), 7.37 - 7.47 (1 H), 7.64 - 7.73 (1 H), 7.80 - 7.88 (1 H), 7.97 - 8.04 (1 H), 8.52 - 8.63(1 H), 9.20 - 9.29 (1 H).5 Pharmacological activity - BIOLOGICAL ASSAYS AND DATAKRAS::SOS1 alphascreen binding assay This assay can be used to examine the potency with which compounds inhibit the protein- protein interaction between SOS1 and KRAS G12C or G12D. This demonstrates the molecular mode of action of compounds. Low IC50values are indicative of high potency of10 the SOS1 inhibitor compound in this assay setting: Reagents: GST-tagged SOS1 (564_1049_GST_TEV_ECO) produced in-house 6xHis-Tev-K-RasG12D / G12C(1-169)Avi produced in-house GDP (Sigma Cat No G7127) 15 AlphaLISA Glutathione Acceptor Beads (PerkinElmer, Cat No AL109) AlphaScreen Streptavidin Donor Beads (PerkinElmer Cat No 6760002) Assay plates: Proxiplate-384 PLUS, white (PerkinElmer, Cat No 6008289) Assay buffer: 1 x PBS 20 0.1% BSA 12-0516-WO-1 0.05% Tween 20 KRAS::SOS1 GDP mix: 7.5 nM (final assay concentration) K-RasG12C, 10nM (final assay concentration) K-RasG12D, 10 µM (final assay concentration) GDP and 5nM (final assay concentration)5 GST-SOS1 are mixed in assay buffer prior to use and kept at rt. Bead mix: AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads are mixed in the dark in assay buffer at a concentration of 10 µg / mL (final assay concentration) each prior to use and kept at rt. Assay protocol: 10 Compounds are diluted to a final start concentration of 100 µM and are tested in duplicate. Assay-ready plates (ARPs) are generated using an Access Labcyte Workstation with a Labcyte Echo 550 or 555 acoustic dispenser. For compound a start concentration of 100 µM, 150 nL of compound solution is transferred per well in 11 concentrations induplicate with serial 1:5 dilutions.15 The assay is run using a fully automated robotic system in a darkened room below 100 Lux.10 µL of KRAS::SOS1 GDP mix is added into columns 1-24 to the 150 nL of compound solution (final dilution in the assay 1:100, final DMSO concentration 1 %). After a 30 minute incubation time, 5 µL of bead mix is added into columns 1-23. Plates are kept at rt in a darkened incubator. After a further 60 minutes incubation, the signal is20 measured using a PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen specifications from PerkinElmer. Each plate contains the following controls: diluted DMSO + KRAS::SOS1 GDP mix + bead mix diluted DMSO + KRAS::SOS1 GDP mix Result calculation: IC50values are calculated and analyzed using a 4 parametric logistic25 model. Table 1: Inhibition values for KRAS G12C as well as for KRAS G12D. Data obtained withthe disclosed assay for a selection of compounds (I) according to the invention. The valueindicates an average value of at least two measurements. nM] 12-0516-WO-1 E34 42 34 E74 26 21E35 57 48 E75 65 60E36 28 22 E76 49 36E37 31 21 E77 27 22E38a 66 45 E78 43 41E38b 59 41 E79 20 14E39 53 54 E80 37 27E40 50 53 E81 25 24cis-E41a 50 38 E82 20 15cis-E41b 41 38 E83 30 26trans-E42a 26 26 E84 38 37trans-E42b 37 36 E85 37 24E43a 42 40 E86 61 44212 12-0516-WO-1 Erk phosphorylation assay ERK phosphorylation assays are used to examine the potency with which compounds inhibit the SOS1-mediated signal transduction in a KRAS mutant human cancer cell line in vitro. This demonstrates the molecular mode of action of compounds by interfering with the 5 RAS-family protein signal transduction cascade. Low IC50 values are indicative of high potency of the SOS1 inhibitor compounds in this assay setting. It is observed that SOS1 inhibitor compounds demonstrate an inhibitory effect on ERK phosphorylation in a KRAS mutant human cancer cell line, thus confirming the molecular mode of action of the SOS1inhibitor compounds on RAS-family protein signal transduction. 10 ERK phosphorylation assays are performed using the following human cell line: NCI-H358 SOS2 KO (Hofmann, Gmachl, Ramharter et al, Cancer Discov.2021, 11(1):142- 15): human lung cancer with a KRAS G12C mutation; Materials used: RPMI-1640 Medium (ATCC® A10491-01™) 15 DMEM Medium (Sigma Aldrich #D6429) Fetal Bovine Serum (FBS) from HyClone (SH30084-03) 384 plates from Greiner Bio-One (781182) Proxiplate™ 384 from PerkinElmer Inc. (6008280)AlphaLISA SureFire Ultra p-ERK1 / 2 (Thr202 / Tyr204) Assay Kit (ALSU-PERK-A10K)20 Acceptor Mix: Protein A Acceptor Beads from PerkinElmer (6760137M) Donor Mix: AlphaScreen Streptavidin-coated Donor Beads from PerkinElmer (6760002) Human EGF 100 µg / mL Peprotech (PNr.: AF-100-15)Complete Mini, Proteaseinhibitor Cocktail Tablets, Roche #11836170001 Assay setup: 25 NCI-H358 SOS2 KO are seeded at 50000 cells per well in 60 µL of DMEM with 2 % FBS, in Greiner TC 384 plates. The cells are incubated overnight in an incubator at 37 °C and 5 %CO2 in a humidified atmosphere. 60 nL compound solution (10 mM DMSO stocksolution) is then added using a Beckman Coulter Labcyte Echo 550 device. After 50 min incubation in the aforementioned incubator, 5nl EGF are added to each well for a final30 concentration of approx. 8 ng / mL using a Beckman Coulter Labcyte Echo 550 device andcells are incubated for another 10-15 minutes before lysis. The medium is removed, and 12-0516-WO-1 the cells are lysed by addition of 20 µL of 1.6-fold lysis buffer from the AlphaLISA SureFireUltra pERK1 / 2 (Thr202 / Tyr204) Assay Kit with added protease inhibitors. After 20 minutes of incubation at rt with shaking, 6 µL of each lysate sample is transferred to a 384-wellProxiplate and analyzed for pERK (Thr202 / Tyr204) with the AlphaLISA SureFire Ultra 5pERK1 / 2 (Thr202 / Tyr204) Assay Kit. 3 µL Acceptor Mix and 3 µL Donor Mix are addedunder subdued light and incubated for 2 h at rt in the dark, before the signal is measuredon a Perkin Elmer Envision plate reader using 384 AlphaScreen settings for Proxiplates. Data are fitted by iterative calculation with variable hill slope. The sigmoidal curve slope is fitted using a default fitting curve to ascertain IC50 values. A minimal efficacy of 35%10 normalized pathway modulation is set as threshold for curve fitting and consideration of resulting IC50 values. Table 2: Erk Phosphorylation assay. The value indicates an average value of at least two measurements. Example Number pER Example Number pERKIC50 IC50 [nM] E1 118 E43b 101E2 92 E44 58E3 155 E45 139E4 336 E46 162E5 324 E47a 162E6 247 E47b 198E7 246 E48 82E8 188 E49 250E10 212 E50 220cis-E11a 173 cis-E52a 115cis-E11b 145 cis-E52b 40E12 110 trans-E53a 143E13 288 trans-E53b 287E14 490 E54 186E15 554 E55 397cis-E16a 320 E57 149cis-E16b 316 E58 122E17a 94 E59 166E17b 201 E60 290E18 54 trans-E61a 391E19 222 trans-E61b 138E20 146 E62 315 12-0516-WO-1 Metabolic stability in human hepatocytes The metabolic degradation of a test compound is performed with hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes are diluted in 5 Dulbecco´s modified eagle medium (supplemented with 3.5 µg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, 50% human serum) to obtain a final cell density of 1.0x106cells / mL.Following a preincubation in a cell culture incubator (37 °C, 10 %CO2), test compound dissolved in DMSO is mixed with the hepatocyte suspension,resulting in a final test compound concentration of 1 µM and a final DMSO concentration of10 0.05 %. 12-0516-WO-1 The cell suspension is incubated at 37°C (cell culture incubator, horizontal shaker) and samples are removed from the incubation after 0, 0.5, 1, 2, 4 and 6 hours. Samples are quenched with acetonitrile (containing internal standard) and pelleted by centrifugation. The supernatant is transferred to a deep-well plate and prepared for analysis of decline of parent5 compound by HPLC-MS / MS. The percentage of remaining test compound is calculated using the peak area ratio (test compound / internal standard) of each incubation time point relative to the time point 0 peak area ratio. The log-transformed data are plotted versus incubation time, and the absolutevalue of the slope obtained by linear regression analysis is used to estimate in vitro half-life 10 (T1 / 2). In vitro intrinsic clearance (CLint) is calculated from in vitro T1 / 2 and scaled to whole liverusing a hepatocellularity of 120x106cells / g liver, a human liver per body weight of 25.7 g liver / kg as well as in vitro incubation parameters, applying the following equation: CL_INTRINSIC_IN VIVO [mL / min / kg] = (CL_INTRINSIC [µL / min / 106cells] x15 hepatocellularity [106cells / g liver] x liver factor [g / kg body weight]) / 1000 Hepatic in vivo blood clearance (CL) is predicted according to the well-stirred liver model considering an average liver blood flow (QH) of 20.7 mL / min / kg: CL [mL / min / kg] = CL_INTRINSIC_IN VIVO [mL / min / kg] x hepatic blood flow [mL / min / kg] / 20 (CL_INTRINSIC_IN VIVO [mL / min / kg] + hepatic blood flow [mL / min / kg]) Results are expressed as percentage of hepatic blood flow: QH [%] = CL [mL / min / kg] / hepatic blood flow [mL / min / kg]) Table 3: Hepatic clearance expressed as percentage of liver blood flow ( QH [%]) of25 exemplified compounds. Data obtained with the disclosed assay for a selection ofcompounds (I) according to the invention. At least one measurement otherwise averagevalues of at least two measurements. Example Number Hepatic Example Number Hepatic clearance -clearanceQH[%] in humanQH[%] inhepatocytes hepatocy E1 17 E43b 25E2 15 E44 16E3 24 E45 <4E4 20 E46 9 12-0516-WO-1Example Number Hepatic Example Number Hepatic clearance -clearanceQH[%] in humanQH[%] inhepatocytes hepatocyE5 16 E47a 30E6 16 E47b 28E7 31 E48 27E8 18 E49 23E10 29 E50 15cis-E11a 38 cis-E52a 7cis-E11b 27 cis-E52b 14E12 12 trans-E53a 45E13 21 trans-E53b 28E14 31 E54 12E15 31 E55 <4cis-E16a 32 E57 15cis-E16b 24 E58 15E17a 13 E59 15E17b 30 E60 26E18 17 trans-E61a 40E19 19 trans-E61b 30E20 19 E62 9cis-E21a 25 E63 23cis-E21b 38 E64a 16E22 19 E64b 23E24 22 E65 38E25 17 E66 32E26 8 E67 10E27 9 E68 12E28 23 E69 <4cis-E29 24 trans-E70a 25E30 18 trans-E70b 19E31 13 E71 7E32 23 E72 21E33 15 E73 24E34 10 E74 8E35 6 E75 9E36 10 E76 20E37 25 E77 <4E38a 10 E78 5E38b 11 E79 8E39 43 E80 <4E40 22 E81 15 12-0516-WO-1 Cytochrome P450 isoenzyme inhibition assays The inhibition of the conversion of a specific substrate to its metabolite is assayed at 37°C with human liver microsomes and used to determine the inhibition of cytochrome 5P450 isoenzymes. For the following cytochrome P450 isoenzymes, these substrates andmetabolic reactions are monitored: P4503A4: hydroxylation of Midazolam (MDZ).The final incubation volume contains TRIS buffer (0.1 M), MgCl2 (5 mM), a certain concentration of human liver microsomes dependent on the P450 isoenzyme measured (P4503A4: 0.1 mg / ml) and a certain concentration of the individual substrate for each10 isoenzyme (P4503A4: Midazolam 5 µM). The effect of the test compound is determined at five different concentrations in duplicate (e.g. highest concentration 50 µM with subsequent serial 1:4 dilutions) or without test compound (high control). Following a short preincubation period, reactions are started with the cofactor (NADPH, 1mM) and stopped by cooling the incubation down to 8°C and15 subsequently by addition of one volume of ACN. An internal standard solution - usually thestable isotope of the formed metabolite - is added after quenching of incubations. Peak areaanalyte (=metabolite formed) and internal standard is determined by LC-MS / MS. The resulting peak area ratio analyte to internal standard in these incubations is compared to a control activity containing no test compound. Within each of the assay runs, the IC50 of a 20 positive control inhibitor dependent on the P450 isoenzyme measured (P450 3A4: ketoconazole) is determined. The assay results are plotted against compoundconcentrations to calculated IC50values (half maximal inhibitory concentrations) for inhibitory compounds utilizing Software IDBS E-WorkBook. 12-0516-WO-1Table 4: Inhibition of P450 isoenzyme 3A4. Data obtained with the disclosed assay for aselection of compounds (I) according to the invention with Midazolam as substrate. Atleast one measurement otherwise average values of at least two measurements. Example Number CYP Example Number CYP3A4 inhibitionIC50 IC50 [µM] E1 >50 E43b >50E2 >50 E44 >50E3 >50 E45 >50 E4 >50 E46 >50E5 >50 E47a >50E6 >50 E47b >50E7 >50 E48 >50E8 >50 E49 >50E10 >50 E50 >50 cis-E11a >50 cis-E52a >50cis-E11b >50 cis-E52b >50E12 >50 trans-E53a >50 E13 >50 trans-E53b >50 E14 >50 E54 >50 E15 >50 E55 >50 cis-E16a >50 E57 >50 cis-E16b >50 E58 >50E17a >50 E59 >50E17b >50 E60 >50 E18 >50 trans-E61a >50E19 >50 trans-E61b >50 E20 >50 E62 >50cis-E21a >50 E63 >50cis-E21b >50 E64a >50 E22 >50 E64b >50 E24 >50 E65 >50E25 >50 E66 >50E26 >50 E67 >50E27 >50 E68 >50E28 >50 E69 >50cis-E29 >50 trans-E70a >50E30 >50 trans-E70b >50 E31 >50 E71 >50 E32 >50 E72 >50 12-0516-WO-1 Mechanism-based inhibition of CYP3A4 assay (MBI 3A4):The mechanism-based inhibition towards CYP3A4 is assayed in human liver microsomeswith midazolam as substrate. The test compounds and water control (wells w / o test 5compound) are preincubated in presence of NADPH (1 mM) with human liver microsomes(0.2 mg / mL) at a concentration of 0, 5 and 25 µM for 0, 10 and 30 min. After preincubation,the incubate is diluted 1:10 (to 0.02 mg / mL) and the substrate midazolam (15 µM) is addedfor the main incubation (10 min). The main incubation is quenched with ACN and theformation of hydroxy-midazolam is quantified via LC / MS-MS. The formation of hydroxy- 10 midazolam from the 30 min preincubation relative to the formation from the 0 min preincubation is used as a readout. Values of less than 100 % mean that the substrate midazolam is metabolized to a lower extent upon 30 min preincubation compared to 0 minpreincubation. In general, low effects upon 30 min preincubation are desired (correspondingto values close to 100 % / not different to the values determined with water control).15 Table 5: Mechanism-based inhibition of P450 isoenzyme 3A4 with midazolam assubstrate. Data obtained with the disclosed assay for a selection of compounds (I)according to the invention. At least one measurement otherwise average values of at leasttwo measurements. 12-0516-WO-1 ition %ctrl. [%] 12-0516-WO-1

Claims

12-0516-WO-1 Claimswherein 5each R1 is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl andhalogen; pdenotes 1, 2 or 3;R2 is H, Me or Et;V is nitrogen (-N=) or carbon10 W is nitrogen (-N=) or carbonat least one of V and / or W is nitrogen (-N=);A1, A2 and A3 are each independently selected from nitrogen (-N=) or carbon (=CH- or=CR3-);single or double bond;15 each R3, if present, is independently selected from the group consisting of C1-6alkyl,C1-6alkoxy, halogen and C1-6haloalkyl; qdenotes 0, 1 or 2;ring system B is selected from C3-10cycloalkyl, C4-10cycloalkenyl, 4-13 memberedheterocyclyl,20 r denotes 0, 1, 2, 3 or 4;12-0516-WO-1 each R4, if present, is independently selected from the group consisting of R5and R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, -CN, -C(=O)R6, -C(=O)OR6, -C(=O)NR6R6, -NHC(=O)OR6and the bivalent substituent =O; 5 each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 4-11 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl and 4-11membered heterocyclyl, are each independently optionally substituted with one or more,identical or different R7and / or R8; 10 each R7is independently selected from the group consisting of -OH, -NH2, -NHR8, -NR8R8, halogen, -CN, and C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-1115 membered heterocyclyl, are each independently optionally substituted with one or more,identical or different R9; each R9is -OH, halogen or C1-6alkoxy; or a salt thereof.

2. The compound or salt according to claim 1, wherein R2 is Me.20 3. The compound or salt according to claim 1 or 2, wherein A1, A2, A3, V andW form a triazole.

4. The compound or salt according to anyone of claims 1 to 3, wherein the ringand is optionally substituted with R3.12-0516-WO-1 5. The compound or salt according to anyone of claims 1 to 4, wherein eachR3, if present, is C1-6alkyl.

6. The compound or salt according to anyone of claims 1 to 5, wherein p is 2and R1is independently selected from the group consisting of C1-6alkyl, 5 C1-6haloalkyl and halogen.

7. The compound or salt according to anyone of claims 1 to 6, wherein R1 isindependently selected from the group consisting of Me, -CFH2, -CF2H, -CF3, -CFMeH, -CFMe2, -CF2Me, and F.

8. The compound or salt according to anyone of claims 1 to 7, wherein ring10 system B is selected from C3-10cycloalkyl, and C4-10cycloalkenyl; and whereinthe C3-10cycloalkyl, and C4-10cycloalkenyl is optionally and independentlysubstituted with r, identical or different R4.

9. The compound or salt according to anyone of claims 1 to 7, wherein ringsystem B is a 4-13 membered heterocyclyl; and the 4-13 membered15 heterocyclyl is optionally and independently substituted with r, identical ordifferent R4.

10. The compound or salt according to anyone of claims 1 to 7, wherein ringsystem B is a 5-6 membered heterocyclyl; and the 5-6 memberedheterocyclyl is optionally and independently substituted with r, identical or20 different R4.

11. The compound or salt according to anyone of claims 1 to 7 or 9, wherein ringsystem B is selected from the group consisting of,12-0516-WO-112-0516-WO-1 ,wherein ring system B can be attached to the compound of formula (I) andto R4 , if present, at any ring position by removal of a hydrogen atom.

12. The compound or salt according to anyone of claims 1 to 11, wherein eachR4, if present, is independently selected from the group consisting of R5and 5 R6; each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, and -CN; each R6is independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, 4-11 10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl and 4-11 membered heterocyclyl, are each independentlyoptionally substituted with one or more, identical or different R7and / or R8; each R7is independently selected from the group consisting of -OH, -NH2,15 -NHR8, -NR8R8, halogen, -CN, and C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-10cycloalkyl, C4-10cycloalkenyl, and 4-11 membered heterocyclyl, are each20 independently optionally substituted with one or more, identical or different R9; each R9is -OH, halogen or C1-6alkoxy.

13. The compound or salt according to anyone of claims 1 to 12, wherein eachR4, if present, is independently selected from the group consisting of R5and25 R6;12-0516-WO-1 each R5is independently selected from the group consisting of -OR6, -NR6R6, halogen, and -CN; each R6is independently selected from the group consisting of hydrogen, C1- 6alkyl, C3-10cycloalkyl, 4-11 membered heterocyclyl, wherein the C1-6alkyl, 5 C3-10cycloalkyl and 4-11 membered heterocyclyl, are each independently optionally substituted with one or more, identical or different R7and / or R8; each R7is independently selected from the group consisting of -OH, halogen, and C1-6alkoxy; each R8is independently selected from the group consisting of C1-6alkyl, 10 C3-10cycloalkyl, and 4-11 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, and 4-11 membered heterocyclyl, are each independentlyoptionally substituted with one or more, identical or different R9; each R9is -OH.

14. The compound or salt according to anyone of claims 1 to 13, wherein each15 R4, if present, is independently selected from the group consisting of , ,12-0516-WO-112-0516-WO-1,12-0516-WO-112-0516-WO-112-0516-WO-1 E E12-0516-WO-112-0516-WO-1 E,12-0516-WO-1 E, ,, , , ,12-0516-WO-1 cis- E46 E52a,,,,,, ,,12-0516-WO-1 , , t,, ,12-0516-WO-1 ,,,12-0516-WO-1or a pharmaceutical acceptable salt thereof.

16. The compound according to any one of claim 1 to 15 – or a pharmaceuticallyacceptable salt thereof – for use as a medicament.12-0516-WO-1 17. The compound according to any one of claim 1 to 15 – or a pharmaceuticallyacceptable salt thereof – for use in the treatment and / or prevention of cancer.

18. The compound – or a pharmaceutically acceptable salt thereof – for use according toclaim 17, wherein said compound or salt is administered in combination with one or more 5 other pharmacologically active substance(s).

19. The compound – or the pharmaceutically acceptable salt thereof – for use accordingto claim 17 or 18, wherein the cancer is selected from the group consisting of pancreaticcancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid 10 leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, gastroesophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

20. A pharmaceutical composition comprising a compound according to any one of claim15 1 to 15 – or a pharmaceutically acceptable salt thereof – and one or more otherpharmaceutically acceptable excipient(s).

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