Piperidinylpyridinylcarbonitrile derivatives as inhibitors of glutaminyl-peptide cyclotransferase and glutaminyl-peptide cyclotransferase-like proteins

Abstract

The present disclosure provides certain piperidinylpyridinylcarbonitrile derivatives, and pharmaceutically acceptable salts thereof, which are inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like proteins (QPCTL), and are therefore useful in treating diseases treatable by inhibition of QPCT / L. Pharmaceutical compositions containing them and methods for preparing the compounds are also provided.

Description

[Technical Field]

[0001] The present disclosure provides certain piperidinylpyridinylcarbonitrile derivatives and pharmaceutically acceptable salts thereof, which are inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like proteins (QPCTL), and are therefore useful in treating diseases treatable by inhibition of QPCT / L. Pharmaceutical compositions containing them and methods for preparing the compounds are also provided. [Background technology]

[0002] Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like proteins (QPCTL) catalyze the intramolecular cyclization of N-terminal glutamine (Q) residues to pyroglutamic acid (pE), liberating ammonia [Stephan Schilling et al., “Identification of Human Glutaminyl Cyclase as a Metalloenzyme: Potent Inhibition by Imidazole Derivatives and Heterocytic Chelators,” Journal of Biological Chemistry 278, no. 50 (2003): 49773-79, https: / / doi.org / 10.1074 / jbc.m309077200; Holger Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Anett Stephan et al., “Mammalian Glutaminyl Cyclases and Their Isoenzymes Have Identical Enzymatic Characteristics,” FEBS Journal 276, no. 22 (2009): 6522-36, https: / / doi.org / 10.1111 / j.1742-4658.2009.07337.x.]. QPCT is a secreted protein, whereas QPCTL is retained within the Golgi complex. Both enzymes share high homology in the active site and similar catalytic specificity. Due to the high homology in the active site, inhibition of the active site blocks the enzymatic activity of both enzymes: QPCT and QPCTL. Therefore, the term "QPCT / L" describes both enzymes at once. Due to the different cellular localizations, differences in the relevance of modification of biological substrates have been reported. Known substrates of intracellular QPCTL and / or extracellular QPCT include CD47 [Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612-19, https: / / doi.org / 10.1038 / s41591-019-0356-z.], various chemokines (e.g., CCL2 and 7 or CX3CL1) [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 23, no. 4 (2022): 568-80, https: / / doi.org / 10.1038 / s41590-022-01153-x; Astrid Kehlen et al., “N-Terminal Pyroglutamate Formation in CX3CL1 Is Essential for Its Full Biological Activity,” Bioscience Reports 37, no. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.], amyloid-b peptide [Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery.”] or hormones such as TRH [Andreas Becker et al., “IsoQC (QPCTL) Knock-out Mice Suggest Differential 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 the N-terminal glutamine to pyroglutamate in the substrate has functional consequences for the protein and can affect various pathological mechanisms in several diseases. CD47 is expressed on the cell surface of virtually all cells in the body, including apoptotic, senescent, and cancer cells [Meike EW Logtenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “The CD47-SIRPα Immune Checkpoint,” Immunity 52, no. 5 (2020): 742–52, https: / / doi.org / 10.1016 / j.immuni.2020.04.011]. The primary ligand for CD47 is signal-regulatory protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells, such as macrophages, monocytes, neutrophils, and dendritic cells. QPCTL-mediated N-terminal pyroglutamate modification on CD47 is required for SIRPα binding [Deborah Hatherley et al., “Paired Receptor Specificity Explained by Structures of Signal Regulatory Proteins Alone and Complexed with CD47,” Molecular Cell 31, no.2 (2008): 266-77, https: / / doi.org / 10.1016 / j.molcel.2008.05.026; Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” 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 macrophages from phagocytizing CD47-expressing cells. Therefore, high expression of CD47 is associated with cancer [Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47- SIRPα Axis and a Target for Cancer Immunotherapy,” 2019; Meike EW Logtenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “The CD47-SIRPα Immune Checkpoint,” 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 Axis in COVID-19 Pathogenesis,” Current Issues in Molecular Biology 43, no. 3 (2021): 1212-25, https: / / doi.org / 10.3390 / cimb43030086.], pulmonary fibrosis [Gerlinde Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases,” Proceedings of the National Academy of Sciences 114, no. 18 (2017): 4757-62, https: / / doi.org / 10.1073 / pnas.1621375114; Lu Cui et al., “Activation of JUN in Fibroblasts Promotes Pro-Fibrotic Programme and Modulates Protective 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 Elimination 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 Experimental Non-alcoholic Steatohepatitis Models,” Liver International 42, no. 4 (2022): 829-41, https: / / doi.org / 10.1111 / liv.15182.]. Increased CD47 expression blocks the clearance of apoptotic cells, leading to profibrotic stimuli and the generation of apoptotic lung epithelial cells that accelerate lung inflammation and scarring [Alexandra L.McCubbrey and 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.]. Because CD47 half-life and function depend primarily on QPCTL enzymatic activity, QPCT and QPCTL inhibition may be used as a treatment in pulmonary fibrosis, such as IPF or SSC-ILD [Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma.”], either alone or in conjunction with current standards of care in pulmonary fibrosis, such as nintedanib [Luca Richeldi et al., “Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis,” The New England Journal of Medicine 370, no. 22 (2014): 2071-82, https: / / doi.org / 10.1056 / nejmoa1402584; Kevin R Flaherty et al., “Nintedanib in Progressive Fibrosing Interstitial Lung Diseases,” New England Journal of Medicine 381, no. 18 (2019): 1718-27, https: / / doi.org / 10.1056 / nejmoa1908681.], or as future treatments such as PDE4 inhibitors [Luca Richeldi et al., “Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis,” New England Journal of Medicine 386, no. 23 (2022): 2178-87, https: / / doi.org / 10.1056 / nejmoa2201737] may be a suitable mechanism. Expression of CD47 allows cancer cells to avoid destruction by the immune system or to evade immune surveillance, for example, by avoiding phagocytosis by immune cells [Stephen B. Willingham 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].

[0003] 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 Glutaminyl Cyclase Is an Important Regulator of Monocyte Infiltration under Inflammatory Conditions,” EMBO Molecular Medicine 3, no. 9 (2011): 545–58, https: / / doi.org / 10.1002 / emmm.201100158]. Formation of N-terminal pGlu has been shown to enhance in vivo activity by both conferring resistance to aminopeptidases and increasing their ability to induce chemokine receptor signaling. Two major monocyte chemoattractants, CCL2 and CCL7, are insensitive to DPP4-inactivation in vivo due to an intracellular mechanism of N-terminal cyclization mediated by the Golgi-associated enzyme QPCTL. QPCTLs have been shown to be critical regulators of monocyte migration into solid tumors [Kaspar Bresser et al., “QPCTL Regulates Macrophage and Monocyte Abundance 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 chemokines has been pursued as a potential strategy to modulate cell trafficking in a variety of disease settings.

[0004] Therefore, it is desirable to provide a potent QPCT / L inhibitor. Jimenez-Sanchez, et al., Nature Chemical Biology, 2015, 11, 347-357 (hereinafter referred to as "JS, NCB 2015"), describes human glutaminyl cyclase (hQC) inhibitors SEN177 and SEN180:

[0005] [ka] (Supplementary Information), where SEN177 had an IC50 of 53 nM for isolated hQC and 13 nM for isolated QPCTL. 50 There (Supplementary Information), SEN180 was disclosed to have an IC of 170 nM for hQC and 58 nM for QPCTL. 50 It is disclosed to have:

[0006] Pozzi, C, et al, Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226 (hereinafter "P, JBIC 2018") further discloses SEN177 and its binding mode within the cavity of hQC, where SEN177 has a K of 20 nM for isolated hQC. i It is disclosed to have:

[0007] WO 2018 / 178384 discloses QPCTL inhibitors of the general formula ABDE, including examples 1094 and 1095 (formula (XIIa) on page 123 and table on page 125).

[0008] [ka] WO 2018 / 178384 does not disclose any biological data for either Examples 1094 or 1095. Summary of the Invention

[0009] The present invention discloses novel piperidinylpyridinylcarbonitrile derivatives of formula (I), which are inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like proteins (QPCTL), possessing suitable pharmacological and pharmacokinetic properties, allowing their use as medicines for treating conditions and / or diseases treatable by inhibition of QPCT / L.

[0010] [ka] (I)

[0011] The compounds of the present invention may offer several advantages, such as improved potency, cellular efficacy, increased metabolic and / or chemical stability, increased selectivity, safety and tolerability, improved solubility, improved permeability, desirable plasma protein binding, improved bioavailability, favorable pharmacokinetic profiles, and the ability to form stable salts. DETAILED DESCRIPTION OF THE INVENTION

[0012] Compounds of the Invention The present invention provides novel piperidinylpyridinylcarbonitrile derivatives, which are surprisingly potent inhibitors of QPCT and QPCTL (Assay A) and also of QPCT / L in cells relevant to, but not limited to, lung disease or cancer (Assay B). Furthermore, this novel piperidinylpyridinylcarbonitrile derivative has suitable membrane permeability and low in vitro efflux (Assay C). As a result, the compounds of the present invention are highly viable for human use.

[0013] The compounds of the present invention are structurally different from SEN177 of Pozzi, C, et al, Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226, in that the pyridinyl ring attached to the piperidinyl ring contains a ring nitrogen in one of two meta positions relative to the piperidinyl ring attachment position. Furthermore, a carbonitrile substituent is attached to the pyridinyl ring in an ortho position relative to the piperidinyl ring attachment position. Furthermore, R 1 and R 2 is not limited to hydrogen or methyl, and A represents a heterocyclic ring system beyond pyridinyl. The compounds of the present invention differ structurally from Examples 1094 and 1095 in WO 2018 / 178384 in that the pyridinyl ring attached to the piperidinyl ring contains a ring nitrogen in one of two meta positions relative to the piperidinyl ring attachment position. Furthermore, a carbonitrile substituent is attached to the pyridinyl ring in an ortho position relative to the piperidinyl ring attachment position. Furthermore, R 1 and R 2 is not limited to hydrogen, and A represents a heterocyclic ring system beyond pyridinyl. Furthermore, the 5-membered heterocyclic ring attached to the piperidinyl ring at the 4-position relative to the piperidinyl nitrogen is an aminothiazolyl ring in Example 1094 and an aminothiadiazolyl ring in Example 1095, while in compounds of the present invention it is a 3-substituted-4-methyl-4H-1,2,4-triazolyl ring.

[0014] These structural differences between the compounds of the present invention and the prior art unexpectedly result in an effective combination of (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells relevant to, but not limited to, lung disease or cancer, and (iii) adequate membrane permeability and low in vitro efflux.

[0015] The compounds of the present invention are therefore 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 to, but not limited to, lung disease or cancer (Assay B) Adequate membrane permeability and low in vitro efflux (Assay C) The present invention provides novel compounds according to formula (I) or salts thereof, particularly pharmaceutically acceptable salts thereof.

[0016] [ka] (I) (In the formula, Y is N and Z is R 4 C, or Y is HC and Z is N; A is A1a, which is a 5- or 6-membered mono-heteroaryl ring, the 5- or 6-membered mono-heteroaryl ring containing one nitrogen or two heteroatom members, the first being nitrogen and the second being selected from nitrogen or sulfur; Alternatively, A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing 1 to 4 nitrogens; A1a or A1b are independently selected from one or two R 3 is replaced by R 1 is H, C 1-4 - selected from R groups consisting of alkyl and halo; R 2 Is, halo, H, C 1-4 -Alkyl, C 3-4 -cycloalkyl and F 1-9 -Fluoro-C 1-4 -alkyl; R 3 H, halo, C 1-4 -Alkyl, C 3-4 -cycloalkyl, C 3-4 -fluorocycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 3-4 -cycloalkyloxy and pyrazolyl,

[0017] [ka] and R groups consisting of: R 4 Is, halo, H, C 1-4 -Alkyl, C 3-4 -cycloalkyl and F 1-9 -Fluoro-C 1-4 -alkyl)

[0018] Another embodiment of the present invention relates to compounds of formula (I): A is A2a, a 5- or 6-membered mono-heteroaryl ring, containing one nitrogen or two heteroatom members, the first being nitrogen and the second being selected from nitrogen or sulfur; A2a independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I): A is A2b, a 9- or 10-membered fused bicyclic heteroaryl ring containing 3 to 4 nitrogen atoms, and A2b is independently one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0019] Another embodiment of the present invention relates to compounds of formula (I) wherein A is selected from A groups consisting of pyridinyl, pyrazinyl, pyrazolyl, isothiazolyl, imidazo[1,2-a]pyrimidyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidyl, pyrazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl and 1H-imidazo[4,5-b]pyridinyl; A is independently selected from one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0020] Another embodiment of the present invention relates to compounds of formula (I) wherein A is selected from the group A consisting of pyridinyl, pyrazinyl, pyrazolyl, isothiazolyl, imidazo[1,2-a]pyrimidyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidyl, and pyrazolo[1,5-b]pyridazinyl; A is independently selected from one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from A groups consisting of pyridinyl, imidazo[1,2-a]pyrimidyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidyl, and pyrazolo[1,5-b]pyridazinyl; A is independently selected from one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0021] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from the group A consisting of pyridinyl and pyrazolo[1,5-b]pyridazinyl, and A is independently selected from one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0022] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from A7 groups consisting of pyridinyl, A7 independently selects one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I) wherein A is selected from the group A consisting of pyrazolo[1,5-b]pyridazinyl, and A is independently selected from one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0023] [ka] and A9 is selected from the group consisting of A9 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0024] [ka] and is selected from the A10 groups consisting of A10 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0025] Another embodiment of the present invention relates to compounds of formula (I), wherein A is [ka] and is selected from the A11 groups consisting of A11 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0026] [ka] and selected from the A12 groups consisting of A12 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0027] [ka] and selected from the A13 groups consisting of: A13 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0028] [ka] and selected from the A14 groups consisting of A14 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein A is

[0029] [ka] and selected from the A15 groups consisting of: A15 independently represents one or two R 3 is replaced by Substituent R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0030] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 is selected from the R groups consisting of H, HC—, HCHC—, HCHCHC—, (HC)HC—, Cl, and F; Substituent A, R 2 , R 3 and R4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 is selected from the R groups consisting of H, H3C-, and F; Substituent A, R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 is selected from the group R consisting of H; Substituent A, R 2 , R 3 and R 4 is defined as in any preceding embodiment.

[0031] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 is selected from the R groups consisting of F; Substituent A, R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 is selected from the R groups consisting of H3C- and F; Substituent A, R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 are H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment.

[0032] Another embodiment of the present invention relates to compounds of formula (I), wherein R2 is H, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 is selected from the R2d groups consisting of H, H3C-, and F3C-; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 is selected from the R groups consisting of H; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment.

[0033] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 is selected from the R2f groups consisting of H3C- and F3C-; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 are F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl; Substituent A, R 1 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I): R 3 H, halo, C 1-4-Alkyl, C 3-4 -cycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 3-4 -cycloalkyloxy and pyrazolyl,

[0034] [ka] and R3b groups consisting of: Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 are H, F, Cl, H3C, (H3C)3C-, H3C-O-, F3C-,

[0035] [ka] and R3c groups consisting of: Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 are H, F, Cl, H3C, (H3C)3C-, H3C-O-, F3C- and

[0036] [ka] and R3d groups selected from the group consisting of: Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 is H, H3C-O-,

[0037] [ka] and R groups consisting of: Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment.

[0038] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 is selected from the R groups consisting of H, HC, (HC)C—, HC—O—, and FC—; Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 is selected from the R3g groups consisting of H, F and Cl; Substituent A, R 1 , R 2 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 are H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl; Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment.

[0039] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 is H, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl; Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 is selected from the R groups consisting of H, H3C-, and F3C-; Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 is selected from R groups consisting of H; Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment.

[0040] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 is selected from the R groups consisting of H3C- and F3C-; Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (Ia):

[0041] [ka] (Ia) Substituent A, R 1 , R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (Ib):

[0042] [ka] (Ib) Substituent A, R 1 , R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (Ic):

[0043] [ka] (I C) Substituent A, R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (Id):

[0044] [ka] (Id) Substituent A, R 2 , R 3 and R 4 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (Ie):

[0045] [ka] (Ie) Substituent A, R 2 and R 3 is defined as in any preceding embodiment. Another embodiment of the present invention relates to compounds of the above formula (I) having the formula (If):

[0046] [ka] (If) Substituent R 2 , R 3 and R 4 is defined as in any preceding embodiment. Further preferred embodiments of compounds of formula (I) are encompassed as embodiments (EMB-1) to (EMB-20) in Table 1 below, using the above substituent definitions.

[0047] [Table 1]

[0048] For example, the compound of embodiment EMB-1 may have R 1 The R type radicals defined above as R1e in combination with other types of radicals as other substituents in formula (I) as defined within the same row of the table. The same applies equally to other variables incorporated into the general formula.

[0049] [ka] [ka] [ka] Particularly preferred are compounds according to formula (I) selected from the group consisting of:

[0050] Particularly preferred are compounds according to formula (I) selected from the group consisting of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, Example 13, Example 14, Example 15, Example 16, Example 17, Example 18, Example 19, Example 20, Example 21, Example 22, Example 23, Example 24, Example 25, Example 26, Example 27, Example 28, Example 29, Example 30, Example 31 and Example 32 described in the Examples below.

[0051] Particularly preferred are compounds according to formula (I) selected from the group consisting of Example 1, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 12, Example 13, Example 15, Example 16, Example 17, Example 19, Example 21, Example 25, Example 26, Example 27, Example 28, Example 29, Example 30, Example 31 and Example 32 described in the Examples below. Particularly preferred are compounds according to formula (I) selected from the group consisting of Example 1, Example 2, Example 3, Example 4, Example 6, Example 7, Example 10, Example 14, Example 16, Example 17, Example 18, Example 26 and Example 27 described in the Examples below.

[0052] The present invention provides novel piperidinylpyridinylcarbonitrile derivatives of formula (I), which are unexpectedly potent QPCT / L inhibitors. Another aspect of the present invention refers to compounds according to formula (I), which surprisingly possess potent inhibition of QPCT / L in cells relevant to, but not limited to, lung disease or cancer. Another aspect of the present invention refers to compounds according to formula (I) as surprisingly potent QPCT / L inhibitors in cells with suitable membrane permeability and low in vitro efflux. Another aspect of the present 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.

[0053] A further aspect of the present invention refers to compounds according to formula (I) for use in the prevention and / or treatment of disorders associated with QPCT / L inhibition. Another aspect of the present invention refers to methods of making the compounds of the present invention. Further aspects of the present invention will become apparent to those skilled in the art directly from the foregoing and following description and examples.

[0054] Terms and definitions used General definition Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in light of this disclosure and the context. However, as used herein, the following terms have the meaning indicated unless otherwise specified, and the following conventions shall be adhered to:

[0055] In the groups, radicals or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1-6Alkyl means an alkyl group or radical having from 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., one skilled in the art can refer to the point of radical attachment to the molecule from the free valence of the group itself. For combined groups containing two or more subgroups, the last named subgroup is the point of radical attachment, e.g., the substituent "aryl-C 1-3 Alkylene (aryl-C 1-3 -alkylene) is C 1-3 It refers to an aryl group bound to an alkyl group, in which the latter is bound to the nucleus or group to which the substituent is attached. In cases where a compound of the invention is depicted in the form of a chemical name and as a formula, in the event of a conflict, the formula shall prevail. An asterisk may be used in a subformula to indicate the bond connecting the core molecule being defined. The numbering of atoms of a substituent begins with the atom closest to the nucleus or group to which the substituent is attached. For example, the term "3-carboxypropyl-group" represents the following substituent:

[0056] [ka] The carboxy group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represents the group:

[0057] [ka] An asterisk may be used in a sub-formula to indicate the bond that connects the core molecule being defined. As used herein, the term "substituted" means that one or more hydrogens on the designated atom are replaced with a group selected from the defined group of substituents, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. Similarly, the term "substituted" can be used in reference to chemical moieties, e.g., "substituted alkyl," "substituted aryl," etc., in place of a single atom. Unless specifically indicated throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereoisomers, E / Z isomers) as well as racemates thereof, mixtures of different ratios of alternative enantiomers, mixtures of diastereoisomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, and solvates thereof, e.g., hydrates.

[0058] Unless specifically indicated, "pharmaceutically acceptable salts," as defined in more detail below, are also intended to encompass solvates thereof, such as hydrates. In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, such as by resolution of racemates or by synthesis, for example, beginning with optically active starting materials and / or using chiral reagents.

[0059] Enantiomerically pure compounds of the invention or intermediates may be prepared via asymmetric synthesis, for example by the 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 the use of chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries. Furthermore, it is known to those skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example, by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of the racemic mixtures using a suitable resolving agent, for example by diastereoisomeric salt formation of the racemates with an optically active acid or base, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemate with an optically active chiral auxiliary reagent, subsequent diastereoisomeric separation and removal of the chiral auxiliary; or by kinetic resolution of the racemate (for example by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0060] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human tissues within the bounds of good medical practice and without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic 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, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. 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.

[0061] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other acid salts than those mentioned above, which are useful, for example, for purifying or separating the compounds of the invention (eg, trifluoroacetate salts), also form part of the invention. The term halogen refers to fluorine, chlorine, bromine and iodine.

[0062] n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6, and "C" alone or in combination with another radical 1-n The term "-alkyl" denotes an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms. For example, C 1-5 The term alkyl includes the radicals HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)- and HC-CH-CH(CHCH)-. k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, and "C 3-k The term "cycloalkyl" refers to a cyclic, saturated, unbranched hydrocarbon radical having 3 to k carbon atoms. For example, C 3-7 The term -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0063] The term "halo" appended to an "alkyl," "alkylene," or "cycloalkyl" group (saturated or unsaturated) defines an alkyl, alkylene, or cycloalkyl group in which one or more hydrogen atoms have been replaced by a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, with fluorine being especially preferred. Examples include HFC-, HFC-, and FC-. The term "mono-heteroaryl ring" means a monocyclic aromatic ring system containing one or more heteroatoms selected from N or S, consisting of 5 to 6 ring atoms. The term "mono-heteroaryl ring" is intended to include all possible isomeric forms. Thus, the term "mono-heteroaryl ring" includes the following exemplary structures (each form is not depicted as a radical, as it is optionally attached through a covalent bond to any atom as long as valency is maintained):

[0064] [ka] The term "fused bicyclic heteroaryl ring" means a bicyclic aromatic ring system of 9 to 10 ring atoms containing one or more heteroatoms selected from N or S. The term "fused bicyclic heteroaryl ring" is intended to include all 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 as long as valency is maintained):

[0065] [ka]

[0066] The term pyridinyl refers to the radical of the ring: [ka] The term pyrazinyl refers to the radical of the ring: [ka]

[0067] The term pyrazolyl refers to a radical of the ring: [ka] The term isothiazolyl refers to a radical of the ring: [ka]

[0068] The term imidazo[1,2-a]pyrimidyl refers to the radical of the ring: [ka] The term pyrazolo[3,4-b]pyridinyl refers to the radical of the ring: [ka]

[0069] The term [1,2,4]triazolo[4,3-a]pyrimidyl refers to the following ring radical: [ka] The term pyrazolo[1,5-b]pyridazinyl refers to the radical of the ring: [ka]

[0070] The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to the radical of the ring: [ka] The term 2H-[1,2,3]triazolo[4,5-b]pyridinyl refers to the radical of the ring: [ka]

[0071] The term 1H-[1,2,3]triazolo[4,5-b]pyridinyl refers to the radical of the ring: [ka] The term 1H-imidazo[4,5-b]pyridinyl refers to the radical of the ring: [ka]

[0072] Many of the terms indicated above may be used repeatedly in the definitions of formulae or groups and in each case have, independently of one another, one of the meanings indicated above.

[0073] Biological assays Evaluation of inhibitory activity against QPCT and QPCTL Assay A: Biochemical QPCT and QPCTL activity assays The activity of the compounds of the present invention may be demonstrated using the following biochemical enzyme activity assays.

[0074] QPCT- or QPCTL-dependent conversion of the N-terminal glutamine of CD47 to pyroglutamate was monitored via MALDI-TOF MS. Test compounds were dissolved in 100% DMSO and serially diluted in a clear 1,536-well microtiter plate. Enzyme reactions were set up in assay buffer containing 20 mM Tris pH 7.5, 0.1 mM TCEP, 0.01% BSA, and 0.001% Tween 20. 2.5 μL of 2× concentrated QPCTL (in-house) or QPCT (Origine #TP700028) enzyme in assay buffer (0.5 nM final concentration, columns 1–23) or plain assay buffer (column 24) was added to each well. Plates were incubated for 10 minutes in a humidified incubator at 24°C. Subsequently, 2.5 μL of CD47 peptide substrate surrogate ( 19 QLLFNKTKSVEFTFC 33 ) was added to each well (final concentration: 10 μM for QPCTL / 20 μM for QPCT). The plate was mixed at 1,000 rpm for 30 seconds and then incubated at 24°C in a humidified incubator for 40 minutes. After incubation, stable isotope-labeled internal standard peptides were added. 19 [Pyr]LLFN(K)TKSVEFTFC 33 The enzyme reaction was stopped by adding 1 μL of a solution containing 1 μL of HCl (final concentration 4.0 μM) and SEN177 (final concentration 10 μM). The plate was sealed with adhesive foil, mixed at 1,000 rpm for 30 seconds, and stored at room temperature until preparation of the MALDI target plate. The MALDI target plate was prepared as previously described. Mass spectra were obtained from the product ( 19 [Pyr]LLFNKTKSVEFTFC 33 , m / z 1,787.9037) and internal standard ( 19 [Pyr]LLFN(K)TKSVEFTFC 33The data were acquired on a rapifleX MALDI-TOF / TOF instrument, tracking the signal of the peptide (m / z 1,795.9179). QPCT or QPCTL activity was monitored by calculating the ratio between the product signal and the internal standard signal, followed by normalization to high (100% activity) and low (0% activity) controls. Compound potency was determined by fitting the dose-response data to a four-parameter logistic equation.

[0075] [Table 2]

[0076] [Table 3]

[0077] Assay B: SIRPα signaling assay (using Raji or A549 cells) The activity of the compounds of the present invention can be demonstrated using the following SIRPα signaling assay, which measures SIRPα association induced by CD47 presented via cell-cell interactions. Two cell types are used independently: the Raji cell line (a lymphoblastoid human cell line derived in 1963 from B lymphocytes of a patient with Burkitt's lymphoma) and A549 cells (human alveolar basal adenocarcinoma cells).

[0078] Test compounds were dissolved in 100% DMSO and serially diluted in white 384-well microtiter cell culture plates (PerkinElmer #60076780 for the Raji assay; PDL-coated plates Greiner #781945 for the A549 assay). Five thousand Raji cells (ATCC #CC86) or 5,000 A549 cells (ATCC #CCL-185) in Assay Complete Cell Plating reagent 30 (DiscoverX #93-0563R30B) were added per well. Assay plates were incubated at 37°C, 95% humidity, and 5% CO for 48 hours. 15,000 reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93-1135C19) were added to each well, and the plates were incubated at 37°C, 95% humidity, and 5% CO for 5 hours. Bioassay Reagent 1 from the PathHunter Bioassay Detection Kit (DiscoverX 93-0001) was added to each well of the plate using a multichannel pipette, followed by a 15-minute incubation at room temperature. Bioassay Reagent 2 was then added, followed by a 60-minute incubation at room temperature (incubated in the dark).

[0079] Data analysis was performed using the luminescent signal generated by beta-galactosidase in the PathHunter reporter cell line. Luminescence measurements were performed using a Pherastar multimode reader. Dose-response curves & IC 50 Data were calculated using a 4-parameter sigmoidal dose-response equation.

[0080] [Table 4]

[0081] [Table 5]

[0082] Permeability assessment Assay C: Permeability in CACO-2 cells Caco-2 cells (1–2 × 105 cells / 1 cm2 area) were seeded onto filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10–25 days.

[0083] Compounds are dissolved in an appropriate solvent (e.g., DMSO, 1-20 mM stock solution). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO × 7H2O, 0.41 mM NaHPO × 7H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare transport solution (0.1-300 μM compound, final DMSO ≤ 0.5%). Transport solution (TL) is applied to the apical or basolateral donor side, respectively, to measure AB or BA permeability (triplicate filters). Samples are collected from the donor at the beginning and end of the experiment and from the receiver at various time intervals for up to 2 hours for concentration determination by HPLC-MS / MS or scintillation counting. The collected receiver volume is replaced with fresh receiver solution. Efflux ratio (ER)=permeability BA / permeability AB

[0084] [Table 6]

[0085] [Table 7]

[0086] Assessment of microsomal clearance Microsomal clearance: Metabolic degradation of test compounds was assayed at 37°C using pooled liver microsomes from various species. A final incubation volume of 60 μl per time point contained TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / mL for humans and dogs, 0.5 mg / mL for other species), and a final concentration of 1 μM test compound at room temperature. Following a short preincubation period at 37°C, the reaction was initiated by the addition of beta-nicotinamide adenine dinucleotide phosphate reduced form (NADPH, 1 mM) and terminated by transferring aliquots into solvent after various time points. After centrifugation (10,000 g, 5 min), aliquots of the supernatant were assayed for the amount of parent compound by LC-MS / MS. Half-lives were determined by the slope of a semi-logarithmic plot of the concentration-time profile. The intrinsic clearance (CL_INTRINSIC) is calculated by taking into account the amount of protein in the incubation: CL_INTRINSIC [μl / min / mg protein] = (Ln2 / half-life [min] × protein content [mg / ml]) × 1000 CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [μL / min / mg protein] × MPPGL [mg protein / g liver] × liver factor [g / kg body weight]) / 1000 Qh[%]=CL[ml / min / kg] / hepatic blood flow [ml / min / kg]) Hepatocellular, human: 120 x 10e6 cells / g liver Liver factor, human: 25.7 g / kg body weight Blood flow, human: 21 ml / (min x kg)

[0087] Assessment of hepatocyte clearance Hepatocyte clearance The metabolic degradation of test compounds is assayed in human hepatocyte suspensions. After recovery from cryopreservation, human hepatocytes are diluted in Dulbecco's modified Eagle's medium (3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, supplemented with 5% human serum) to a concentration of 1.0 × 106 The final cell density was obtained in cells / mL. Following a 30 minute pre-incubation in a cell culture incubator (37° C., 10% CO 2 ), the test compound solution is spiked into the hepatocyte suspension to give a final test compound concentration of 1 μM and a final DMSO concentration of 0.05%.

[0088] The cell suspension is incubated at 37°C (cell culture incubator, horizontal shaker) and samples are removed from the incubation at 0, 0.5, 1, 2, 4, and 6 hours. The samples are quenched with acetonitrile (containing an internal standard) and pelleted by centrifugation. The supernatant is transferred to a 96-deep well plate and prepared for analysis of parent compound depletion by HPLC-MS / MS. The percentage of test compound remaining is calculated using the peak area ratio (test compound / internal standard) at each incubation time point relative to the peak area ratio at time point 0. Log-transformed data are plotted against incubation time, and the absolute value of the slope obtained by linear regression analysis is used to estimate the in vitro half-life (T1 / 2).

[0089] In vitro intrinsic clearance (CLint) is calculated from the in vitro T1 / 2 and scaled to whole liver using the following equation: hepatocellularity of 120 x 106 cells / g liver, human liver per kg body weight of 25.7 g liver / kg, and in vitro incubation parameters: CL_INTRINSIC_IN VIVO[mL / min / kg]=(CL_INTRINSIC[μL / min / 1 cell]×hepatocytic [10 6 cells / g liver) × liver factor (g / body weight) / 1000 Hepatic in vivo blood clearance (CL) is predicted according to the well-stirred liver model, considering a mean hepatic blood flow (QH) of 20.7 mL / min / kg: CL[mL / min / kg]=CL_INTRINSIC_IN VIVO[mL / min / kg]×hepatic blood flow [mL / min / kg] / (CL_INTRINSIC_IN VIVO[mL / min / kg]+hepatic blood flow [mL / min / kg]) Results are expressed as a percentage of hepatic blood flow. QH[%]=CL[mL / min / kg] / hepatic blood flow [mL / min / kg])

[0090] Evaluation of plasma protein binding The equilibrium dialysis technique was applied to Dianorm Teflon dialysis cells (micro 0.2) to determine the approximate in vitro fractional binding of test compounds to plasma proteins. Each dialysis cell consisted of a donor and acceptor chamber separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. A stock solution of each test compound was prepared in DMSO at 1 mM and serially diluted to achieve a final test concentration of 1 μM. Subsequent dialysis solutions were prepared in plasma (supplemented with NaEDTA as an anticoagulant), and aliquots of 200 μl of the test compound dialysis solution in plasma were dispensed into the donor (plasma) chamber. Aliquots of 200 μl of dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7% dextran) were dispensed into the buffer (acceptor) chamber. To establish equilibrium, incubation was performed at 37°C for 2 h with rotation. At the end of the dialysis period, aliquots from the donor and acceptor chambers were transferred into reaction tubes and processed for HPLC-MS / MS analysis. Analyte concentrations were quantified in the sample aliquots by HPLC-MS / MS against a calibration curve. Percent binding is calculated using the following formula: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) x 100

[0091] Solubility evaluation Saturated solutions are prepared in a well plate (robotically formatted) by adding an appropriate volume of the selected aqueous medium (typically in the range of 0.25-1.5 ml) to each well containing a known amount of solid drug substance (typically in the range of 0.5-5.0 mg). The wells are shaken or agitated for a predetermined period (typically in the range of 2-24 hours) and then filtered using an appropriate filter membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter absorption is avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance is determined by UV spectroscopy. The pH of the saturated aqueous solution is then measured using a glass-electrode pH meter.

[0092] Assessment of metabolism in human hepatocytes in vitro The metabolic pathway of the test compound is investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes are incubated in Dulbecco's modified Eagle's medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg / 500 ml hydrocortisone. Following a 30-minute preincubation in a cell culture incubator (37°C, 10% CO2), test compound solutions were spiked into the hepatocyte suspension to give 1.0 x 10 6 ~4.0×10 6 A final cell density of 100 cells / ml (according to the compound turnover rate observed in primary human hepatocytes), a final test compound concentration of 10 μM, and a final DMSO concentration of 0.05% are achieved.

[0093] Cells are incubated for 6 hours on a horizontal shaker in a cell culture incubator, and samples are removed from incubation after 0, 0.5, 1, 2, 4, or 6 hours depending on turnover rate. Samples are quenched with acetonitrile and pelleted by centrifugation. Supernatants are transferred to 96-deep-well plates, evaporated under nitrogen, and resuspended prior to bioanalysis by liquid chromatography-high-resolution mass spectrometry to identify putative metabolites. The structure was analyzed by Fourier transform MS.n Assignments are tentatively made based on the data. Metabolites are reported as percentages of the parent in human hepatocyte incubations with a threshold of ≥4%.

[0094] Evaluation of pharmacokinetic properties Test compounds are administered intravenously or orally to each test species. Blood samples are taken at several time points after application of the test compound, anticoagulated, and centrifuged.

[0095] The concentrations of the administered compound and / or metabolite analyte are quantified in plasma samples. PK parameters are calculated using non-compartmental methods. AUC and Cmax are normalized to a dose of 1 μmol / kg.

[0096] Treatment method The present invention is directed to compounds of general formula (I) that are useful for the prevention and / or treatment of diseases and / or conditions 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 disease.

[0097] The compounds of general formula (I) are useful in the prevention and / or treatment of: (1) Pulmonary fibrotic diseases, such as connective tissue diseases, e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, pneumonitis or interstitial pneumonitis associated with polymyositis and dermatomyositis, idiopathic interstitial pneumonia, e.g., pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans' cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known etiology, such as occupational exposures, e.g., asbestosis, silicosis, coal miner's lung (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne triggers, e.g., metals Interstitial pneumonitis as a result of powder or mycobacteria, or as a result of treatment, such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapy, or in granulomatous diseases, such as polyangitis granulomatosis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonitis caused by different causes, such as inhalation of toxic gases, vapors, heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis or cystic fibrosis, or bronchitis or pneumonitis or interstitial pneumonitis caused by alpha-I-antitrypsin deficiency. (2) Other fibrotic diseases, such as hepatic bridging fibrosis, cirrhosis, nonalcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, glial scarring, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloids, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; pulmonary fibrosis and spontaneous acute exacerbations in progressive pulmonary fibrosis, or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, frozen biopsy), air pollution, prior exacerbations, and drugs. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid tumors, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer cancer), bowel cancer, small intestine cancer, large intestine cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, genitourinary cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, seminoma, teratocarcinoma, liver cancer, kidney cancer, bladder cancer, urothelial cancer, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, schwannoma, glioblastoma, or sarcoma, gastrointestinal cancer, stomach cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma (NHL), urothelial carcinoma, or peritoneal cancer. (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, 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 skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (such as necrotizing, cutaneous and hypersensitivity vasculitis), or erythema nodosum. (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion disease. Thus, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0098] Furthermore, the present invention relates to the use of compounds of general formula (I) for treating and / or preventing diseases and / or conditions associated with or modulated by QPCT / L activity.

[0099] 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 treating and / or preventing cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney diseases.

[0100] 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 treating and / or preventing: (1) Pulmonary fibrotic diseases, such as connective tissue diseases, e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, pneumonitis or interstitial pneumonitis associated with polymyositis and dermatomyositis, idiopathic interstitial pneumonia, e.g., pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known etiology, e.g., occupational exposure, e.g., asbestosis, silicosis, coal miner's lung (coal dust), Interstitial pneumonitis as a result of farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne triggers, e.g., metal dust or mycobacteria, or as a result of treatment, e.g., radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy, or in granulomatous diseases, e.g., granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonitis caused by different causes, e.g., toxic gases, vapor inhalation, inhalation, heart failure, x-rays, radiation, chemotherapy, M. boeck, or sarcoidosis, granulomatosis, cystic fibrosis, or alpha-I-antitrypsin deficiency. (2) Other fibrotic diseases, such as hepatic bridging fibrosis, cirrhosis, nonalcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, glial scarring, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloids, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; pulmonary fibrosis and spontaneous acute exacerbations in progressive pulmonary fibrosis, or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, frozen biopsy), air pollution, prior exacerbation, and drugs. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid tumors Lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, stomach cancer, intestinal cancer, small intestine cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, genitourinary cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, seminoma, teratocarcinoma, liver cancer, kidney cancer , bladder cancer, urothelial cancer, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal 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, intestinal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma (NHL), urothelial carcinoma, or peritoneal carcinoma. (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, 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 skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (such as necrotizing, cutaneous and hypersensitivity vasculitis), or erythema nodosum. (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion disease.

[0101] 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 the above-mentioned diseases and conditions.

[0102] In a further aspect, 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 preparing a medicament for treating and / or preventing the above-mentioned diseases and conditions.

[0103] In a further aspect, the present invention relates to a method for treating or preventing the above-mentioned diseases and conditions, which method comprises administering to a human an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0104] Combination therapy The compounds of the present 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 described above, particularly those useful in the treatment of diseases or conditions related to cancer, fibrotic diseases, Alzheimer's disease, atherosclerosis, infectious diseases, chronic kidney disease and autoimmune diseases. Suitable additional therapeutic agents for such combinations include, in particular, those that enhance the therapeutic effect of one or more of the agents for one of the mentioned indications and / or those that reduce the dosage of one or more of the agents. Thus, the compounds of the present 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, antitussives, anti-inflammatory agents, anti-atopic dermatitis agents, and bronchodilators.

[0105] Chemotherapy is a type of cancer treatment that uses one or more chemical anti-cancer agents, such as cytostatic or cytotoxic agents, cell growth inhibitors, anti-angiogenic agents, etc. Examples include folic acid (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cis-platin, azacitidine, gemcitabine, alkylating agents, antimitotic agents, taxanes, and further state-of-the-art or standard-of-care compounds.

[0106] 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 growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (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.

[0107] Cancer immunotherapy is a type of treatment that uses substances to stimulate or suppress the immune system to help the body fight cancer. Cancer immunotherapy includes therapeutic antibodies, such as anti-Her2 antibodies, anti-EGFR antibodies, and anti-PDGFR antibodies; anti-GD2 (ganglioside G2) antibodies. Examples include dinutuximab, olaratumab, trastuzumab, pertuzumab, ertumaxomab, cetuximab, necitumumab, nimotuzumab, panitumumab, or rituximab. Cancer immunotherapy also includes therapeutic antibodies that are checkpoint inhibitors, such as anti-PD1, anti-PD-L1 antibodies, or CTLA4 inhibitors. Examples include atezolizumab, avelumab, and durvalumab, ipilimumab, nivolumab, or pembrolizumab. Cancer immunotherapies also include agents that target (inhibit) the CD47-SIRPα signaling axis, such as agents that 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 immunotherapies also include STING-targeting agents or T cell engagers, such as blinatumomab.

[0108] Antifibrotic agents include, for example, nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors, such as roflumilast, or certain PDE4b inhibitors such as BI 1015550, autotaxin inhibitors, such as GLPG-1690 or BBT-877; connective tissue growth factor (CTGF) blocking antibodies, such as pamrevlumab; B-cell activating factor receptor (BAFF-R) blocking antibodies, such as ianalumab (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 -JNK inhibitors, such as CC-90001; galectin-3 inhibitors, such as TD-139; G-protein coupled receptor 84 (GPR84) inhibitors; G-protein coupled receptor 84 / G-protein coupled receptor 40 dual inhibitors, such as PBI-4050; Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitors, such as KD-025; heat shock protein 47 (HSP47) small interfering RNA, such as BMS-986263 / ND-L02 s0201; Wnt pathway inhibitors, e.g., SM-04646; LD4 / PDE3 / 4 inhibitors, e.g., tipelukast; recombinant immunomodulatory domain of histidyl tRNA synthetase (HARS), e.g., ATYR-1923; prostaglandin synthase inhibitors, e.g., ZL-2102 / SAR-191801; 15-hydroxy-eicosapentaenoic acid (15-HEPE, e.g., DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors, e.g., PAT-1251, PXS-5382 / PXS-5338; phosphoinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) dual inhibitors, 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 interfering RNA, such as TRKZSO / BNC-1021; or lysophosphatidic acid receptor antagonist, such as BMS986278;

[0109] The dosage of the combination partners mentioned above is usually from 1 / 5 of the minimum normally recommended dose to a maximum of 1 / 1 of the normally recommended dose. Therefore, in another aspect, the present invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents as described above and below for treating a disease or condition that may be affected or mediated by QPCT / L, in particular a disease or condition as described above and below.

[0110] In a further aspect, the present invention relates to a method for treating a disease or condition that can be affected by inhibition of QPCT / L in a patient, comprising administering to a 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, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of a disease or condition that can be affected by the inhibition of QPCT / L in a patient in need thereof. In yet another aspect, the present invention relates to a method for treating a disease or condition mediated by QPCT / L activity in a patient, comprising administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the invention in combination with therapeutically effective amounts of one or more additional therapeutic agents as described above and below.

[0111] The use of compounds according to the present invention in combination with additional therapeutic agents may be done simultaneously or at staggered times. The compound according to the invention and the one or more additional therapeutic agents may either be present together in one formulation, e.g., a tablet or capsule, or may be present separately in two identical or different formulations, e.g., as a so-called kit-of-parts. Consequently, in another aspect, the present invention relates to pharmaceutical compositions comprising a compound according to the invention and one or more additional therapeutic agents as described above and below, optionally together with one or more inert carriers and / or diluents. Other features and advantages of the present invention will become apparent from the following more detailed description of the embodiments which illustrate, by way of example, the principles of the invention.

[0112] preparation The compounds according to the invention and intermediates thereto can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compounds are obtained in a manner analogous to the methods of preparation described more fully below, in particular in the experimental section. In some cases, the order in which the reaction steps are carried out can be varied. Variants of the reaction methods known to those skilled in the art but not described in detail here can also be used.

[0113] General methods for preparing compounds according to the invention will be apparent to one skilled in the art upon studying the following schemes. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art. The compounds according to the present invention are prepared by the synthetic methods described below, where the substituents of the general formula have the meanings indicated above. These methods are intended as illustrations of the present invention, without restricting the subject matter and scope of the claimed compounds to these examples. If the preparation of starting compounds is not described, they can be commercially obtained or prepared from known compounds or in accordance with the methods described herein. Materials described in the literature are prepared according to published synthetic methods. Abbreviations are as defined in the Examples section. Examples 1-25 can be prepared as shown in Scheme I below. Scheme I:

[0114] [ka] In Scheme I, N-methyltriazolylpiperidine (Z = CH, CF, C-Me) (A) undergoes nucleophilic aromatic substitution with a heteroaryl fluoride (one Y = N, one Y = CR; X = Cl, Br, I) (B). The reaction can typically be carried out at ambient temperature or at elevated temperatures (up to 110 °C) in the presence of a base (e.g., diisopropylethylamine). Intermediate (C) then undergoes Suzuki cross-coupling with a heteroaryl boronic acid derivative in the presence of a suitable catalyst (e.g., Pd(dppf)Cl) and a suitable base at elevated temperatures (e.g., 100 °C) to provide compounds of general formula (I). Intermediate I can be prepared as shown in Scheme II below: Scheme II:

[0115] [ka]

[0116] Compounds of formula (A) with Z=CF, C-Me, or CH can be prepared from the corresponding piperidinyl ester (R=Me, Et) (D) with a suitable protecting group (PG, e.g., BOC) by treatment with a suitable hydrazine source (e.g., NH * HO) at elevated temperature (e.g., 50 °C). The resulting hydrazide (E) is then activated with DMF / DMA at elevated temperature (e.g., 50 °C), followed by treatment with methylamine at elevated temperature (e.g., 90 °C) to give triazole derivative (F). Compounds of formula (A) are obtained by cleaving the protecting group under suitable conditions (e.g., 4 M HCl in dioxane for PG=BOC). The resulting hydrochloride salt of (A) is treated with ammonia and passed through a Biotage SNAP cartridge KP-NH column to release the free amine of (A). Compounds of formula (A) with Z=CH and C-Me are also available as hydrochloride salts from commercial sources. Intermediate II can be prepared as shown in Scheme III below: Scheme III:

[0117] [ka] In the case where R=H, the intermediate of formula (B) can be prepared from the corresponding carboxylic acid (G). The carboxylic acid moiety is converted to the corresponding amide (H) using a suitable combination of reagents, such as 1,1'-carbonyldiimidazole and ammonia at ambient temperature. The compound of formula (B) is then obtained by treating (H) with a suitable dehydrating agent, such as Burgess's reagent, at ambient temperature. In the case where R=Me or CF3, deprotonation of pyridine (J) at low temperature (e.g., -65°C) and quenching with DMF provides the corresponding aldehyde (K). In the case where R=Me, the aldehyde (K) can be directly converted to the nitrile (B) using ammonia in combination with a suitable oxidizing agent (e.g., iodine) at ambient temperature. In the case where R=CF3, the aldehyde (K) can be converted to the amide (H) using a suitable reagent, such as phenyltrimethylammonium tribromide, at ambient temperature, which can then be converted to the nitrile (B) as described above in the case where R=H. [Example]

[0118] preparation The compounds according to the present invention and intermediates thereto can be obtained using synthetic methods known to those skilled in the art and described in the literature on organic synthesis, for example, the methods described in "Comprehensive Organic 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 according to the methods of preparation described more fully below, in particular in the experimental section. In some cases, the sequence employed in carrying out the reaction schemes may be varied. Variants of these reactions known to those skilled in the art but not described in detail herein may also be used. General methods for preparing compounds according to the present invention will be apparent to those skilled in the art upon studying the schemes that follow. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared analogously or similarly thereto. Prior to carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art and described in the literature, for example, in "Protecting 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 interchangeably and designate a temperature of about 20° C., e.g., 19-24° C.

[0119] [Table 8-1] [Table 8-2] Preparation of intermediates Intermediate I.1

[0120] [ka]

[0121] tert-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 hours. After cooling to ambient temperature, the mixture is concentrated under reduced pressure to give tert-butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate in 80% purity. C 11 H 20 FN3O3 (M = 261.3 g / mol) ESI-MS: 284.2 [M+Na]+ Rt(HPLC): 0.62 min (Method A)

[0122] 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. N,N-Dimethylformamide dimethyl acetal (137 mL, 1.03 mol) is added to the mixture at ambient temperature. The reaction mixture is heated to 50° C. and stirred for 1 hour. A solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) is added to the mixture. The resulting reaction mixture is heated to 90° C. and stirred for 11 hours. The mixture is concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / EtOAc gradient 20:1 to 0:1) to give tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate. C 13 H 21 FN4O2 (M = 284.3 g / mol) ESI-MS: 285.1 [M+H] + Rt(HPLC): 0.77 min (Method A)

[0123] 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 slowly added at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 12 hours. The desired product is collected by filtration, washed with methanol, and dried to give 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride.

[0124] 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, gradient DCM / MeOH 4:1 to 7:3). C8H 13 FN4 (M = 184.2 g / mol) ESI-MS: 185 [M+H] + Rt(HPLC): 0.20 min (Method B)

[0125] 4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine (MFCD09055373, CAS: 297172-18-0), 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride (MFCD19440843), 1-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine (MFCD27979337, CAS: 67869-95-8), and 4-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine dihydrochloride (MFCD32875324) were obtained from commercial vendors. The hydrochlorides were converted to the free piperidines or piperazines according to the procedure described for Int. I. Intermediate II.1

[0126] [ka] 2-Bromo-3-fluoropyridine-4-carboxamide 2-Bromo-3-fluoropyridine-4-carboxylic acid (25.0 g, 0.114 mol) is suspended in THF (250 mL) and 1,1'-carbonyldiimazole (22.1 g, 0.136 mol) is added in several small portions. The reaction mixture is stirred at ambient temperature for 3 hours, and then a solution of ammonia (32% in HO, 64.8 mL, 0.938 mol) is slowly added. The resulting reaction mixture is stirred at ambient temperature for an additional 3 hours. The mixture is concentrated, and the residue is loaded onto Extrelut® and purified by column chromatography (SiO, DCM / MeOH 9:1) to give 2-bromo-3-fluoropyridine-4-carboxamide. C6H4BrFN2O (M=219.0g / mol) ESI-MS: 219 / 221[M+H] + Rt(HPLC): 0.28 min (Method C)

[0127] Intermediate II.1: 2-Bromo-3-fluoropyridine-4-carbonitrile 2-Bromo-3-fluoropyridine-4-carboxamide (17.4 g, 79.5 mmol) is added to dichloromethane (250 mL). Burgess reagent (CAS: 29684-56-8, 22.0 g, 89.5 mmol) is added, and the resulting reaction mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated to half its original volume and purified by column chromatography (SiO, DCM) to give 2-bromo-3-fluoropyridine-4-carbonitrile. C6H2BrFN2 (M = 201.0 g / mol) ESI-MS: No mass detected Rt(HPLC): 0.41 min (Method F) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, J=4.9 Hz, 1 H), 8.05 (t, J=4.8 Hz, 1 H). Intermediate II.2

[0128] [ka] 2-Chloro-3-fluoropyridine-4-carboxamide 2-Chloro-3-fluoropyridine-4-carboxylic acid (1.00 g, 5.41 mmol) is suspended in THF (25 mL) and 1,1'-carbonyldiimazole (1.05 g, 6.49 mmol) is added in several small portions. The reaction mixture is stirred at ambient temperature for 2 hours, and then a solution of ammonia (32% in HO, 3.09 mL, 44.6 mmol) is slowly added. The resulting reaction mixture is stirred at ambient temperature for an additional 2 hours. The mixture is concentrated, and the residue is loaded onto Extrelut® and purified by column chromatography (SiO, CyH / EtOAc gradient 1:0 to 1:1) to give 2-chloro-3-fluoropyridine-4-carboxamide. C6H4ClFN2O (M=174.6g / mol) ESI-MS: 174[MH] - Rt(HPLC): 0.11 min (Method B)

[0129] Intermediate II.2: 2-chloro-3-fluoropyridine-4-carbonitrile 2-Chloro-3-fluoropyridine-4-carboxamide (748 mg, 4.29 mmol) is added to DCM (20 mL). Burgess reagent (CAS: 29684-56-8, 1.26 g, 3.64 mmol) is added, and the resulting reaction mixture is stirred at ambient temperature for 16 h. The mixture is concentrated to half its original volume and purified by column chromatography (SiO2, CyH / EtOAc gradient 1:0 to 7:3) to give 2-chloro-3-fluoropyridine-4-carbonitrile. C6H2ClFN2 (M = 156.5 g / mol) ESI-MS: No mass detected Rt(HPLC): 0.41 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=4.9 Hz, 1 H), 8.06 (t, J=4.7 Hz, 1 H) Intermediate II.3

[0130] [ka] 2-Bromo-3-fluoro-6-methylpyridine-4-carbaldehyde Under an argon atmosphere, 2-bromo-3-fluoro-6-methylpyridine (1.00 g, 5.16 mmol) is added to THF (50 mL) and the resulting mixture is cooled to -65 °C. A solution of lithium diisopropylamide (1 M in THF, 5.42 mL, 5.42 mmol) is added dropwise, and the mixture is stirred at -65 °C for an additional 30 minutes. A solution of DMF (476 μL DMF in 3 mL THF, 6.19 mmol) is added dropwise. The mixture is stirred at -65 °C for 20 minutes and then warmed to ambient temperature. The reaction is quenched by adding saturated aqueous ammonium chloride and Me-THF. The phases are separated, and the organic phase is washed with water, dried over MgSO4, and concentrated to give 2-bromo-3-fluoro-6-methylpyridine-4-carbaldehyde. C7H5BrFNO (M=218.0g / mol) ESI-MS: No mass detected Rt(HPLC): 0.41 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1 H), 7.64 (d, J=4.6 Hz, 1 H), 2.53 (d, J=1.0 Hz, 3 H)

[0131] Intermediate II.3: 2-Bromo-3-fluoro-6-methylpyridine-4-carbonitrile 2-Bromo-3-fluoro-6-methylpyridine-4-carbaldehyde (460 mg, 2.11 mmol) is added to THF (4.6 mL), and a solution of ammonia (28% in HO, 4.6 mL) and iodine (580 mg, 2.28 mmol) is added. The resulting reaction mixture is stirred at ambient temperature for 5 hours. The reaction mixture is diluted with ethyl acetate and washed twice with saturated aqueous NH4Cl. The organic phase is concentrated, loaded onto Extrelut®, and purified by column chromatography (SiO2, CyH / EtOAc gradient 1:0 to 4:1) to give 2-bromo-3-fluoro-6-methylpyridine-4-carbonitrile. C7H4BrFN2 (M = 215.0 g / mol) ESI-MS: 215 / 217[M+H] + Rt(HPLC): 0.40 min (Method C) Intermediate II.4

[0132] [ka] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde Under an argon atmosphere, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine (1.00 g, 4.1 mmol) is added to THF (25 mL) and the resulting mixture is cooled to -70 °C. A solution of lithium diisopropylamide (1 M in THF, 4.51 mL, 4.51 mmol) is added dropwise, and the mixture is stirred at -70 °C for 45 min. DMF (0.378 mL, 4.92 mmol) is added dropwise. The mixture is further stirred at -70 °C for 30 min. The reaction is quenched by adding acetic acid (800 μL) and diluted with water and ethyl acetate. The organic phase is separated, dried over MgSO 4 , and concentrated. The residue is purified by column chromatography (SiO 2 , CyH / EtOAc gradient 1:0 to 4:1) to give 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde. C7H2BrF4NO (M=272.0g / mol) ESI-MS: No mass detected Rt(HPLC): 0.48 min (Method E) 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 8.26 (d, J=4.3 Hz, 1 H).

[0133] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide Ammonium acetate (5.53 g, 71.8 mmol) and 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde (2.17 g, 7.18 mmol) are mixed and acetonitrile (44 mL) is added. Phenyltrimethylammonium tribromide (5.57 g, 14.4 mmol) is added portionwise, and the resulting reaction mixture is stirred at ambient temperature for 72 h. The mixture is filtered, the residue is washed with acetonitrile, and purified by column chromatography (Celite® dry-packed, SiO2, CyH / EtOAc gradient 1:0 to 7:3) to give the desired product. C7H3BrF4N2O (M=287.0g / mol) ESI-MS: 285 / 287[MH] - Rt(HPLC): 0.50 min (Method B) Intermediate II.4: 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbonitrile

[0134] The product of the previous step, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide (975 mg, 3.40 mmol), is suspended in dichloromethane (80 mL) and Burgess reagent (CAS: 29684-56-8, 1.25 g, 5.10 mmol) is added at ambient temperature. The resulting reaction mixture is stirred for 40 h and then directly purified by column chromatography (Celite® dry-packed, SiO2, CyH / EtOAc gradient 1:0 to 9:1) to give the desired product. C7HBrF4N2 (M = 268.9 g / mol) ESI-MS: 268 / 270[M+H] + Rt(HPLC): 0.59 min (Method C)

[0135] General procedure for the synthesis of intermediate III [ka]

[0136] 2-Bromo-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile Int.II.1 (500 mg, 2.49 mmol) and Int.I.1 (687 mg, 3.73 mmol) are suspended in DMSO (5.0 mL), and DIPEA (861 μL, 4.98 mmol) is added at ambient temperature. The resulting mixture is stirred at ambient temperature for 72 hours. The mixture is diluted with water (0.1 mL), and the precipitate is collected by filtration, washed with water, and dried to obtain the desired product, 2-bromo-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile, which is used in the next step without further purification. C 14 H 14 BrFN6 (M = 365.2 g / mol) ESI-MS: 365 / 367 [M+H] + Rt(HPLC): 0.42 min (Method C)

[0137] [Table 9-1] [Table 9-2]

[0138] [ka]

[0139] 4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride (180 mg, 0.89 mmol), 3-fluoro-4-iodoopicolinonitrile (200 mg, 0.81 mmol), and potassium carbonate (334 mg, 2.42 mmol) were suspended in DMF (4.0 mL), and the resulting reaction mixture was heated to 90° C. and stirred for 18 h. After cooling to ambient temperature, the mixture was concentrated, redissolved in a mixture of acetonitrile, water, and methanol, filtered, and purified by preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH) to give the desired product along with a by-product resulting from iodine displacement. C 14 H 15 IN6 (M = 394.2 g / mol) ESI-MS: 395[M+H] + Rt(HPLC): 0.38 min (Method C)

[0140] [Table 10]

[0141] [ka]

[0142] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine 5-Bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 19.8 mmol) is suspended in toluene (23 mL) and tert-butyl acetate (26.6 mL, 198 mmol) is added. Methanesulfonic acid (1.3 mL, 19.8 mmol) is slowly added. The resulting reaction mixture is heated to 80° C. and stirred for 1 hour. After cooling to ambient temperature, additional methanesulfonic acid (1.3 mL, 19.8 mmol) is added, and the reaction mixture is heated to 80° C. and stirred for 1 hour. After cooling to ambient temperature, the reaction mixture is concentrated and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine. C 10 H 12 BrN3 (M = 254.1 g / mol) ESI-MS: 254 / 256 [M+H] + Rt(HPLC): 0.50 min (Method C)

[0143] Intermediate V.1 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.50 g, 3.87 mmol), bis(pinacoloto)diboron (1.21 g, 4.78 mmol), and potassium acetate (763 mg, 7.77 mmol) were added to 1,4-dioxane (15 mL), and the resulting mixture was degassed for 10 minutes by passing a stream of argon through the mixture. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) dichloromethane complex (Pd(dppf)Cl*CHCl, CAS: 95464-05-4) (190 mg, 0.232 mmol) was added, and the mixture was degassed for another 3 minutes. The mixture was then heated to 110 °C and stirred at this temperature for 4 hours. After cooling to ambient temperature, the mixture is concentrated, and the residue is dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give {2-tert-butyl-2H-pyrazolo[3,4-b]pyridin-5-yl}boronic acid. C 10 H14 BN3O2 (M = 219.1 g / mol) ESI-MS: 220[M+H] + Rt(HPLC): 0.27 min (Method C)

[0144] Intermediate V.2 [ka] 6-Bromo-3-tert-butyl-[1,2,4]triazolo[4,3-a]pyrimidine 5-Bromo-2-hydrazinopyrimidine (200 mg, 1.01 mmol) and pivaloyl chloride (985 mg, 8.09 mmol) are added to a microwave vial, which is then sealed. The mixture is heated to 120 ° C and stirred at this temperature for 22 hours. Water and ACN are added, and the mixture is concentrated. The residue is taken up in ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C9H 11 BrN4 (M = 255.1 g / mol) ESI-MS: 255 / 257[M+H] + Rt(HPLC): 0.46 min (Method C)

[0145] Intermediate V.2 6-Bromo-3-tert-butyl-[1,2,4]triazolo[4,3-a]pyrimidine (75.0 mg, 0.294 mmol), bis-(pinacolato)-diboron (100 mg, 0.394 mmol), and potassium acetate (90.0 mg, 0.917 mmol) were added to 1,4-dioxane (1.5 mL). The mixture was degassed for 15 minutes by passing a stream of argon through the mixture. Bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2; 20.4 mg, 0.029 mmol) was added, and the mixture was degassed for another 3 minutes. The resulting reaction mixture was heated to 60°C and stirred at this temperature for 20 hours. After cooling to ambient temperature, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated and taken up in a mixture of ACN, water, and TFA. This is then purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to give the desired compound. C9H 13 BN4O2 (M = 220.0 g / mol) ESI-MS: 221[M+H] + Rt(HPLC): 0.34 min (Method C)

[0146] Intermediate V.3 [ka]

[0147] 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine 2-Amino-5-bromopyrimidine (250 mg, 1.41 mmol) and 1-chloropinacoline (285 μL, 2.11 mmol) are added to ethanol (2.0 mL), and the resulting reaction mixture is stirred at 90° C. for 96 h. After cooling to ambient temperature, the mixture is diluted with ACN and purified by column chromatography (SiO, DCM / MeOH gradient 1:0 to 9:1) to give the desired product. C 10 H 12 BrN3 (M = 254.1 g / mol) ESI-MS: 254 / 256[M+H]+ Rt(HPLC): 0.28 min (Method C)

[0148] Intermediate V.3 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine (144 mg, 0.567 mmol), bis-(pinacolato)-diboron (215 mg, 0.850 mmol), and potassium acetate (167 mg, 1.70 mmol) were added to 1,4-dioxane (1.0 mL). The mixture was degassed for 10 minutes by passing a stream of argon through the mixture. Bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2; 39.8 mg, 56.7 μmol) was added, and the mixture was degassed for another 3 minutes. The resulting reaction mixture was heated to 90° C. and stirred at this temperature for 5 hours. After cooling to ambient temperature, the mixture was concentrated. The residue is taken up with a mixture of water and ACN and then purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired compound. C 10 H 14 BN3O2 (M = 219.1 g / mol) ESI-MS: 220[M+H] + Rt(HPLC): 0.25 min (Method C)

[0149] Intermediate V.4 [ka]

[0150] 6-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine 2-Amino-5-bromopyrimidine (1.0 g, 5.6 mmol) and 1-chloro-3,3,3-trifluoroacetone (889 μL, 8.45 mmol) were added to ethanol (8 mL), and the resulting reaction mixture was stirred at 90° C. for 120 h. After cooling to ambient temperature, the mixture was concentrated and loaded onto Extrelut®. It was then purified by column chromatography (SiO, DCM / MeOH gradient 1:0 to 9:1) to give the desired product. C7H3BrF3N3 (M = 266.0 g / mol) ESI-MS: 266 / 268[M+H] + Rt(HPLC): 0.38 min (Method C)

[0151] Intermediate V.4 6-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine (373 mg, 1.40 mmol), bis-(pinacolato)-diboron (215 mg, 1.54 mmol), and potassium acetate (412 mg, 4.21 mmol) are added to 1,4-dioxane (1.0 mL). The mixture is degassed for 10 minutes by passing a stream of argon through the mixture. Bis(triphenylphosphine)palladium(II) dichloride (98.4 mg, 0.140 mmol) is added, and the mixture is degassed for another 3 minutes. The resulting reaction mixture is heated to 90°C and stirred at this temperature for 5 hours. After cooling to ambient temperature, the mixture is concentrated. The residue is taken up in a mixture of water and ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired compound. C7H5BF3N3O2 (M = 230.9 g / mol) ESI-MS: 232[M+H] + Rt(HPLC): 0.29 min (Method C)

[0152] Intermediates VI.1 [ka]

[0153] 5-Bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine 5-Bromo-2-fluoropyridin-3-ol (3.00 g, 15.3 mmol) is added to DCM (40 mL) and DIPEA (5.3 mL, 31 mmol) is added. 2-(Trimethylsilyl)ethoxymethyl chloride (3.15 mL, 16.8 mmol) is added dropwise, and the resulting reaction mixture is stirred at ambient temperature for 90 min. The mixture is concentrated, loaded onto Extrelut®, and purified by column chromatography (SiO2, CyH / EtOAc 1:0 to 3:1) to give the desired product. C 11 H 17 BrFNO2Si (M=322.2g / mol) ESI-MS: 322 / 324[M+H] + Rt(HPLC): 0.84 min (Method C)

[0154] (6-Fluoro-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-3-yl)boronic acid Under an argon atmosphere, 1,4-dioxane (30 mL) is added to a mixture of 5-bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine (4.80 g, 14.9 mmol), bis(pinacolato)diboron (3.50 g, 13.8 mmol), and potassium acetate (4.39 g, 44.7 mmol). The suspension is degassed for 10 minutes by passing a stream of argon through the mixture. [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) dichloromethane complex (Pd(dppf)Cl*CHCl, CAS: 95464-05-4) (545 mg, 0.745 mmol) is added, and the mixture is degassed for another 3 minutes. The mixture is then heated to 80 °C and stirred at this temperature for 18 hours. After cooling to ambient temperature, the mixture is diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated. The residue is purified by preparative HPLC (XBridge C18, ACN / water gradient) to give the desired product in 80% purity. C11 H 19 BFNO4Si (M=287.2g / mol) ESI-MS: 288[M+H] + Rt(HPLC): 0.60 min (Method C)

[0155] 6'-Fluoro-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5'-{[2-(trimethylsilyl)ethoxy]methoxy}-[2,3'-bipyridine]-4-carbonitrile Under an argon atmosphere, 1,4-dioxane (3.0 mL) is added to a mixture of intermediate III.1 (211 mg, 0.578 mmol), (6-fluoro-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-3-yl)boronic acid (80% pure, 519 mg, 1.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (66.8 mg, 0.058 mmol). The suspension is degassed for 10 min by passing a stream of argon through the mixture. A solution of cesium carbonate (2 M in H2O, 867 μL, 1.73 mmol) is added, and the mixture is degassed again for 3 min. The reaction mixture is then heated to 80 °C and stirred at this temperature for 8 h. After cooling to ambient temperature, the mixture is concentrated. The residue is taken up with ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product. C 25 H 31 F2N7O2Si (M=527.6g / mol) ESI-MS: 528[M+H] + Rt(HPLC): 0.67 min (Method C)

[0156] Intermediates VI.1 6'-Fluoro-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5'-{[2-(trimethylsilyl)ethoxy]methoxy}-[2,3'-bipyridine]-4-carbonitrile (290 mg, 0.45 mmol) is added to dichloromethane, and a solution of hydrochloric acid (4 M in dioxane, 563 μL, 2.25 mmol) is added. The resulting reaction mixture is stirred at ambient temperature for 2 hours. The mixture is diluted with MTBE, and the precipitated solid is collected by filtration, washed with MTBE, and dried to give the desired product. C 19 H 17 F2N7O (M=397.4g / mol) ESI-MS: 398[M+H] + Rt(HPLC): 0.39 min (Method C)

[0157] Intermediate VI.2 [ka] 6'-Fluoro-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5'-formyl-[2,3'-bipyridine]-4-carbonitrile Under an argon atmosphere, intermediate III.1 (1.0 g, 2.74 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (CAS: 1333319-63-3; 796 mg, 3.01 mmol), and a solution of potassium carbonate (2 M in water, 2.74 mL, 5.48 mmol) are added to 1,4-dioxane (30 mL). The mixture is degassed for 10 min by passing a stream of argon through the mixture. Then, [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (200 mg, 0.274 mmol) is added, and the mixture is degassed for another 3 min. The reaction mixture is then heated to 100°C and stirred at this temperature for 1 hour. After cooling to ambient temperature, the mixture is diluted with EtOAc and water. The organic phase is separated, dried over sodium sulfate and concentrated. The residue is taken up in DMF and purified by preparative HPLC (ZORBAX StableBond C18, ACN / water gradient containing 0.1% TFA) to give the desired product. C 20 H 17 F2N7O (M=409.4g / mol) ESI-MS: 410[M+H] + Rt(HPLC): 0.73 min (Method G)

[0158] Intermediate VI.2 6'-Fluoro-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5'-formyl-[2,3'-bipyridine]-4-carbonitrile (660 mg, 1.61 mmol) and tetrabutylammonium iodide (59.5 mg, 0.161 mmol) are added to DMSO (20 mL). Sodium azide (212 mg, 3.22 mmol) is then added portionwise at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 1 hour, and then diluted with semi-saturated aqueous sodium chloride solution. The organic phase is extracted with EtOAc (3x), and the combined organic layers are dried over sodium sulfate and concentrated to give the desired product, which is used in the next step without further purification. C 20 H 17 FN 10 O (M = 432.4 g / mol) ESI-MS: 433 [M+H] + Rt(HPLC): 0.66 min (Method G) Preparation of final compounds

[0159] Example 1 [ka] Under an argon atmosphere, intermediate III.1 (1.43 g, 3.92 mmol) and 2-fluoropyridine-5-boronic acid pinacol ester (873 mg, 3.92 mmol) are suspended in 1,4-dioxane (15 mL), and a solution of potassium carbonate (2 M in water, 3.9 mL, 7.8 mmol) is added. The resulting mixture is degassed for 15 min by passing a stream of argon through the solution. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (286 mg, 0.392 mmol) is added, and the mixture is degassed for another 3 min. The reaction mixture is heated to 100 °C and stirred for 5 h. After cooling to ambient temperature, it is diluted with ethyl acetate and filtered over Celite®. The filtrate is concentrated and purified via preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% NH3) to give the desired compound. C 19 H 17 F2N7 (M = 381.4 g / mol) ESI-MS: 382[M+H] + Rt(HPLC): 0.40 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (d, J=4.9 Hz, 1 H), 8.50 (d, J=2.3 Hz, 1 H), 8.48 (s, 1 H), 8.25 (td, J=8.2, 2.5 Hz, 1 H), 7.82 (d, J=4.8 Hz, 1 H), 7.34 (dd, J=8.4, 2.6 Hz, 1 H), 3.73 (d, J=1.6 Hz, 3 H), 3.15 - 3.28 (m, 4 H), 2.09 - 2.27 (m, 4 H) Examples synthesized according to the procedure described in Example 1

[0160] [Table 11-1] [Table 11-2]

Table 11-3

Table 11-4

Table 11-5

Table 11-6

[0161]

Table 12-1

Table 12-2

Table 12-3

Table 12-4

Table 12-5

Table 12-6

Table 12-7

Table 12-8

[0162] (Example 26)

change

[0163] Intermediate VI.1 (90.0 mg, 0.207 mmol) and cesium carbonate (135.2 mg, 0.414 mmol) are added to DMF (2.0 mL), and (iodomethyl)cyclopropane (56.6 mg, 0.311 mmol) is added. The resulting reaction mixture is heated to 80 °C and stirred at this temperature for 8 h. After cooling to ambient temperature, it is diluted with a mixture of ACN / water / TFA and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product. C 23 H 23 F2N7O (M=451.5g / mol) ESI-MS: 452[M+H] + Rt(HPLC): 0.52 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H), 8.51 - 8.53 (m, 1 H), 8.52 (d, J=4.8 Hz, 1 H), 7.94 (t, J=1.6 Hz, 1 H), 7.88 (dd, J=10.1, 1.8 Hz, 1 H), 7.82 (d, J=4.9 Hz, 1 H), 3.99 (d, J=7.1 Hz, 2 H), 3.74 (d, J=1.6 Hz, 3 H), 3.15 - 3.32 (m, 4 H), 2.09 - 2.30 (m, 4 H), 1.20 - 1.33 (m, 1 H), 0.52 - 0.65 (m, 1 H), 0.30 - 0.42 (m, 2 H). Example synthesized according to the procedure described in Example 26

[0164] [Table 13]

[0165] [Table 14]

[0166] Example 29 [ka]

[0167] Under an argon atmosphere, intermediate VI.2 (20.0 mg, 0.046 mmol) and iron(II) bromide (2.0 mg, 9.5 μmol) are suspended in DMSO (1.0 mL). 1,1,1-trifluoro-2-methyl-propan-2-amine hydrochloride (11.3 mg, 0.069 mmol) is added, and the resulting reaction mixture is heated to 120 ° C. and stirred at this temperature for 2 hours. After cooling to ambient temperature, the mixture is diluted with water and purified by preparative HPLC (ZORBAX StableBond C18, water / ACN gradient containing 0.1% TFA) to give the desired product. C 24 H 23 F4N9 (M = 513.5 g / mol) ESI-MS: 514[M+H] + Rt(HPLC): 0.65 min (Method L) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1 H), 8.92 (d, J=2.2 Hz, 1 H), 8.56 (d, J=4.8 Hz, 1 H), 8.49 (s, 1 H), 8.41 (d, J=2.2 Hz, 1 H), 7.81 (d, J=4.8 Hz, 1 H), 3.71 (d, J=1.3 Hz, 3 H), 3.23 - 3.28 (m, 4 H), 2.15 - 2.30 (m, 4 H), 2.03 (s, 6 H). Example synthesized according to the procedure described in Example 29

[0168] [Table 15]

[0169] [Table 16]

[0170]

Table 17

Table 18

[0171]

Table 19

[0172] Table 20

[0173] Table 21

[0174] Table 22

[0175] Table 23

[0176] Table 24

[0177] Table 25

[0178] Table 26

[0179] Table 27

[0180] Table 28

[0181] Table 29

Claims

1. A compound of formula (I) or a salt thereof. 【Chemical 1】 (I) (In the formula, Y is N and Z is R 4 C, or Y is HC and Z is N; A is A1a which is a 5 or 6 membered mono-heteroaryl ring, the 5 or 6 membered mono-heteroaryl ring containing one nitrogen or two heteroatom members, the first being nitrogen and the second being selected from nitrogen or sulfur; Alternatively, A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing 1 to 4 nitrogens; A1a or A1b are independently selected from one or two R 3 is replaced by R 1 is H, C 1-4 - selected from the R groups consisting of alkyl and halo; R 2 Is, halo, H, C 1-4 -Alkyl, C 3-4 -cycloalkyl and F 1-9 -Fluoro-C 1-4 -alkyl; R 3 is H, halo, C 1-4 -Alkyl, C 3-4 -cycloalkyl, C 3-4 -fluorocycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 3-4 -cycloalkyloxy and pyrazolyl, 【Chemistry 2】 and R groups consisting of: R 4 Is, halo, H, C 1-4 -Alkyl, C 3-4 -cycloalkyl and F 1-9 -Fluoro-C 1-4 -alkyl)

2. A is selected from the group A3 consisting of pyridinyl, pyrazinyl, pyrazolyl, isothiazolyl, imidazo[1,2-a]pyrimidyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidyl, pyrazolo[1,5-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 2H-[1,2,3]triazolo[4,5-b]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, and 1H-imidazo[4,5-b]pyridinyl; A is independently selected from one or two R 3 2. The compound of formula (I) according to claim 1, or a salt thereof, substituted with:

3. A is selected from the group A consisting of: 3 2. The compound of formula (I) according to claim 1, or a salt thereof, substituted with: 【Chemistry 3】

4. R 2 But H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 4. The compound of formula (I) or a salt thereof according to claim 1, wherein R2b is selected from the group consisting of -alkyl.

5. R 3 But, H, halo, C 1-4 -Alkyl, C 3-4 -cycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 3-4 -cycloalkyloxy and pyrazolyl, 【Chemistry 4】 The compound of formula (I) or a salt thereof according to any one of claims 1 to 4, wherein R3b is selected from the group consisting of:

6. The compound of formula (I) according to any one of claims 1 to 5, having the formula (Ia), or a salt thereof. 【Chemistry 5】 (Ia)

7. The compound of formula (I) according to any one of claims 1 to 5, having the formula (I-b), or a salt thereof: 【Chemistry 6】 (Ib)

8. 2. A compound of formula (I) according to claim 1, or a salt thereof, selected from the group consisting of: 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】

9. A pharmaceutically acceptable salt of a compound according to one or more of claims 1 to 8.

10. A pharmaceutical composition comprising one or more compounds according to one or more of claims 1 to 8 or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

11. 10. A pharmaceutical composition comprising one or more compounds according to one or more of claims 1 to 8 or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

12. 12. The pharmaceutical composition of claim 11, wherein the one or more additional therapeutic agents are selected from the group consisting of anti-cancer agents and anti-fibrotic agents.

13. A compound according to one or more of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

14. 10. A method for treating a disease, such as cancer or a fibrotic disease, and conditions associated with these diseases, in a patient in need thereof, characterized in that one or more of the compounds according to one or more of claims 1 to 8 or pharmaceutically acceptable salts thereof are administered to the patient.

15. 10. A compound or a pharmaceutically acceptable salt thereof according to one or more of claims 1 to 8 for use in a method for treating cancer, a fibrotic disease, a neurodegenerative disease, atherosclerosis, an infectious disease or chronic kidney disease.

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