Piperidinylphenylcarbonitrile derivatives as inhibitors of glutaminyl-peptide cyclotransferase and glutaminyl-peptide cyclotransferase like protein

Abstract

The present disclosure provides certain piperidinylphenylcarbonitrile derivatives, and pharmaceutically acceptable salts thereof, that are inhibitors of Glutaminyl -peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), and are therefore useful for the treatment of diseases treatable by inhibition of QPCT / L. Also provided are pharmaceutical compositions containing the same, and processes for preparing said compounds.

Description

01-3588 ff-text BI International GmbH1 / 74 PIPERIDINYLPHENYLCARBONITRILE DERIVATIVES AS INHIBITORS OFGLUTAMINYL-PEPTIDE CYCLOTRANSFERASE AND GLUTAMINYL-PEPTIDE CYCLOTRANSFERASE LIKE PROTEIN TECHNICAL FIELDThe present disclosure provides certain piperidinylphenylcarbonitrile derivatives, and phar-maceutically acceptable salts thereof, that are inhibitors of Glutaminyl-peptide cyclotrans-ferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), and are there-fore useful for the treatment of diseases treatable by inhibition of QPCT / L. Also provided are pharmaceutical compositions containing the same, and processes for preparing said com- pounds. BACKGROUND INFORMATION Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyze the intramolecular cyclization of N-terminal glutamine (Q) resi- dues into pyroglutamic acid (pE) liberating ammonia [Stephan Schilling et al., “Identifica- tion of Human Glutaminyl Cyclase as a Metalloenzyme POTENT INHIBITION BY IMID- AZOLE DERIVATIVES AND HETEROCYCLIC CHELATORS,” Journal of BiologicalChemistry 278, no. 50 (2003): 49773–79, https: / / doi.org / 10.1074 / jbc.m309077200; HolgerCynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery,” Journal ofMolecular Biology 379, no. 5 (2008): 966–80, https: / / doi.org / 10.1016 / j.jmb.2008.03.078;Anett Stephan et al., “Mammalian Glutaminyl Cyclases and Their Isoenzymes Have Identi-cal Enzymatic Characteristics,” FEBS Journal 276, no. 22 (2009): 6522–36,https: / / doi.org / 10.1111 / j.1742-4658.2009.07337.x.]. While QPCT is a secreted protein, QPCTL is retained within the Golgi complex. Both enzymes share a high homology in the active site and similar catalytic specificity. Because of the high homology in the active site, inhibition of the active site blocks the enzymatic activity of both enzymes: QPCT and QPCTL. Hence the term “QPCT / L” describes both enzymes at once. Due to their different cellular localisation, differences in their relevance for modification of biological substrates have been reported. Known substrates of the intracellular QPCTL and / or extracellular QPCTare CD47 [Meike E. W. Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifierof the CD47- SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25,01-3588 ff-text BI International GmbH2 / 74 no. 4 (2019): 612–19, https: / / doi.org / 10.1038 / s41591-019-0356-z.], different chemokines(like for example CCL2 and 7 or CX3CL1) [Rosa Barreira da Silva et al., “Loss of the In-tracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltrationto Augment Tumor Immunity,” Nature Immunology 23, no. 4 (2022): 568–80,https: / / doi.org / 10.1038 / s41590-022-01153-x; Astrid Kehlen et al., “N-Terminal Pyrogluta- mate Formation in CX3CL1 Is Essential for Its Full Biologic Activity,” Bioscience Reports 37, no. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.], Amyloid-b pep- tides [Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention inthe Golgi Complex Suggests Involvement in the Protein Maturation Machinery.”] or hor-mones like TRH [Andreas Becker et al., “IsoQC (QPCTL) Knock-out Mice Suggest Differ-ential Substrate Conversion by Glutaminyl Cyclase Isoenzymes,” Biological Chemistry 397,no.1 (2016): 45–55, https: / / doi.org / 10.1515 / hsz-2015-0192.]. The modification of N-termi- nal glutamine to pyroglutamate on the substrates has functional consequences for the pro- teins and could impact different pathomechanisms in several diseases. CD47 is expressed on the cell surface of virtually all cells of the body, including apoptotic cells, senescent cells orcancer cells. [Meike E.W. Logtenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “TheCD47-SIRPα Immune Checkpoint,” Immunity 52, no. 5 (2020): 742–52,https: / / doi.org / 10.1016 / j.immuni.2020.04.011]. The main ligand for CD47 is signal-regula-tory protein alpha (SIRP^), an inhibitory transmembrane receptor present on myeloid cells, such as macrophages, monocytes, neutrophils, dendritic cells and others. QPCTL mediatedN-terminal pyroglutamate modification on CD47 is required for SIRP^ binding [DeborahHatherley et al., “Paired Receptor Specificity Explained by Structures of Signal RegulatoryProteins Alone and Complexed with CD47,” Molecular Cell 31, no. 2 (2008): 266–77,https: / / doi.org / 10.1016 / j.molcel.2008.05.026; Meike E. W. Logtenberg et al., “GlutaminylCyclase Is an Enzymatic Modifier of the CD47- SIRPα Axis and a Target for Cancer Immu-notherapy,” Nature Medicine 25, no. 4 (2019): 612–19, https: / / doi.org / 10.1038 / s41591-019-0356-z.] This signaling axis induces a “Don’t Eat Me Signal”, preventing engulfment ofCD47 expressing cells by macrophages. Thus, high expression of CD47 is connected to thepathogenesis of cancer [Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier ofthe CD47- SIRPα Axis and a Target for Cancer Immunotherapy,” 2019; Meike E.W. Log-tenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “The CD47-SIRPα Immune Check-point,” Immunity 52, no. 5 (2020): 742–52, https: / / doi.org / 10.1016 / j.immuni.2020.04.011.],COVID-19 [Katie-May McLaughlin et al., “A Potential Role of the CD47 / SIRPalpha Axis01-3588 ff-text BI International GmbH3 / 74in COVID-19 Pathogenesis,” Current Issues in Molecular Biology 43, no. 3 (2021): 1212–25, https: / / doi.org / 10.3390 / cimb43030086.], lung fibrosis [Gerlinde Wernig et al., “Unify-ing Mechanism for Different Fibrotic Diseases,” Proceedings of the National Academy ofSciences 114, no. 18 (2017): 4757–62, https: / / doi.org / 10.1073 / pnas.1621375114; Lu Cui etal., “Activation of JUN in Fibroblasts Promotes Pro-Fibrotic Programme and Modulates Pro-tective Immunity,” Nature Communications 11, no. 1 (2020): 2795,https: / / doi.org / 10.1038 / s41467-020-16466-4.], systemic sclerosis [Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases”; Tristan Lerbs et al., “CD47 Prevents the Elim-ination of Diseased Fibroblasts in Scleroderma,” JCI Insight 5, no. 16 (2020): e140458,https: / / doi.org / 10.1172 / jci.insight.140458.] and liver fibrosis [Taesik Gwag et al., “Anti‐CD47 Antibody Treatment Attenuates Liver Inflammation and Fibrosis in ExperimentalNon‐alcoholic Steatohepatitis Models,” Liver International 42, no. 4 (2022): 829–41,https: / / doi.org / 10.1111 / liv.15182.]. Since enhanced CD47 expression blocks the clearance of apoptotic cells, there is an accrual of apoptotic lung epithelial cells, leading to a pro-fibrotic stimulus and accelerating lung inflammation and -scaring [Alexandra L. McCubbreyand Jeffrey L. Curtis, “Efferocytosis and Lung Disease,” Chest 143, no. 6 (2013): 1750–57,https: / / doi.org / 10.1378 / chest.12-2413; Brennan D. Gerlach et al., “Efferocytosis Induces Macrophage Proliferation to Help Resolve Tissue Injury,” Cell Metabolism, 2021, https: / / doi.org / 10.1016 / j.cmet.2021.10.015.]. Since CD47 half-life and function is majorly dependent on QPCTL enzyme activity, QPCT and QPCTL inhibition could be a suitablemechanism as a treatment in lung fibrosis such as IPF or SSC-ILD [Lerbs et al., “CD47Prevents the Elimination of Diseased Fibroblasts in Scleroderma.”], alone or together with current standard of care in pulmonary fibrosis like Nintedanib [Luca Richeldi et al., “Effi- cacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis,” The New England Journalof Medicine 370, no. 22 (2014): 2071–82, https: / / doi.org / 10.1056 / nejmoa1402584; Kevin RFlaherty et al., “Nintedanib in Progressive Fibrosing Interstitial Lung Diseases,” New Eng-land Journal of Medicine 381, no. 18 (2019): 1718–27,https: / / doi.org / 10.1056 / nejmoa1908681.] or future treatments like a PDE4 inhibitor [LucaRicheldi et al., “Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmo-nary Fibrosis,” New England Journal of Medicine 386, no. 23 (2022): 2178–87,https: / / doi.org / 10.1056 / nejmoa2201737]. By expression of CD47, cancer cells can evade destruction by the immune system or evade immune surveillance, e.g. by evading phagocytosis by immune cells [Stephen B. Willingham01-3588 ff-text BI International GmbH4 / 74 et al., “The CD47-Signal Regulatory Protein Alpha (SIRPa) Interaction Is a Therapeutic Target for Human Solid Tumors,” Proceedings of the National Academy of Sciences 109,no.17 (2012): 6662–67, https: / / doi.org / 10.1073 / pnas.1121623109]. In addition to CD47, chemokines, such as CCL2 and CX3CL1, have been identified as QPCTL and / or QPCT substrates [Holger Cynis et al., “The Isoenzyme of GlutaminylCyclase Is an Important Regulator of Monocyte Infiltration under Inflammatory Condi- tions,” EMBO Molecular Medicine 3, no. 9 (2011): 545–58,https: / / doi.org / 10.1002 / emmm.201100158]. The formation of the N-terminal pGlu wasshown to increase in vivo activity, both by conferring resistance to aminopeptidases and by increasing its capacity to induce chemokine receptor signaling. Two main monocyte chem- oattractants CCL2 and CCL7 are insensitive to DPP4-inactivation in vivo because of an in- tracellular mechanism of N-terminal cyclization mediated by the Golgi-associated enzyme QPCTL. It has been shown that QPCTL is a critical regulator of monocyte migration into solid tumors [Kaspar Bresser et al., “QPCTL Regulates Macrophage and Monocyte Abun-dance and Inflammatory Signatures in the Tumor Microenvironment,” Oncoimmunology 11, no.1 (2022): 2049486, https: / / doi.org / 10.1080 / 2162402x.2022.2049486; Rosa Barreira da Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology, 2022, 1–13, https: / / doi.org / 10.1038 / s41590-022-01153-x]. Targeting of chemokines has longbeen pursued as a potential strategy for modulating cellular trafficking in different disease settings. It is therefore desirable to provide potent QPCT / L inhibitors. discloses QPCTL modulators of the general formula:which includes compound 14:01-3588 ff-text BI International GmbH5 / 74Compound 14 in WO 2023 / 205173 is disclosed therein

[0470] as having inhibitory activ- ity on isolated QPCTL of IC50< 1µM and cellular activity in A549 cells of EC50<1µM.Yu, L., Zhao, P., Sun, Y. et al. Sig Transduct Target Ther 8, 454 (2023) (herein “STTT2023”) disclose compounds QP5020 and QP5038 as potent benzonitrile-based inhibitors ofglutaminyl-peptide cyclotransferase-like protein (QPCTL) with antitumor efficacy:Compound QP5020 is disclosed therein as having QPCTL inhibition activity of IC5015.0+ / - 5.5 nM and QP5038 as having QPCTL inhibition activity of IC503.8 + / - 0.7 nM.WO 2024 / 020517 discloses inhibitors of general formula:which includes compound (1):01-3588 ff-text BI International GmbH6 / 74Compound (1) in WO 2024 / 020517 is disclosed therein

[0698] as having inhibitory activ-ity on isolated QPCTL of IC50 < 0.1µM, cellular activity in Ramos cells of IC50 <0.1µM,and inhibitory activity of DLD-1 cellular QPCTL activity in an imaging assay of < 0.1 µM. Compound (1) in WO 2024 / 020517 and QP5020 are identical. Further selected examples in WO 2024 / 020517 are:Compound 35. Inhibitory activity on isolated QPCTL of IC50 < 0.1 µM; Inhibitory activity of DLD-1 cellular QPCTL activity in an imaging assay of < 0.1 µM.Compound 44.01-3588 ff-text BI International GmbH7 / 74 Inhibitory activity on isolated QPCTL of IC50< 0.1 µM; Inhibitory activity of DLD-1 cellular QPCTL activity in an imaging assay of < 0.1 µM. LEGEND TO THE FIGURESFigure 1 – Introduction of the fluoro substituent on the piperidyl ring at the 4-positionleads to increased permeability for QPCT / L inhibitors bearing a pyrido- or benzonitrilecore.Figure 2 – Introduction of the fluoro substituent on the piperidyl ring at the 4-positionleads to decreased efflux ratio for QPCT / L inhibitors bearing a pyrido- or benzonitrilecore. DETAILED DESCRIPTION OF THE INVENTIONThe present invention discloses novel piperidinylphenylcarbonitrile derivatives of formula(I)that are inhibitors of Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), possessing appropriate pharmacological and phar- macokinetic properties enabling their use as medicaments for the treatment of conditions and / or diseases treatable by inhibition of QPCT / L.01-3588 ff-text BI International GmbH8 / 74 The compounds of the present invention may provide several advantages, such as enhanced potency, cellular potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein bind- ing, enhanced bioavailability, suitable pharmacokinetic profiles, and the possibility to form stable salts. Compounds of the inventionThe present invention provides novel piperidinylphenylcarbonitrile derivatives that surpris-ingly, are potent inhibitors of QPCT and QPCTL (Assay A), as well as potent inhibitors of QPCT / L in cells relevant for, but not limited to, lung diseases or cancer, (Assay B).Furthermore, the present novel piperidinylphenylcarbonitrile derivatives have appropriatemembrane permeability and a low in vitro efflux (Assay C).Furthermore, the compounds of the present invention have a favorable CYP induction pro- file as indicated by a low n-fold induction of CYP3A4 mRNA after incubation with the compound at 10 µM concentration (Assay D). Furthermore, the compounds of the present invention show improved stability in murine hepatocytes that facilitates preclinical compound evaluation (Assay E). Compounds of the present invention bear a fluoro substituent attached to the 4-position of the piperidyl ring (noted herein below as “4-fluoropiperidyl” in the tables), which show surprisingly higher permeability in CACO2-Cells and reduced efflux, (Assay C). This ef- fect is demonstrated with the following comparisons with the analogous non-fluoro com- pound: Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidyl1-3588 ff-text BI International GmbH9 / 74Example 133 in WO 2024 / 020517 Example 1 in EP 22188580.9CACO2 Perm. 4.8 x 10-6 cm / sec CACO2 Perm. 28.0 x 10-6 cm / secEfflux ratio (BA / AB) 3.5 Efflux ratio (BA / AB) 2.3Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylExample 18 in WO 2024 / 020517 Example 18 in EP 23161417.3CACO2 Perm. 23.0 x 10-6 cm / sec CACO2 Perm. 66.0 x 10-6 cm / secEfflux ratio (BA / AB) 3.3 Efflux ratio (BA / AB) 1.0Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylExample 132 in WO 2024 / 020517 Example 10 in EP 22188580.9CACO2 Perm. 1.8 x 10-6 cm / sec CACO2 Perm. 11.0 x 10-6 cm / secEfflux ratio (BA / AB) 7.8 Efflux ratio (BA / AB) 5.61-3588 ff-text BI International GmbH10 / 74Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylQP5020 / Example 1 in WO 2024 / 020517 Example 56 in EP 23161417.3CACO2 Perm. 28.0 x 10-6 cm / sec CACO2 Perm. 50.0 x 10-6 cm / secEfflux ratio (BA / AB) 2.4 Efflux ratio (BA / AB) 0.7Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylExample 70 in WO 2024 / 020517 Example 4 in EP 23161417.3CACO2 Perm. 9.0 x 10-6 cm / sec CACO2 Perm. 40.5 x 10-6 cm / secEfflux ratio (BA / AB) 10.4 Efflux ratio (BA / AB) 1.301-3588 ff-text BI International GmbH11 / 741-3588 ff-text BI International GmbH12 / 74Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylN N N N N N F N N N N N N N N N N N F N F F F F F F F F F F FExample 13 in EP 23189886.7 Example 4 in EP 23189886.7CACO2 Perm. 3.7 x 10-6 cm / sec CACO2 Perm. 99.5 x 10-6 cm / secEfflux ratio (BA / AB) 5.7 Efflux ratio (BA / AB) 0.6Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylN N N N N N F N N N N N N N N N N N Cl N Cl F F F F F FHitherto unpublished reference compound Example 3 in EP 23189886.7CACO2 Perm. 1.0 x 10-6 cm / sec CACO2 Perm. 47.0 x 10-6 cm / secEfflux ratio (BA / AB) 36.4 Efflux ratio (BA / AB) 1.01-3588 ff-text BI International GmbH13 / 74Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylN N N N N N F N N N N N N N N N N Cl ClExample 17 in EP 23161417.3 Example 19 in EP 23161417.3CACO2 Perm. 2.5 x 10-6 cm / sec CACO2 Perm. 18.0 x 10-6 cm / secEfflux ratio (BA / AB) 21.2 Efflux ratio (BA / AB) 4.5Compound without 4-fluoropiperidyl Compound with 4-fluoropiperidylN N N N N N F N N N N N N N N N N F F F F F FExample 32 in EP 23161417.3 Example 30 in EP 23161417.3CACO2 Perm. 0.2 x 10-6 cm / sec CACO2 Perm. 1.7 x 10-6 cm / secEfflux ratio (BA / AB) 145.8 Efflux ratio (BA / AB) 22.901-3588 ff-text BI International GmbH14 / 74Example 11 in WO 2024 / 020517 Example 52 in EP 22216126.7CACO2 Perm. 0.3 x 10-6 cm / sec CACO2 Perm. 15.0 x 10-6 cm / secEfflux ratio (BA / AB) 28.1 Efflux ratio (BA / AB) 1.1The increase in permeability in CACO2-Cells between the compared pairs of compoundsis depicted in Figure 1. The decrease in efflux between the compared pairs of compounds is depicted in Figure 2. Consequently, compounds of the present invention are more viable for human use.01-3588 ff-text BI International GmbH15 / 74 Compounds of the present invention differ structurally from Compound 14 in WO2023 / 205173 in that the triazolyl ring in the 4-position of the piperidyl ring does not containan amino substituent. Furthermore, the 4-position of the piperidyl ring is further substitutedwith fluoro. Still furthermore, the phenyl ring attached to the 1-position of the piperidyl hasfour substituents instead of three.Compounds of the present invention differ structurally from the compounds in WO 2024 / 020517 including QP5020 / Compound (1) in that the 4-position of the piperidyl ring is substituted with fluoro in addition to the triazolyl ring. Furthermore, the phenyl ring attachedto the 1-position of the piperidyl ring has four substituents, with a heteroaryl substituent atthe para-position relative to the piperidyl ring. This differs to compounds disclosed in WO 2024 / 020517 which have three substituents or a fourth heteroaryl substituent at the meta-position relative to the piperidyl ring, such as Compound 1, Compound 35 and Compound44. These structural differences between compounds of the present invention and the prior art unexpectedly lead to a favourable combination of (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells relevant for, but not limited to, lung diseases orcancer, (iii) appropriate membrane permeability and a low in vitro efflux, (iv) no or stillacceptable induction of CYP3A4 mRNA levels and (v) improved stability in murine hepato-cytes which facilitates preclinical compound evaluation and selection. Compounds of the invention are thus superior to those disclosed in the prior art in terms of the combination of the following parameters: ^potent inhibition of QPCT and QPCTL (Assay A)^ potent inhibition of QPCT / L in cells relevant for, but not limited to, lung diseasesor cancer (Assay B) ^appropriate membrane permeability and a low in vitro efflux (Assay C)^ no or still acceptable induction of CYP3A4 mRNA levels (Assay D)^ improved stability in murine hepatocytes which facilitates preclinical compoundevaluation and selection (Assay E)The present invention provides novel compounds according to formula (I)01-3588 ff-text BI International GmbH16 / 74whereinA is HOC(CH3)2C,,or a salt thereof, particularly a pharmaceutically acceptable salt thereof. Particularly preferred is the compound according to formula (I) selected from the group consisting of01-3588 ff-text BI International GmbH17 / 74Particularly preferred is the compound according to formula (I) selected from the group consisting of example 1, example 2, example 3, example 4, example 5 and example 6, ex- ample 7, example 8 and example 9as described hereinafter in EXAMPLES.01-3588 ff-text BI International GmbH18 / 74 Particularly preferred is the compound according to formula (I) selected from the groupconsisting of example 1 and example 4, as described hereinafter in EXAMPLES.Particularly preferred is the compound according to formula (I) selected from the groupconsisting of example 1, example 2, example 4, example 5 and example 6, as describedhereinafter in EXAMPLES.The present invention provides novel piperidinylpyridinylcarbonitrile derivatives of for-mula (I) that are surprisingly potent QPCT / L inhibitors. Another aspect of the invention refers to compounds according to formula (I) as surpris- ingly having potent inhibition of QPCT / L in cells relevant for, but not limited to, lung dis- eases or cancer. Another aspect of the invention refers to compounds according to formula (I) as surpris- ingly cellular potent QPCT / L inhibitors having appropriate membrane permeability, low invitro efflux and low DDI perpetrator risk due to an appropriate CYP induction profile.Another aspect of the invention refers to pharmaceutical compositions, containing at least one compound according to formula (I) optionally together with one or more inert carriers and / or diluents. A further aspect of the present invention refers to compounds according to formula (I), for the use in the prevention and / or treatment of disorders associated with QPCT / L inhibition. Another aspect of the invention refers to processes of manufacture of the compounds of the present invention. Further aspects of the present invention will become apparent to the skilled artisan directly from the foregoing and following description and the examples.01-3588 ff-text BI International GmbH19 / 74 USED TERMS AND DEFINITIONS General Definitions 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. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical hav- ing 1 to 6 carbon atoms. In general 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. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkylene" means an aryl group which is bound to a C1-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is at- tached. In case a compound of the present invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail. An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as de- fined. The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached. For example, the term "3-carboxypropyl-group" represents the following substituent:wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups:01-3588 ff-text BI International GmbH20 / 74The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The term "substituted" as used herein, means that one or more hydrogens on the designated atom are replaced by a group selected from a defined group of substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. Likewise, the term “substituted” may be used in connection with a chemical moiety instead of a single atom, e.g. “substituted alkyl”, “substituted aryl” or the like. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geo- metrical isomers (e.g. enantiomers, diastereomers, E / 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 enantio- mers exist, as well as solvates thereof such as for instance hydrates. Unless specifically indicated, also “pharmaceutically acceptable salts” as defined in more detail below shall encompass solvates thereof such as for instance hydrates. In general, substantially pure stereoisomers can be obtained according to synthetic princi- ples 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. 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.01-3588 ff-text BI International GmbH21 / 74 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 separa- tion 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 derivatiza- tion of the corresponding racemic compounds with optically active chiral auxiliary rea- gents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystal- lization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chi- ral auxiliary. 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 judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salt" 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 ororganic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, ma- leic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-ben- zenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations from ammonia,L-arginine, calcium, 2,2’-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine ,potassium, sodium and tris(hydroxymethyl)-aminomethane.01-3588 ff-text BI International GmbH22 / 74 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 meth- ods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an or- ganic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. 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 com- prise a part of the invention. The term halogen denotes fluorine, chlorine, bromine and iodine. The term "C1-n-alkyl", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-al- kyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-,H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.The term "C3-k-cycloalkyl", wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to k C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "halo" added to an "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsatu- rated) defines an alkyl, alkylene or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, prefer- ably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC-, HF2C-, F3C-.01-3588 ff-text BI International GmbH23 / 74 The term "mono-heteroaryl ring" means a monocyclic aromatic ring system, containing one or more heteroatoms selected from N, O or S, consisting of 5 to 6 ring atoms. The term "mono-heteroaryl ring" is intended to include all the possible isomeric forms. Thus, the term "mono-heteroaryl ring" includes the following exemplary structures (not de- picted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): .The term "fused bicyclic-heteroaryl ring" means a bicyclic aromatic ring system, contain- ing one or more heteroatoms selected from N, O or S, consisting of 9 to 10 ring atoms. The term "fused bicyclic-heteroaryl ring" is intended to include all the possible isomeric forms.Thus, the term "bicyclic-heteroaryl ring" includes the following exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained):01-3588 ff-text BI International GmbH24 / 74.The term phenyl refers to the radical of the following ring:.The term pyridyl refers to the radical of the following ring:.The term pyridazinyl refers to the radical of the following ring:.The term pyrimidyl refers to the radical of the following ring:.The term pyrazolyl refers to the radical of the following ring:. The term oxazolyl refers to the radical of the following ring:.The term pyrazolopyridinyl refers to the radical of the following ring:01-3588 ff-text BI International GmbH25 / 74. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one an- other. BIOLOGICAL ASSAYS Evaluation of inhibitory activity on QPCT and QPCTL Assay A: Biochemical QPCT and QPCTL Activity Assay The activity of the compounds of the invention may be demonstrated using the following biochemical enzyme activity assay: QPCT or QPCTL dependent conversion of N-terminal glutamine to pyroglutamate of CD47 was monitored via MALDI-TOF MS. Test compounds were dissolved in 100 % DMSO and serially diluted into clear 1,536-well microtiter plates. Enzymatic reactions were set up in assay buffer containing 20 mM Tris pH 7.5, 0.1 mM TCEP, 0.01% BSA, and 0.001% Tween20.2.5 µL of 2x concentrated QPCTL (in-house) or QPCT (Origine #TP700028) enzyme in assay buffer (0.5 nM final concentration, columns 1-23) or plain assay buffer (columns 24) were added to each well. The plates were incubated for 10 min in a humidified incubator at 24°C. Subsequently, 2.5 µL of CD47 peptide substrate surro- gate (19QLLFNKTKSVEFTFC33) was added to each well (final concentration: 10 µM for QPCTL / 20 µM for QPCT). The plates were mixed for 30 sec at 1,000 rpm and subse- quently incubated for 40 min in a humidified incubator at 24°C. After incubation, the enzy- matic reaction was stopped by adding 1 µL containing stable isotope labeled internal stand- ard peptide19[Pyr]LLFN(K)TKSVEFTFC33(final concentration 4.0 µM) as well as SEN177 (final concentration 10 µM). The plates were sealed with an adhesive foil, mixed for 30 s at 1,000 rpm and stored at room temperature until preparation of the MALDI tar- get plates. MALDI target plates were prepared as described previously.1 Mass spectra were acquired with a rapifleX MALDI-TOF / TOF instrument tracking the signals of the product (19[Pyr]LLFNKTKSVEFTFC33, m / z 1,787.9037) as well as internal standard01-3588 ff-text BI International GmbH26 / 74 (19[Pyr]LLFN(K)TKSVEFTFC33, m / z 1,795.9179) peptide. QPCT or QPCTL activity was monitored by calculating the ratio between product and internal standard signals followed by normalization to high (100% activity) and low (0% activity) controls. Determination ofcompound potencies was obtained by fitting the dose-response data to a four-parameter lo-gistical equation. Table 2: Biological data for compounds of the invention as obtained in Assay A. Example Inhibition of Inhibition of QPCTL: QPCT: IC50[nM] IC50[nM] 11 12 2 43 4 54 2 35 2 26 3 47 3 48 2 39 3 6Table 3: Biological data for prior art compounds as obtained in Assay A. Prior artReference Inhibition ofInhibition of Compound QPCTL: QPCT: IC50[nM] IC50[nM] Compound 14 WO 2023 / 205173 1 <1QP5038 STTT 2023 2 5Compound WO 2024 / 020517 / 27(1) / QP5020 STTT2023 Compound 35 WO 2024 / 020517 2 4Compound 44 WO 2024 / 020517 1 501-3588 ff-text BI International GmbH27 / 74Assay B: SIRP^ signalling assay (using either Raji or A549 cells)The activity of the compounds of the invention may be demonstrated using the followingSIRP^ signalling assay that measures SIRPα engagement induced by CD47 presented viacell-cell interaction. Two cell types are independently used: the Raji cell line (lymphoblast-like human cell line derived from B lymphocytes from a Burkitt’s lymphoma patient in 1963) and A549 cells (adenocarcinomic human alveolar basal epithelial cells). Test compounds were dissolved in 100 % DMSO and serially diluted into a white 384-well microtiter cell culture plate (PerkinElmer #60076780 in case of Raji assay; PDL-coated plates Greiner #781945 in case of A549 assay). 5000 Raji cells (ATCC #CC86) or 5000 A549 cells (ATCC #CCL-185) in Assay Complete Cell Plating reagent 30 (DiscoverX 93- 0563R30B) were added per well. The assay plate was incubated for 48 h at 37 °C, 95% humidity and 5 % CO2.15000 reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93- 1135C19) were added to each well, and the plate was incubated for 5 h at 37 °C, 95 % humidity and 5 % CO2. Bioassay reagent 1 of the PathHunter Bioassay detection kit (Dis-coverX 93-0001) was added to each well of the plate using a multichannel pipette followedby a 15 min incubation at room temperature. Afterwards bioassay reagent 2 was added fol- lowed by 60 min incubation at room temperature (incubation in the dark). The analysis of the data was performed using the luminescence signal generated by beta- galactosidase in the PathHunter reporter cell line. The luminescence measurement was done using a Pherastar Multi-Mode Reader. Dose-response curves & IC50data were calculated with 4-parameter sigmoidal dose response formula. Table 4: Biological data for compounds of the invention as obtained in Assay B. Example Inhibition of Inhibition of SIRPα signalling SIRPα signalling induced by Raji induced by A549 cells: cells: IC50[nM] IC50[nM] 126 882 180 363 330 4501-3588 ff-text BI International GmbH28 / 74 552 256 139 337 100 378 267 6519 108 67Table 5: Biological data for prior art compounds as obtained in Assay B. Prior artReference Inhibition ofInhibition of Compound SIRPα signalling SIRPα signalling induced by Raji induced by A549 cells: cells: IC50[nM] IC50[nM] Compound 14 WO 2023 / 205173 4 4QP5038 STTT 2023 21 6Compound WO 2024 / 020517 / 51 8(1) / QP5020 STTT2023 Compound 35 WO 2024 / 020517 28 9Compound 44 WO 2024 / 020517 121 67Evaluation of permeabilityAssay C: Permeability in CACO-2 cellsCaco-2 cells (1 - 2 x 105 cells / 1 cm2 area) are seeded on filter inserts (Costar transwell pol-ycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.Compounds are dissolved in appropriate solvent (like DMSO, 1 - 20 mM stock solutions).Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4x 7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare thetransport solutions (0.1 - 300 μM compound, final DMSO <= 0.5 %). The transport solution(TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (3 filter replicates), respectively. Samples are collected at the start and end of experiment from the donor and at various time intervals for up to 2 hours also from the receiver side for01-3588 ff-text BI International GmbH29 / 74 concentration measurement by HPLC-MS / MS or scintillation counting. Sampled receiver volumes are replaced with fresh receiver solution. Efflux ratio (ER) = permeability B-A / permeability A-B Table 7: Biological data for compounds of the invention as obtained in Assay C. Example Permeability A-B Efflux Ratio [10-6cm / s] 14.2 11.92 26.0 3.33 11.0 7.84 5.0 8.85 5.4 6.76 19.0 4.67 4.8 7.98 0.7 20.39 4.8 5.2Table 8: Biological data for prior art compounds as obtained in Assay C. Prior artReference Permeability A-BEfflux Ratio Compound [10-6cm / s] Compound 14 WO 2023 / 205173 0.7 22.2QP5038 STTT 2023 61.0 0.8Compound WO 2024 / 020517 / 28.0 2.4(1) / QP5020 STTT2023 Compound 35 WO 2024 / 020517 4.9 12.2Compound 44 WO 2024 / 020517 0.5 47.9Evaluation of CYP3A4 induction Assay D: CYP induction screening assay in primary human hepatocytes Cryopreserved plateable human hepatocytes (single donor, BioIVT) were thawed and plated in Collagen-I coated 96-well-plates at a cell density of 0.07 million cells per well.01-3588 ff-text BI International GmbH30 / 74 After a 6h attachment period, the seeding medium was replaced by serum-free William’s medium E supplemented with Matrigel (0.25 mg / ml) and allowed to recover overnight. 24h post-seeding, serum-free Williams E medium containing the test compound at a final concentration of 10 µM and a final DMSO content of 0.1% and 0.1% DMSO (solvent- treated control), respectively, was added to predefined wells. Exposure solutions were re- newed after 24h. After 48h of treatment in total, the effect of the test compounds on CYP3A4 mRNA ex- pression was assessed using the QuantiGene Plex Gene Expression Assay. Hepatocytes were lysed and total RNA was extracted using the QuantiGene Sample Processing Kit ac- cording to the instructions of the manufacturer. mRNA quantification was conducted using a customized QuantiGene Plex Panel to ana- lyse CYP3A4 and the housekeeper genes RPL32, EIF4E2 and GUSB according to the in-structions of the manufacturer and measured on a Luminex™ instrument. Signal was re-ported as median fluorescence intensity (MFI), which is proportional to the number of tar- get RNA molecules present in the sample. For calculation of CYP3A4 mRNA induction, the signal for CYP3A4 was normalized against the geometric mean of the signal obtained for the housekeeper genes for hepato- cytes exposed to test compounds in relation to solvent-treated samples according to the fol- lowing equation: n-fold induction = (MFI CYP3A4 (treated) / X̅geo MFI (RPL32,EIF4E2,GUSB)) / (MFI CYP3A4 (solvent control) / X̅geo MFI (RPL32,EIF4E2,GUSB)) Table 9: Biological data for compounds of the invention as obtained in Assay D. Example n-fold induction of CYP3A4 at 10 µM 12.22 1.63 1.74 2.05 7.76 1.801-3588 ff-text BI International GmbH31 / 74 70.78 0.99 1.4Table 10: Biological data for prior art compounds as obtained in Assay D. Prior artReference n-fold induction ofCompound CYP3A4 at 10 µM Compound 14 WO 2023 / 205173 1.9QP5038 STTT 2023 58.5Compound WO 2024 / 020517 / 3.4 (1) / QP5020 STTT 2023 Compound 35 WO 2024 / 020517 3.0Compound 44 WO 2024 / 020517 1.0Evaluation of hepatic stability (mouse) Assay E: Stability in murine hepatocytes The metabolic degradation of the test compound is assayed in a murine hepatocyte suspen- sion. Murine hepatocytes (typically cryopreserved) are incubated in an appropriate buffer system (e.g. Dulbecco´s modified eagle medium plus 3.5µg glucagon / 500mL, 2.5mg insu- lin / 500mL and 3.75mg / 500mL hydrocortison) containing 5% species serum. Following a (typically) 30 min preincubation in an incubator (37°C, 10% CO2) 5 µl of test compound solution (80 µM; from 2mM in DMSO stock solution diluted 1:25 with me- dium) are added into 395 µl hepatocyte suspension (cell density in the range 0.25-5 Mio cells / mL, typically 1 Mio cells / mL; final concentration of test compound 1µM, final DMSO concentration 0.05%). The cells are incubated for six hours (incubator, orbital shaker) and samples (25µl) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min). The supernatant is transferred to a new 96-deepwell plate, evapo- rated under nitrogen and resuspended. Decline of parent compound is analyzed by HPLC-MS / MS01-3588 ff-text BI International GmbH32 / 74 CLint is calculated as follows CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD + clast / k) x 1000 / 60. C0: initial concentration in the incubation [µM], CD: cell density of vi- tal cells [10e6cells / mL], AUD: area under the data [µM x h], clast: concentration of last data point [µM], k: slope of the regression line for parent decline [h-1]. The calculated in vitro hepatic intrinsic clearance can be scaled up to the intrinsic in vivo hepatic Clearance and used to predict hepatic in vivo blood clearance (CL) by the use of a liver model (well stirred model). CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [µL / min / 10e6cells] x hepato- cellularity [10e6 cells / g liver] x liver factor [g / kg bodyweight]) / 1000 CL [ml / min / kg] = CL_INTRINSIC_INVIVO [ml / min / kg] x hepatic blood flow [ml / min / kg] / (CL_INTRINSIC_INVIVO [ml / min / kg] + hepatic blood flow [ml / min / kg]) QH[%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg]) Hepatocellularity, mouse: 120x10e6 cells / g liver Liver factor, mouse: 55 g / kg bodyweight Blood flow, mouse: 90 ml / (min x kg) Table 12: Biological data for compounds of the invention as obtained in Assay E. Example Mouse Hepatocyte Stability QH[%] 1232 153 254 215 <126 357 488 2001-3588 ff-text BI International GmbH33 / 74 920Table 13: Biological data for prior art compounds as obtained in Assay E. Prior artReference MouseCompound Hepatocyte Stability QH[%] Compound 14 WO 2023 / 205173 31QP5038 STTT 2023 97Compound WO 2024 / 020517 / 82 (1) / QP5020 STTT 2023 Compound 35 WO 2024 / 020517 16Compound 44 WO 2024 / 020517 65Evaluation of Microsomal Clearance Microsomal clearance: The metabolic degradation of the test compound was assayed at 37 °C with pooled liver microsomes from various species. The final incubation volume of 60 μl per time point con- tains TRIS buffer pH 7.6 at room temperature (0.1 M), magnesium chloride (5 mM), micro- somal protein (1 mg / mL for human and dog, 0.5 mg / mL for other species) and the test com- pound at a final concentration of 1 μM. Following a short preincubation period at 37°C, the reactions were initiated by addition of betanicotinamide adenine dinucleotide phosphate, re- duced form (NADPH, 1 mM), and terminated by transferring an aliquot into solvent after different time points. After centrifugation (10000 g, 5 min), an aliquot of the supernatant was assayed by LC-MS / MS for the amount of parent compound. The half-life was deter- mined by the slope of the semi-logarithmic plot of the concentration-time profile. The intrinsic clearance (CL_INTRINSIC) is calculated by considering the amount of pro- tein in the incubation: CL_INTRINSIC [µl / min / mg protein] = (Ln 2 / (half-life [min] * protein content [mg / ml])) * 1000 CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [µL / min / mg protein] x MPPGL [mg protein / g liver] x liver factor [g / kg bodyweight]) / 100001-3588 ff-text BI International GmbH34 / 74 Qh [%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg]) Hepatocellularity, human: 120x10e6 cells / g liver Liver factor, human: 25.7 g / kg bodyweight Blood flow, human: 21 ml / (min x kg) Evaluation of Hepatocyte Clearance Human Hepatocyte clearance The metabolic degradation of a test compound is assayed in a human hepatocyte suspen- sion. After recovery from cryopreservation, human hepatocytes are diluted in 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, 5% human serum) to obtain a final cell density of 1.0x106cells / mL. Following a 30 minutes preincubation in a cell culture incubator (37 °C, 10 % CO2), test compound solution is spiked into the hepatocyte suspension, resulting in a final test com- pound concentration of 1 µM and a final DMSO concentration of 0.05 %. 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 96-deepwell plate, and prepared for analysis of decline of parent 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 peakarea 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 (T1 / 2). In vitro intrinsic clearance (CLint) is calculated from in vitro T1 / 2 and scaled to whole liver using a hepatocellularity of 120x106 cells / 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 / 106 cells] x hepato- cellularity [106 cells / g liver] x liver factor [g / kg body weight]) / 100001-3588 ff-text BI International GmbH35 / 74 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] / (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]) Evaluation of plasma protein binding Equilibrium dialysis technique is used to determine the approximate in vitro fractional binding of test compounds to plasma proteins applying Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consists of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound are prepared in DMSO at 1 mM and serially diluted to obtain a final test concentration of 1 µM. The subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 µl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. Aliquots of 200 µl dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7 % Dextran) are dispensed into the buffer (acceptor) chamber. Incubation is carried out for 2 hours under rotation at 37°C for establishing equilibrium. At the end of the dialysis period, aliquots obtained from donor and acceptor chambers, respectively, are transferred into reaction tubes and processed for HPLC-MS / MS analysis. Analyte concentrations are quantified in aliquots of samples by HPLC-MS / MS against calibration curves. Percent bound is calculated using the formula:%bound = (plasma concentration - buffer concentration / plasma concentration) X 100Evaluation of solubility Saturated solutions are prepared in well plates (format depends on robot) by adding an ap-propriate volume of selected aqueous media (typically in the range of 0.25 - 1.5 ml) into01-3588 ff-text BI International GmbH36 / 74 each well which contains a known quantity of solid drug substance (typically in the range0.5 - 5.0 mg). The wells are shaken or stirred for a predefined time period (typically in arange of 2 - 24 h) and then filtered using appropriate filter membranes (typically PTFE-fil-ters with 0.45 µm pore size). Filter absorption is avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance is determined by UV spectroscopy. In addition, the pH of the aqueous saturated solution is measured using a glass-electrode pH meter. Evaluation of Metabolism in human hepatocytes in vitro The metabolic pathway of a test compound is investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes are incubated in Dulbecco´s modified eagle medium containing 5% human serum and supplemented with 3.5 µg glucagon / 500ml, 2.5mg insulin / 500ml and 3.75mg / 500ml hydrocortisone. Following a 30 min preincubation in a cell culture incubator (37°C, 10% CO2), test com- pound solution is spiked into the hepatocyte suspension to obtain a final cell density of 1.0*106to 4.0*106cells / ml (depending on the metabolic turnover rate of the compound ob- served with primary human hepatocytes), a final test compound concentration of 10 µM, and a final DMSO concentration of 0.05%. The cells are incubated for six hours in a cell culture incubator on a horizontal shaker, and samples are removed from the incubation after 0, 0.5, 1, 2, 4 or 6 hours, depending on the metabolic turnover rate. Samples are quenched with acetonitrile and pelleted by centrifuga- tion. The supernatant is transferred to a 96-deepwell plate, evaporated under nitrogen and resuspended prior to bioanalysis by liquid chromatography-high resolution mass spectrom- etry for identification of putative metabolites. The structures are assigned tentatively based on Fourier-Transform-MSndata. Metabolites are reported as percentage of the parent in human hepatocyte incubation with a threshold of≥ 4%.Evaluation of pharmacokinetic characteristics The test compound is administered either intravenously or orally to the respective test spe- cies. Blood samples are taken at several time points post application of the test compound, anticoagulated and centrifuged.01-3588 ff-text BI International GmbH37 / 74The concentration of analytes - the administered compound and / or metabolites - are quanti-fied in the plasma samples. PK parameters are calculated using non compartment methods. AUC and Cmax are normalized to a dose of 1 μmol / kg. METHOD OF TREATMENT The present invention is directed to compounds of general formula (^) which are useful in the prevention and / or treatment of a disease and / or condition associated with or modulated by QPCT / L activity, including but not limited to the treatment and / or prevention of cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney diseases. The compounds of general formula (I) are useful for the prevention and / or treatment of: (1) Pulmonary fibrotic diseases such as pneumonitis or interstitial pneumonitis associated with collagenosis, e g. lupus erythematodes, systemic scleroderma, rheumatoid arthritis, polymyositis and dermatomysitis, idiopathic interstitial pneumonias, such as pulmonary lung fibrosis (IPF), non-specific interstitial pneumonia, respiratory bronchiolitis associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic orgainizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymangi- oleiomyomatosis, pulmonary alveolar proteinosis, Langerhan's cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known cause, such as interstitial pneumonitis as a result of occupational exposures such as asbestosis, silicosis, miners lung (coal dust), farmers lung (hay and mould), Pidgeon fanciers lung (birds) or other occupa- tional airbourne triggers such as metal dust or mycobacteria, or as a result of treatment such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapeutics, or for granulomatous disease, such as granulomatosis with polyangitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonitis caused by different origins, e g. aspiration, inhalation of toxic gases, vapors, bronchitis or pneumonitis or inter- stitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis, or alpha-I-antitrypsin defi- ciency. (2) Other fibrotic diseases such as hepatic bridging fibrosis, liver cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction,01-3588 ff-text BI International GmbH38 / 74 glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelotibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; spontaneous acute exacerba- tions in pulmonary fibrosis and progressive pulmonary fibrosis or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobi- opsy), air pollution, prior exacerbation and medications. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lym- phoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma (NHL), hairy cell lymphoma, Burkett’s lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid cancer, lung cancer, adenocar- cinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinum cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer, bowel cancer, small bowel cancer, large bowel cancer, colon cancer, colon adeno- carcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast can- cer, gynaecological cancer, genito-urinary cancer, ovarian cancer, endometrial cancer, cer- vical cancer, prostate cancer, testicular cancer, seminoma, teratocarcinoma, liver cancer, kidney cancer, bladder cancer, urothelial cancer, biliary tract cancer, pancreatic cancer, ex- ocrine pancreatic carcinoma, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cancer, squamous cell carci- noma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, kera- toacanthoma, bone cancer, bone sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosar- coma, thyroid gland cancer, thyroid follicular cancer, adrenal gland cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, schwannoma, glioblastoma, or sarcoma, gastrointestinal cancer, gastric cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, bowel can- cer, large bowel cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal can- cer, ovarian cancer, pancreatic cancer, exocrine pancreatic carcinoma, leukemia, acute my- eloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non- Hodgkin’s lymphoma (NHL), urothelial cancer, or peritoneal cancer. (4) Inflammatory, auto-immune or allergic diseases and conditions such as asthma, pediat- ric asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema,01-3588 ff-text BI International GmbH39 / 74 bronchitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, pulmonary emphysema; autoimmune dis- eases, such as rheumatoid arthritis, Graves’ disease, Sjogren's syndrome psoriatic arthritis, multiple sclerosis, systemic lupus Erythematosus, inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e g, necrotizing, cutaneous, and hypersensi- tivity vasculitis), or erythemanodosum. (5) Neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion diseases. Accordingly, the present invention relates to a compound of general formula (I) or a phar- maceutically acceptable salt thereof for use as a medicament. Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and / or prevention of a disease and / or condition associated with or modu- lated by QPCT / L activity. Furthermore, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment and / or prevention of cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney diseases. Furthermore, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment and / or prevention of: (1) Pulmonary fibrotic diseases such as pneumonitis or interstitial pneumonitis associated with collagenosis, e g. lupus erythematodes, systemic scleroderma, rheumatoid arthritis, polymyositis and dermatomysitis, idiopathic interstitialpneumonias, such as pulmonary lung fibrosis (IPF), non-specific interstitial pneumonia,respiratory bronchiolitis associated interstitial lung disease, desquamative interstitial pneu- monia, cryptogenic orgainizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymangioleiomyomatosis, pulmonary alveolar proteinosis,01-3588 ff-text BI International GmbH40 / 74 Langerhan's cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known cause, such as interstitial pneumonitis as a result of occupational exposures such as asbestosis, silicosis, miners lung (coal dust), farmers lung (hay and mould), Pidgeon fanciers lung (birds) or other occupational airbourne triggers such as metal dust or myco- bacteria, or as a result of treatment such as radiation, methotrexate, amiodarone, nitrofu- rantoin or chemotherapeutics, or for granulomatous disease, such as granulomatosis with polyangitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or intersti- tial pneumonitis caused by different origins, e g. aspiration, inhalation of toxic gases, va- pors, bronchitis or pneumonitis or interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis or muco- viscidosis, or alpha-I-antitrypsin deficiency. (2) Other fibrotic diseases such as hepatic bridging fibrosis, liver cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelotibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; spontaneous acute exacerba- tions in pulmonary fibrosis and progressive pulmonary fibrosis or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobi- opsy), air pollution, prior exacerbation and medications. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lym- phoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma (NHL), hairy cell lymphoma, Burkett’s lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid cancer, lung cancer, adenocar- cinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinum cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer, bowel cancer, small bowel cancer, large bowel cancer, colon cancer, colon adeno- carcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast can- cer, gynaecological cancer, genito-urinary cancer, ovarian cancer, endometrial cancer, cer- vical cancer, prostate cancer, testicular cancer, seminoma, teratocarcinoma, liver cancer, kidney cancer, bladder cancer, urothelial cancer, biliary tract cancer, pancreatic cancer, ex- ocrine pancreatic carcinoma, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cancer, squamous cell01-3588 ff-text BI International GmbH41 / 74 carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, bone sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosar- coma, thyroid gland cancer, thyroid follicular cancer, adrenal gland cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, schwannoma, glioblastoma, or sarcoma, gastrointestinal cancer, gastric cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, bowel can- cer, large bowel cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal can- cer, ovarian cancer, pancreatic cancer, exocrine pancreatic carcinoma, leukemia, acute my- eloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non- Hodgkin’s lymphoma (NHL), urothelial cancer, or peritoneal cancer. (4) Inflammatory, auto-immune or allergic diseases and conditions such as asthma, pediat- ric asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bron- chitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, pulmonary emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves’ disease, Sjogren's syndrome psoriatic arthritis, multiple scle- rosis, systemic lupus Erythematosus, inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, scleroderma; psoriasis (including T-cell mediated psoriasis) and in- flammatory dermatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e g, necrotizing, cutaneous, and hypersensitivity vasculitis), or erythemanodosum. (5) Neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion diseases. In a further aspect the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment and / or prevention of above-mentioned diseases and conditions. In a further aspect the present invention relates to the use of a compound of general for- mula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for the treatment and / or prevention of above- mentioned diseases and conditions.01-3588 ff-text BI International GmbH42 / 74 In a further aspect of the present invention the present invention relates to methods for the treatment or prevention of above-mentioned diseases and conditions, which method com- prises the administration of an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a hu- man being. COMBINATION THERAPY The compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent. According to one embodiment the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described hereinbefore, in particular associated with cancer, fibrotic diseases, Alzheimer’s diseases, atherosclerosis, infectious diseases, chronic kidney diseases and auto-immune disease. Additional therapeutic agents that are suitable for such combinations include in particular those, which, for example, potentiate the therapeutic effect of one or more active sub- stances with respect to one of the indications mentioned and / or allow the dosage of one or more active substances to be reduced. Therefore, a compound of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of chemotherapy, targeted cancer therapy, cancer immunotherapy, irradiation, antifibrotic agents, anti-tussive agents, anti- inflammatory agents, anti-atopic dermatitis, and broncho dilators. Chemotherapy is a type of cancer therapy that uses one or more chemical anti-cancer drugs, such as cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angio- genic substances and the like. Examples include folic acid (Leucovorin), 5-Fluorouracil, Irinotecan, Oxaliplatin, cis-platin Azacytidine, gemcitabine, alkylation agents, antimitotic agents, taxanes and further state-of-the-art or standard-of-care compounds. Targeted therapy is a type of cancer treatment that uses drugs to target specific genes and proteins that help cancer cells survive and grow. Targeted therapy includes agents such as inhibitors of growth factors (e.g. platelet derived growth factor (PDGF), fibroblast growthfactor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF),01-3588 ff-text BI International GmbH43 / 74 insulin-like growth factors (IGF), human epidermal growth factor (HER, e.g. HER2, HER3, HER4) and hepatocyte growth factor), tyrosine-kinases, KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinases, or MDM2. Cancer immunotherapy is a type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer. Cancer immunotherapy includes a thera- peutic antibody, such as: anti-Her2 antibody, an anti-EGFR antibody, and an anti-PDGFR antibody; an anti-GD2 (Ganglioside G2) antibody. Examples include Dinutuximab, Olara- tumab, Trastuzumab, Pertuzumab, Ertumaxomab, Cetuximab, Necitumumab, Nimotuzumab, Panitumumab, or rituximab. Cancer immunotherapy also includes a thera- peutic antibody which is a checkpoint inhibitor, such as an anti PD1, anti PD-L1 antibody or CTLA4 inhibitor. Examples include Atezolizumab, Avelumab, and Durvalumab, Ipili- mumab, nivolumab, or pembrolizumab. Cancer immunotherapy also includes agents which target (inhibit) the CD47-SIRPα signaling axis, such as agents which bind to CD47 or SIRPα. Non-limiting examples include antibodies such as anti-CD47 antibodies and anti- SIRPα antibodies, and recombinant Fc-fusion proteins such as CD47-Fc and SIRPα-Fc. Cancer immunotherapy also includes STING-targeting agent, or T cell engagers, such as blinatumomab. Antifibrotic agents are for example nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors such as roflumilast or specific PDE4b inhibitors like BI 1015550, autotaxin in- hibitors such as GLPG-1690 or BBT-877; connective tissue growth factor (CTGF) block- ing antibodies such as Pamrevlumab; B-cell activating factor receptor (BAFF-R) blocking antibodies such as Lanalumab, alpha-V / beta-6 blocking inhibitors such as BG-00011 / STX- 100, recombinant pentraxin-2 (PTX-2) such as PRM-151; c-Jun-N-terminal kinase (JNK) inhibitors such as CC-90001; galectin-3 inhibitors such as TD-139; G-protein coupled re- ceptor 84 (GPR84) inhibitors ; G-protein coupled receptor 84 / G-protein coupled receptor 40 dual inhibitors such asPBI-4050, Rho Associated Coiled-Coil Containing Protein Ki- nase 2 (ROCK2) inhibitors such as KD-025, heat shock protein 47 (HSP47) small interfer- ing RNA such as BMS-986263 / ND-L02-s0201; Wnt pathway inhibitor such as SM-04646; LD4 / PDE3 / 4 inhibitors such as Tipelukast; recombinant immuno-modulatory domains of histidyl tRNA synthetase(HARS) such as ATYR-1923, prostaglandin synthase inhibitors such as ZL-2102 / SAR-191801; 15-hydroxy-eicosapentaenoic acid (15-HEPE e.g. DS- 102); Lysyl Oxidase Like 2 (LOXL2) inhibitors such as PAT-1251, PXS-5382 / PXS-5338;01-3588 ff-text BI International GmbH44 / 74 phosphoinositide 3-kinases (PI3K) / mammalian target of rapamycin (mTOR) dual inhibi- tors such as HEC-68498; calpain inhibitors such as BLD-2660; mitogen-activated protein kinase kinase kinase (MAP3K19) inhibitors such as MG-S-2525; chitinase inhibitors such as OATD-01,mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) inhibitors such as MMI-0100; transforming growth factor beta I (TGF-beta I) small inter- fering RNA such as TRKZSO / BNC-1021; or lysophosphatidic acid receptor antagonists such as BMS986278. The dosage for the combination partners mentioned above is usually 1 / 5 of the lowest dose normally recommended up to 1 / 1 of the normally recommended dose. Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment of diseases or conditions which may be af- fected or which are mediated by QPCT / L, in particular diseases or conditions as described hereinbefore and hereinafter. In a further aspect this invention relates to a method for treating a disease or condition which can be influenced by the inhibition of QPCT / L in a patient that includes the step of administering to the patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents. In a further aspect this invention relates to the use of a compound of formula (I) or a phar- maceutically acceptable salt thereof in combination with one or more additional therapeu- tic agents for the treatment of diseases or conditions which can be influenced by the inhibi- tion of QPCT / L in a patient in need thereof. In yet another aspect the present invention relates to a method for the treatment of a disease or condition mediated by QPCT / L activity in a patient that includes the step of administer- ing to the patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically ef- fective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter.01-3588 ff-text BI International GmbH45 / 74 The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times. The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts. Consequently, in another aspect, this invention relates to a pharmaceutical composition that comprises a compound according to the invention and one or more additional thera- peutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and / or diluents. Other features and advantages of the present invention will become apparent from the fol- lowing more detailed examples which illustrate, by way of example, the principles of the invention. PREPARATION The compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as de- scribed in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. 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. Any functional groups in the starting materials or intermediates may be protected using conventional pro- tecting 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.01-3588 ff-text BI International GmbH46 / 74 The compounds according to the invention are prepared by the methods of synthesis de- scribed hereinafter in which the substituents of the general formulae have the meanings given herein before. 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 ob- tainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published meth- ods of synthesis. Abbreviations are as defined in the Examples section. Example 1 may be prepared as shown in Scheme I below.Compound (C) can be prepared by reaction of piperidines (A) with fluoro-benzonitriles (B) in the presence of a suitable base (e.g. diisopropylethylamine). The aryl bromide moietycan be transformed into the corresponding ester upon reaction with a suitable catalyst (e.g.Pd(OAc)2 + dppf) under a CO atmosphere in the presence of a suitable alcohol (e.g. meth- anol). Compound (D) may be further converted into tertiary alcohol (E) upon reaction with01-3588 ff-text BI International GmbH47 / 74 a suitable organometallic reagent (e.g. MeMgBr). The intermediate (E) is then subjected to a Suzuki-cross coupling with a fluoro-pyridine boronic acid derivative in the presence of a suitable catalyst (e.g. Pd XPhos G4) and a suitable base at elevated temperature (e.g.100 °C) to afford example 1. Examples 2-9 may be prepared as shown in Scheme II below. Scheme II:Compounds (C) can be prepared by reaction of piperidines (A) with fluoro-benzonitriles (B) in the presence of a suitable base (e.g. di-isopropylethylamine). The reaction can typi- cally be run at ambient temperature or at elevated temperature (up to 110 °C) in the pres- ence of a base (e.g. diisopropylethylamine). The intermediate (C) is then subjected to a Su- zuki-cross coupling with a hetero-aryl boronic acid derivative in the presence of a suitable catalyst (e.g. Pd(dtbpf)Cl2) and a suitable base at elevated temperature (e.g.100 °C) to af- ford compounds of general formula (F). Examples 2-9 can be obtained by Suzuki-cross coupling with a fluoro-pyridine boronic acid derivative in the presence of a suitable01-3588 ff-text BI International GmbH48 / 74 catalyst (e.g. Pd XPhos G3) and a suitable base at elevated temperature (e.g.100 °C) to af- ford examples 2-9. Compounds of formula (A) may be prepared as shown in Scheme III below: Scheme III:Compounds of formula (A) can be prepared from the corresponding piperidinyl esters (G) equipped with a suitable protecting group (PG, e.g. BOC) by treatment with a suitable hy- drazine source (e.g. N2H4*H2O) at elevated temperature (e.g.50 °C). The obtained hydra- zide (H) is then activated with DMF / DMA at elevated temperature (e.g.50 °C) and subse- quently treated with methyl amine at elevated temperature (e.g.90 °C) to yield the triazole derivative (I). Compounds of formula (A) can be obtained by cleaving the protecting group under suitable conditions (e.g. TFA). EXAMPLES Preparation The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the lit- erature of organic synthesis for example using methods described in “Comprehensive Or- ganic Transformations”, 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010, and “March’s Advanced Organic Chemistry”, 7th Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably the compounds are obtained analogously to the methods of prepara- tion explained more fully hereinafter, in particular as described in the experimental section. In some cases the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled artisan but are not described in de- tail herein may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled man on studying the schemes that01-3588 ff-text BI International GmbH49 / 74 follow. Starting compounds are 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. Before the reaction is carried out, any corresponding functional groups in the starting compounds may be protected using conventional protecting groups. These protect- ing groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man and described in the literature for example in “Protect- ing Groups”, 3rd Edition, Philip J. Kocienski, Thieme, 2005, and “Protective Groups in Organic Synthesis”, 4th Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006. The terms "ambient temperature" and "room temperature" are used inter- changeably and designate a temperature of about 20 °C, e.g. between 19 and 24 °C. Abbreviations: ACN acetonitrileAq. aqueousbrine saturated aqueous NaCl solution°C degree celsiusCyH / CH cyclohexaneCO2carbon dioxide conc. concentratedCs2CO3 cesium carbonate DCM dichloromethaneDIPA N,N-diisopropylamineDIPEA N,N-diisopropylethylamineDMF N,N-dimethylformamideDMSO dimethyl sulfoxideESI-MS Electrospray ionisation mass spectrometryEtOAc / EA ethyl acetateEtOH ethanolex exampleeq equivalentFA formic acidh hour1-3588 ff-text BI International GmbH50 / 74H2O waterHCl hydrochloric acidHPLC high performance liquid chromatographyInt. intermediateK2CO3 potassium carbonate K3PO4 tripotassium phosphateKOAc potassium acetateKOH potassium hydroxideL literLDA lithium diisopropylamideLiOH lithium hydroxideM Molar (mol / L)MeOH methanolMeTHF methyl tetrahydrofuranMgSO4 magnesium sulfatemin minutemL milliliterMTBE Methyl-tert-butyletherµL microliterN2 nitrogenn-BuLi n-ButyllithiumNBS N-BromosuccinimideNCS N-ChlorosuccinimideNa2CO3 sodium carbonate NaHCO3 sodium bicarbonate NH3ammoniaNH4Cl ammonium chlorideNaOH sodium hydroxideNa2SO4 sodium sulfate PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride Pd(dppf)Cl2 1,1'-Bis(diphenylphosphino)ferrocene palladium(II)dichloride Pd(dtbpf)Cl21,1'-Bis(di-tert-butylphosphino)ferrocene palladium(II)dichloride01-3588 ff-text BI International GmbH51 / 74 Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PE petroleum etherPrep. preparativeRP reversed phaseRT / rt room temperature (about 20°C)sat. saturatedSFC Supercritical Fluid ChromatographySiO2silica TEA triethylamineTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranXphos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate XPhos Pd G4 ((SP-4-3)-[Dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′-bi- phenyl]-2-yl-κC]palladium Preparation of intermediates Synthesis of Intermediate I.1tert‐Butyl 4‐fluoro‐4‐(hydrazinecarbonyl)piperidine‐1‐carboxylate 1‐tert‐Butyl 4‐ethyl 4‐fluoropiperidine‐1,4‐dicarboxylate (160 g, 0.58 mol) is suspended in ethanol (640 mL) in a round-bottom flask. Hydrazine hydrate (70.6 mL, 1.16 mol) is added to the mixture at ambient temperature. The reaction mixture is heated to 50 °C and stirred for 12 h. After cooling to ambient temperature, the mixture is concentrated under reduced01-3588 ff-text BI International GmbH52 / 74 pressure to yield tert‐butyl 4‐fluoro‐4‐(hydrazinecarbonyl)piperidine‐1‐carboxylate in 80% purity. C11H20FN3O3 (M = 261.3 g / mol) ESI-MS: 284 [M+Na]+Rt (HPLC): 0.62 min (method A)tert‐Butyl 4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidine‐1‐carboxylate tert‐Butyl 4‐fluoro‐4‐(hydrazinecarbonyl)piperidine‐1‐carboxylate (135 g, 0.413 mol, 80% purity) is mixed with dioxane (945 mL) in a round-bottom-flask.Dimethylformamid- dimethylacetal (137 mL, 1.03 mol) is added to the mixture at ambient temperature. The re- action mixture is heated to 50 °C and stirred for 1 h. A solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) are added into the mixture. The resulting reaction mixture is heated to 90 °C and stirred for 11 h. After cooling to ambient temperature, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / EtOAc gradient 20:1 to 0:1) to obtain tert‐butyl 4‐fluoro‐ 4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidine‐1‐carboxylate. C13H21FN4O2 (M=284.3 g / mol)ESI-MS: 285 [M+H]+Rt (HPLC): 0.77 min (method A)Intermediate I.1: 4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidine tert‐Butyl 4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidine‐1‐carboxylate (90 g, 0.32 mol) is combined with methanol (90 mL) in a round-bottom flask. A solution of HCl (4 m in MeOH, 450 mL, 1.8 mol) is added slowly at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 12 h. The desired product is collected by filtra- tion, washed with methanol, and dried to yield 4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐ yl)piperidine hydrochloride salt. The hydrochloride salt (13.5 g) is added to a solution of ammonia in methanol (7 M, 150 mL) and purified by column chromatography (Biotage SNAP Cartridge KP-NH 110 g, gra- dient DCM / MeOH 4:1 to 7:3) to afford the title compound. C8H13FN4 (M=184.2 g / mol)ESI-MS: 185 [M+H]+Rt (HPLC): 0.20 min (method B)01-3588 ff-text BI International GmbH53 / 74 Intermediate II.1: 5‐bromo‐3‐chloro‐2‐fluorobenzonitrileInt. II.1 (5-bromo-3-chloro-2-fluorobenzonitrile) was obtained from commercial suppliers (CAS: 1000577-76-3). Intermediate III.1: 5‐bromo‐3‐chloro‐2‐[4‐fluoro‐4‐(4‐methyl‐4H‐ 1,2,4‐triazol‐3‐yl)piperidin‐1‐yl]benzonitrileInt. II.1 (1.5 g, 6.21 mmol) is suspended in a mixture of DMSO (10.0 mL) and DIPEA (2.1mL, 12.4 mmol) and Int. I.1 (1.5 g, 6.21 mmol) is added. The resulting reaction mixture is stirred at 50 °C for 86 h. The reaction mixture is cooled to 5°C before water (5 mL) is addedand the mixture is stirred for another 30 min. The precipitated solid is collected by filtration,washed with water and dried to afford the desired compound.C15H4BrClFN5(M=398.7 g / mol)ESI-MS: 398 / 400 [M+H]+Rt (HPLC): 0.69 min (method B)01-3588 ff-text BI International GmbH54 / 74 Synthesis of Intermediate V.1: 3‐chloro‐2‐[4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidin‐1‐yl]‐5‐(2‐hydroxy- propan‐2‐yl)benzonitrileInt. III.1 Int. IV.1 Int. V.1Intermediate IV.1 To a mixture of Int. III.1 (2.8 g, 7.02 mmol) in MeOH (10 mL) and 1,4-dioxane (10 mL) in a high-pressure reaction vessel is added Pd(OAc)2 (306 mg, 1.36 mmol), 1,1’-bis(diphe- nylphosphino)ferrocene (389 mg, 0.702 mmol) and sodium acetate (1.53 g, 18.6 mmol). A CO pressure of 8 bar is applied and the reaction mixture stirred at 60°C for 24 h. After cooling to ambient temperature and releasing the pressure, the mixture is concentrated, sus- pended in DMF and purified by preparative HPLC (Zorbax StableBond C18, MeCN / water gradient containing 0.3% TFA). C17H17ClFN5O2(M=377.8 g / mol)ESI-MS: 378 [M+H]+Rt (HPLC): 0.86 min (method C)Intermediate V.1 To a mixture of Int. IV.1 (50 mg, 132 µmol) in THF (4.0 mL) is added a solution of methyl- magnesium bromide (3.2 M in THF, 0.097 mL, 291 µmol) at 0 °C under vigorous stirring. The reaction mixture is warmed to ambient temperature and stirred for 2 h. The mixture is concentrated and the residue purified by column chromatography (SiO2, EtOAc / MeOH gra- dient) to yield the title compound.C18H21ClFN5O (M=377.8 g / mol)ESI-MS: 378 [M+H]+Rt (HPLC): 0.79 min (method D)01-3588 ff-text BI International GmbH55 / 74 Synthesis of Intermediate V.2: 3‐chloro‐2‐[4‐fluoro‐4‐(4‐methyl‐4H‐1,2,4‐triazol‐3‐yl)piperidin‐1‐yl]‐5‐(2‐methyl‐1,3‐ oxazol‐5‐yl)benzonitrileInt. III.1 Int. V.2To a mixture of Int. III.1 (100 mg, 251 µmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-diox- aborolan-2-yl)oxazole (66.2 mg, 301 µmol) in 1,4-dioxane (3.0 mL) is added a solution ofpotassium carbonate (2 M in water, 376 µL, 753 µmol). The resulting mixture is purged bypassing an argon stream through the mixture for 5 min. Pd(dtbpf)Cl2 (16.3 mg, 25.1 µmol) is added, and the mixture is further purged for 2 min. The reaction mixture is stirred at 85 °C for 18 h. After cooling to ambient temperature, the mixture is diluted with acetonitrile and filtered. The filtrate is purified by preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% NH3) to yield the title compound.C19H18ClFN6O (M=400.8 g / mol)ESI-MS: 401 [M+H]+Rt (HPLC): 0.84 min (method E)01-3588 ff-text BI International GmbH56 / 74 Intermediates synthesized analogous to the procedure described for Int. V.1 Molecular For- mula (MW) Starting Deviation from Int. Structure ESI-MS material general procedure HPLC retention time (method) C21H23ClFN7Int. III.1 (M=427.9 + g / mol) (1,3,5-tri- ESI-MS: V.3 methyl-1H- - 428 [M+H]+pyrazol-4- Rt (HPLC): 0.85 yl)boronic min acid (method E) Int. III.1 + C20H21ClFN7 1,3-dime- (M=413.9 thyl-4- g / mol) (4,4,5,5-tet- ESI-MS: V.4 - ramethyl- 414 [M+H]+1,3,2-diox- Rt (HPLC): 0.60 aborolan-2- min yl)-1H-py- (method B) razole Pd(dtbpf)Cl2 and boronic acid were C19H19ClFN7 Int. III.1 added again after (M=399.9 + 18 h at 80 °C; g / mol) 1-Methyl- stirred again for ESI-MS: V.5 1H pyra- 18 h at 80 °C. pu- 400 [M+H]+zole-4-bo- rification by pre- Rt (HPLC): 0.69 ronic acid parative HPLC min (Sunfire C18, (method F) MeCN / water-3588 ff-text BI International GmbH57 / 74 gradient contain- ing 0.1% TFA) Int. III.1 C20H18ClFN6 + Purified by pre- (M=396.9 3-(4,4,5,5- parative HPLC g / mol) tetrame- (Sunfire C18, ESI-MS: V.6 thyl-1,3,2- MeCN / water gra- 397 [M+H]+dioxaboro- dient containing Rt (HPLC): 0.52 lan-2- 0.1% TFA) min yl)pyridine (method F) C20H19ClFN7 Int. III.1 (M=411.9 + g / mol) (2- ESI-MS: V.7 methylpy- - 412 [M+H]+rimidin-5- Rt (HPLC): 0.79 yl)boronic min acid (method E) Int. III.1 C19H17ClFN7 + (M=397.8 4-(4,4,5,5- g / mol) tetrame- ESI-MS: V.8 thyl-1,3,2- - 398 [M+H]+dioxaboro- Rt (HPLC): 0.73 lan-2- min yl)pyri- (method E) dazine01-3588 ff-text BI International GmbH58 / 74 Int. III.1 C20H16ClF4N7+ Purified by pre- (M=465.8 (2-(trifluo- parative HPLC g / mol) rome- (Sunfire C18, ESI-MS: V.9 thyl)pyrim- MeCN / water con- 466 [M+H]+idin-5- taining 0.1% Rt (HPLC): 0.88 yl)boronic TFA) min acid (method F) Preparation of Final Compounds Example 1To a mixture of Int. V.1 (35.0 mg, 92.6 µmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (32.3 mg, 0.139 mmol) in 1,4-dioxane (1 mL) is added a solution of potassium carbonate (2 M in water, 139 µL, 0.278 mmol). The resulting mixture is purged by passing an argon stream through the mixture. XPhos Pd G4 ((SP-4-3)-[Dicyclo- hexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2′- (methylamino-κN)[1,1′-biphenyl]-2-yl-κC]palladium, CAS: 1599466-81-5) (4.1 mg, 4.6 µmol) is added, and the mixture is further purged with argon. The reaction mixture is stirred at 100 °C for 5 h. After cooling to ambient temperature, the mixture is concentrated and purified by column chromatography (SiO2, EtOAc / MeOH gradient) to yield the title com- pound.01-3588 ff-text BI International GmbH59 / 74 Example 2To a mixture of Int. V.2 (26.0 mg, 64.8 µmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (20.7 mg, 90.8 µmol) in 1,4-dioxane (1.5 mL) is added a solution of sodium carbonate (2 M in water, 81.1 µL, 0.162 mmol). The resulting mixture is purged by passing an argon stream through the mixture. XPhos Pd G3 ((2-Dicyclohexylphosphino- 2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesul-fonate, CAS: 1445085-55-1) (4.1 mg, 4.9 µmol) is added, and the mixture is further purgedwith argon for 5 min. The reaction mixture is stirred at 95 °C for 12 h. After cooling to ambient temperature, the mixture is diluted with an ACN / water mixture, filtered, and puri- fied by preparative HPLC (Sunfire C18 column, ACN / water gradient containing 0.1% TFA) to yield the title compound.01-3588 ff-text BI International GmbH60 / 74 Examples synthesized analogous to the procedure described for Example 2 Deviation from general example Starting materials Structureprocedure V.3 + 2-fluoro-5-(4,4,5,5- 3 - tetramethyl-1,3,2-di- oxaborolan-2-yl)pyr- idine V.4 4 h at 95 °C; + Purification by prepara- 2-fluoro-5-(4,4,5,5- tive HPLC (X-Bridge 4 tetramethyl-1,3,2-di- C18, MeCN / water gra- oxaborolan-2-yl)pyr- dient containing 0.1% idine NH3) V.5 4 h at 95 °C; + Purification by prepara- 2-fluoro-5-(4,4,5,5- tive HPLC (X-Bridge 5 tetramethyl-1,3,2-di- C18, MeCN / water gra- oxaborolan-2-yl)pyr- dient containing 0.1% idine NH3)-3588 ff-text BI International GmbH61 / 74 V.6 + 2-fluoro-5-(4,4,5,5- 6 3.5 eq. Na2CO3solution tetramethyl-1,3,2-di- oxaborolan-2-yl)pyr- idine V.7 + 3.5 eq. Na2CO3 solu- 2-fluoro-5-(4,4,5,5- 7 tion; tetramethyl-1,3,2-di- 22 h at 95 °C. oxaborolan-2-yl)pyr- idine V.8 + 3.5 eq. Na2CO3solu- 2-fluoro-5-(4,4,5,5- 8 tion; tetramethyl-1,3,2-di- 22 h at 95 °C. oxaborolan-2-yl)pyr- idine01-3588 ff-text BI International GmbH62 / 74 V.9 + 3.5 eq. Na2CO3 solu- 2-fluoro-5-(4,4,5,5- 9 tion; tetramethyl-1,3,2-di- 22 h at 95 °C. oxaborolan-2-yl)pyr- idine Analytical data of synthesized examples Molecular Formula (MW)1H NMR (400 MHz, example StructureESI-MS DMSO-d6): δ in ppmHPLC retention time (method) 8.47 (s, 1 H), 8.30 (d, J=2.4 Hz, 1 H), 8.08 (td, J=8.2, 2.5 Hz, 1 H), C23H24F2N6O 7.83 (d, J=2.3 Hz, 1 H), (M=438.5 g / mol) 7.62 (d, J=2.3 Hz, 1 H), ESI-MS: 7.30 (dd, J=8.4, 2.7 Hz, 1 439 [M+H]+1 H), 5.23 (s, 1 H), 3.72 Rt (HPLC): 0.81 min (d, J=1.5 Hz, 3 H), 3.13 (method D)- 3.26 (m, 2 H), 3.04 -3.12 (m, 2 H), 2.00 - 2.21 (m, 4 H), 1.45 (s, 6 H)-3588 ff-text BI International GmbH63 / 74 8.56 (s, 1 H), 8.36 (d, J=2.5 Hz, 1 H), 8.13 (td, J=8.2, 2.5 Hz, 1 H), C24H21F2N7O 8.09 (d, J=2.2 Hz, 1 H), (M=461.5 g / mol) 7.82 (d, J=2.2 Hz, 1 H), ESI-MS: 2 7.65 (s, 1 H), 7.34 (dd, 462 [M+H]+J=8.5, 2.7 Hz, 1 H), Rt (HPLC): 0.69 min 3.73 (d, J=1.5 Hz, 3 H), (method G) 3.10 - 3.25 (m, 4 H),2.47 (s, 3 H), 2.02 - 2.22(m, 4 H) 8.62 (s, 1 H), 8.34 (d, J=2.4 Hz, 1 H), 8.12 (td, J=8.2, 2.5 Hz, 1 H), C26H26F2N8 7.68 (d, J=2.2 Hz, 1 H), (M=488.5 g / mol) 7.42 (d, J=2.2 Hz, 1 H), ESI-MS: 3+7.31 (dd, J=8.4, 2.6 Hz, 489 [M+H] 1 H), 3.75 (d, J=1.6 Hz, Rt (HPLC): 0.65 min 3 H), 3.70 (s, 3 H), 3.09 (method G) -3.28 (m, 4 H), 2.25 (s,3 H), 2.05 - 2.21 (m, 7H) 8.48 (s, 1 H), 8.36 (d, J=2.4 Hz, 1 H), 8.14 (td, J=8.2, 2.5 Hz, 1 H), C25H24F2N88.04 (s, 1 H), 7.82 (d, (M=474.5 g / mol) J=2.3 Hz, 1 H), 7.60 (d, ESI-MS: J=2.3 Hz, 1 H), 7.32 4 475 [M+H]+(dd, J=8.5, 2.7 Hz, 1 H), Rt (HPLC): 0.58 min 3.78 (s, 3 H), 3.73 (d, (method B) J=1.6 Hz, 3 H), 3.15 - 3.27 (m, 2 H), 3.07 - 3.14 (m, 2 H), 2.32 (s, 3 H), 2.01 - 2.21 (m, 4 H)-3588 ff-text BI International GmbH64 / 74 8.48 (s, 1 H), 8.36 (d, J=2.4 Hz, 1 H), 8.28 (s, 1 H), 8.13 (td, J=8.2, 2.5 Hz, 1 H), 8.04 (d, J=2.3 C24H22F2N8Hz, 1 H), 8.00 (d, J=0.6 (M=460.5 g / mol) Hz, 1 H), 7.80 (d, J=2.2 ESI-MS: 5+Hz, 1 H), 7.33 (dd, 461 [M+H] J=8.4, 2.6 Hz, 1 H), Rt (HPLC): 0.57 min 3.86 (s, 3 H), 3.73 (d, (method B) J=1.6 Hz, 3 H), 3.15 - 3.26 (m, 2 H), 3.05 - 3.14 (m, 2 H), 1.99 - 2.20 (m, 4 H) 9.18 (d, J=2.2 Hz, 1 H), 8.74 (dd, J=5.1, 1.2 Hz, 1H), 8.55 - 8.60 (m, 2H), 8.43 (d, J=2.4 Hz, 1 C25H21F2N7 H), 8.32 (d, J=2.3 Hz, 1 (M=457.5 g / mol) H), 8.18 (td, J=8.2, 2.5 ESI-MS: 6 Hz, 1 H), 8.03 (d, J=2.3 458 [M+H]+Hz, 1 H), 7.79 (dd, Rt (HPLC): 0.47 min J=8.1, 5.2 Hz, 1 H), (method G) 7.36 (dd, J=8.5, 2.7 Hz, 1 H), 3.75 (d, J=1.5 Hz, 3H), 3.14 - 3.28 (m, 4H), 2.07 - 2.27 (m, 4 H)9.14 (s, 2 H), 8.60 (s, 1 H), 8.41 (d, J=2.4 Hz, 1 C25H22F2N8 H), 8.31 (d, J=2.4 Hz, 1 (M=472.5 g / mol) H), 8.17 (td, J=8.2, 2.5 ESI-MS: 7+Hz, 1 H), 8.02 (d, J=2.3 473 [M+H] Hz, 1 H), 7.35 (dd, Rt (HPLC): 0.46 min J=8.5, 2.7 Hz, 1 H), (method H) 3.75 (d, J=1.5 Hz, 3 H), 3.12 - 3.28 (m, 4 H),01-3588 ff-text BI International GmbH65 / 74 2.67 (s, 3 H), 2.05 - 2.24(m, 4 H) 9.76 (dd, J=2.5, 1.1 Hz, 1 H), 9.29 (dd, J=5.6, 1.1 Hz, 1 H), 8.48 (s, 1 C24H20F2N8H), 8.47 (d, J=2.4 Hz, 1 (M=458.5 g / mol) H), 8.43 (d, J=2.4 Hz, 1 ESI-MS: H), 8.18 (td, J=8.3, 2.6 8 459 [M+H]+Hz, 1 H), 8.13 - 8.15 (m,Rt (HPLC): 0.40 min 2 H), 7.36 (dd, J=8.5, (method H) 2.7 Hz, 1 H), 3.73 (d, J=1.6 Hz, 3 H), 3.16 - 3.25 (m, 4 H), 2.08 - 2.25 (m, 4 H) 9.51 (s, 2 H), 8.54 (s, 1 H), 8.45 (d, J=2.3 Hz, 1 C25H19F5N8 H), 8.43 (d, J=2.4 Hz, 1 (M=526.5 g / mol) H), 8.18 (td, J=8.2, 2.5 ESI-MS: Hz, 1 H), 8.15 (d, J=2.4 9 527 [M+H]+Hz, 1 H), 7.37 (dd, Rt (HPLC): 0.59 min J=8.4, 2.6 Hz, 1 H), (method H) 3.74 (d, J=1.5 Hz, 3 H), 3.12 - 3.31 (m, 4 H),2.08 - 2.26 (m, 4 H)Analytical HPLC methods Method A Vol% water Vol% ACN Flow time (min) (incl.0.04% TFA) (incl.0.02% TFA) [mL / min] 0.00 95 5 1.50.70 5 95 1.51.16 5 95 1.501-3588 ff-text BI International GmbH66 / 74 1.50 95 5 1.5Analytical column: Kinetex EVO C18_2.1 x 30 mm_5 μm; column temperature: 40°C Method B Vol% water Flow time (min) Vol% ACN (incl.0.1% NH3) [mL / min] 0.00 95 5 1.30.02 95 5 1.31.00 0 100 1.31.30 0 100 1.3Device description: Waters Acquity; Analytical column: XBridge (Waters) BEH C18_2.1 x 30 mm_2.5µm; column temperature: 60°C Method C Vol% water Flow time (min) Vol% ACN (incl.0.1% TFA) [mL / min] 0.00 97 3 2.20.20 97 3 2.21.20 0 100 2.21.25 0 100 3.01.40 0 100 3.0Device description: Agilent 1200; Analytical column: Zorbax (Agilent) StableBondC18_3.0 x 30 mm_1.8 µm; column temperature: 60 °CMethod D Vol% water Flow time (min) Vol% ACN (incl.0.1% FA) [mL / min] 0.00 97 3 2.20.20 97 3 2.21.20 0 100 2.201-3588 ff-text BI International GmbH67 / 74 1.25 0 100 3.01.40 0 100 3.0Device description: Agilent 1200; Analytical column: Sunfire C18_3.0 x 30 mm_2.5μm;column temperature: 60°C Method E Vol% water Flow time (min) Vol% ACN (incl.0.1% NH3) [mL / min] 0.00 97 3 2.20.20 97 3 2.21.20 0 100 2.21.25 0 100 3.01.40 0 100 3.0Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0 x 30mm_2.5 µm; column temperature: 60°C Method F Vol% water Flow time (min) Vol% ACN (incl.0.1% TFA) [mL / min] 0.00 95 5 1.51.30 0 100 1.51.50 0 100 1.5Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30mm_2.5 µm; column temperature: 60°C Method G Vol% waterVol% ACN (incl.Flow time (min) (incl.0.1%TFA) 0.08% TFA) [mL / min] 0.00 95 5 1.51.30 0 100 1.51.50 0 100 1.51.60 95 5 1.51-3588 ff-text BI International GmbH68 / 74Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30mm_2.5 μm; column temperature: 60°C Method H Vol% water Flow time (min) Vol% ACN (incl.0.1% TFA) [mL / min] 0.00 99 1 1.60.02 99 1 1.61.00 0 100 1.61.10 0 100 1.6Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1 x 30 mm_1.7µm; column temperature: 60°C

Claims

AMENDED CLAIMS received by the International Bureau on 01 July 2025 (01.07.2025)WHAT IS CLAIMED1. A compound selected from the group consisting ofor a salt thereof.

2. A pharmaceutically acceptable salt of a compound according to claim 1.

3. A pharmaceutical composition comprising one or more compounds according to claim 1, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

4. A pharmaceutical composition comprising one or more compounds according to claim 1, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

5. The pharmaceutical composition according to claim 4 wherein the one or more additional therapeutic agents are selected from the group consisting of anticancer agents and antifibrotic agents.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

7. A method for the treatment of diseases, such as cancer or fibrotic diseases, and conditions associated with these diseases, in a patient in need thereof, the method being characterized in that one or more compounds according to claim 1 or pharmaceutically acceptable salts thereof are administered to the patient.

8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method for the treatment of cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, or chronic kidney diseases.

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