Piperidinyl pyridinyl formonitrile derivatives as inhibitors of glutaminyl peptide cyclotransferases and glutaminyl peptide cyclotransferase-like proteins

Abstract

The present invention provides certain piperidinyl pyridinyl formonitrile derivatives, and pharmaceutically acceptable salts thereof, which are inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like protein (QPCTL), and are thus useful in the treatment of diseases that can be treated by inhibition of QPCT / L. The invention also provides pharmaceutical compositions containing the same and methods for preparing the compounds.

Description

Technical Field

[0001] The present invention provides certain piperidinyl pyridinyl carbonitrile derivatives and their pharmaceutically acceptable salts, which are inhibitors of glutaminyl peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like protein (QPCTL), and are therefore useful for treating diseases treatable by inhibiting QPCT / L. The present invention also provides pharmaceutical compositions containing piperidinyl pyridinyl carbonitrile derivatives and their pharmaceutically acceptable salts and methods for preparing these compounds. Background Art

[0002] Glutamine peptide cyclotransferase (QPCT) and glutamine peptide cyclotransferase-like protein (QPCTL) catalyze the intramolecular cyclization of N-terminal glutamine (Q) residues to pyroglutamate (pE), thereby releasing ammonia [Stephan Schilling et al., “Identification of Human Glutaminyl Cyclase as a Metalloenzyme POTENTINHIBITION BY IMIDAZOLE DERIVATIVES AND HETEROCYCLIC 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 Maturation Machinery,” Journal of Molecular Biology 379, No. 5 (2008): 966-80, https: / / doi.org / 10.1016 / j.jmb.2008.03.078; Anett Stephan et al., "Mammalian Glutaminyl Cyclases and Their Isoenzymes Have Identical Enzymatic Characteristics", FEBS Journal 276, No. 22 (2009): 6522-36, https: / / doi.org / 10.1111 / j.1742-4658.2009.07337.x.]. Although QPCT is a secreted protein, QPCTL is retained in the high-base complex. The two enzymes have 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 the same time. Due to their different cellular localization, differences in their relevance to modification of biological substrates have been reported. A known substrate for intracellular QPCTL and / or extracellular QPCT is CD47 [Meike EWLogtenberg 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.], different 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 Biologic Activity”, Bioscience Reports 37, No. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.], amyloid-β-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 hormone-like 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.]. Modification of the N-terminal glutamine on the substrate to pyroglutamate has functional effects on the protein and can affect different pathological mechanisms of several diseases. CD47 is expressed on the cell surface of almost all cells in the body, including apoptotic cells, senescent cells or 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 main ligand for CD47 is signal regulatory protein α (SIRPα), an inhibitory transmembrane receptor present on myeloid cells (such as macrophages, monocytes, neutrophils, dendritic cells, etc.). SIRPα binding requires QPCTL-mediated N-terminal pyroglutamate modification on CD47 [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 E. W. 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.] These signaling axes induce a "Don't Eat Me Signal" that prevents macrophages from phagocytosing cells expressing CD47. Therefore, high expression of CD47 is associated with the following pathogenesis: 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.]. Because enhanced CD47 expression blocks the clearance of apoptotic cells, apoptotic lung epithelial cells increase, leading to profibrotic stimulation and accelerated 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.Since CD47 half-life and function are primarily dependent on QPCTL enzyme activity, QPCT and QPCTL inhibition may be a suitable mechanism for the treatment of pulmonary fibrosis (such as IPF or SSC-ILD) [Lerbs et al., "CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma"], alone or in combination with current standards of care for 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 other 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]. .

[0003] Through the expression of CD47, cancer cells can escape destruction by the immune system or 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].

[0004] 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 was shown to increase in vivo activity by conferring resistance to aminopeptidases and by increasing their ability to induce chemokine receptor signaling. Two major monocyte chemoattractants, CCL2 and CCL7, are insensitive to DPP4 activation in vivo due to an intracellular mechanism of N-terminal cyclization mediated by the high matrix-associated enzyme QPCTL. QPCTL has been shown to be a key regulator of monocyte migration into solid tumors [Kaspar Bresser et al., “QPCTLRegulates 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 of chemokines has long been considered a potential strategy for modulating cellular trafficking in different disease settings.

[0005] Therefore, there is a need to provide potent QPCT / L inhibitors.

[0006] Jimenez-Sanchez et al., Nature Chemical Biology, 2015, 11, 347-357, (hereinafter "JS, NCB 2015") disclose human glutaminyl cyclase (hQC) inhibitors SEN177 and SEN180:

[0007]

[0008] SEN177 is disclosed in (Supplementary Information) as having an IC of 53 nM for isolated hQC and 13 nM for isolated QPCTL. 50 SEN180 is disclosed in (Supplementary Information) as having an IC of 170 nM for hQC and 58 nM for QPCTL. 50 .

[0009] Pozzi, C et al., Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226, (hereinafter "P, JBIC 2018") further disclosed SEN177 and its binding mode in the hQC cavity. SEN177 is disclosed therein as having a K of 20 nM for isolated hQC. i .

[0010] 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):

[0011]

[0012] WO 2018 / 178384 does not disclose any biological data for Examples 1094 or 1095. Summary of the invention

[0013] The present invention discloses novel piperidinylpyridinylcarbonitrile derivatives of formula (I),

[0014]

[0015] It is an inhibitor of glutaminyl peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like protein (QPCTL), having suitable pharmacological and pharmacokinetic properties so that it can be used as a pharmaceutical agent for treating disorders and / or diseases that can be treated by inhibiting QPCT / L.

[0016] The compounds of the present invention may offer several advantages, such as enhanced potency, cellular potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein binding, enhanced bioavailability, a suitable pharmacokinetic profile and the possibility of forming stable salts.

[0017] Compounds of the present invention

[0018] The present invention provides novel piperidinylpyridinylcarbonitrile derivatives that are surprisingly potent inhibitors of QPCT and QPCTL (Assay A), and of QPCT / L in cells associated with, but not limited to, lung disease or cancer (Assay B).

[0019] Furthermore, the novel piperidinylpyridinylcarbonitrile derivatives of the present invention have suitable membrane permeability and low in vitro efflux (Assay C).

[0020] Therefore, the compounds of the present invention are more feasible for human use.

[0021] The compounds of the present invention differ structurally from SEN177 in Pozzi, C et al., Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226 in that the pyridyl ring attached to the piperidyl ring contains a ring nitrogen that is located in either of the two meta positions of the piperidyl ring attachment position. In addition, the carbonitrile substituent is attached to the pyridyl ring in the ortho position of the piperidyl ring attachment position. Furthermore, R 1 and R 2 It is not limited to hydrogen or methyl and A represents a heterocyclic ring system other than pyridyl.

[0022] The compounds of the present invention differ structurally from Examples 1094 and 1095 in WO 2018 / 178384 in that the pyridyl ring attached to the piperidyl ring contains a ring nitrogen located in either of the two meta positions of the piperidyl ring attachment position. In addition, the carbonitrile substituent is attached to the pyridyl ring in the ortho position of the piperidyl ring attachment position. Furthermore, R 1 and R 2 It is not limited to hydrogen and A represents a heterocyclic ring system other than pyridyl. Further, the 5-membered heterocyclic ring attached to the piperidinyl ring at the 4 position relative to the piperidinyl nitrogen is an aminothiazolyl ring in Embodiment 1094 and an aminothiadiazolyl ring in Embodiment 1095, while in the compounds of the present invention, it is a 3-substituted-4-methyl-4H-1,2,4-triazolyl ring.

[0023] These structural differences between the compounds of the present invention and the prior art unexpectedly result in the following advantageous combination: (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells associated with (but not limited to) lung disease or cancer, and (iii) appropriate membrane permeability and low in vitro efflux.

[0024] Therefore, the compounds of the present invention are superior to those disclosed in the prior art with respect to the combination of the following parameters:

[0025] · Potent inhibition of QPCT and QPCTL (Assay A)

[0026] Potent inhibition of QPCT / L in cells associated with (but not limited to) lung disease or cancer (Assay B)

[0027] ·Suitable membrane permeability and low in vitro efflux (Assay C)

[0028] The present invention provides novel compounds according to formula (I)

[0029]

[0030] in

[0031] Y is N and Z is R 4 C or Y is HC and Z is N;

[0032] A is A1a which is a 5- or 6-membered monoheteroaryl ring containing one nitrogen or containing two heteroatom members, one of which is nitrogen and the second is selected from nitrogen or sulfur;

[0033] or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing one to four nitrogen atoms; and wherein A1a or A1b is independently substituted by one or two R 3 replace;

[0034] R 1 Choose from H, C 1-4 - A group R1a consisting of an alkyl group and a halogen group;

[0035] R 2 Selected from halogen, H, C 1-4 -alkyl, C 3-4 -Cycloalkyl and F 1-9 -Fluoro-C 1-4 - an alkyl group R2a;

[0036] R 3 Selected from H, halogen, C 1-4 -alkyl, C 3-4 -Cycloalkyl, C 3-4 -Fluorinated cycloalkyl, F 1-9 -Fluoro-C1-4 -alkyl, C 1-4 -alkoxy, C 3-4 -cycloalkoxy and pyrazolyl, The group R3a composed of

[0037] R 4 Selected from halogen, H, C 1-4 -alkyl, C 3-4 -Cycloalkyl and F 1-9 -Fluoro-C 1-4 - an alkyl group R4a;

[0038] or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

[0039] Another embodiment of the present invention relates to compounds of formula (I), wherein

[0040] A is A2a, which is a 5- or 6-membered monoheteroaryl ring containing one nitrogen or containing two heteroatom members, wherein one heteroatom is nitrogen and the second heteroatom is selected from nitrogen or sulfur; and wherein A2a is independently substituted by one or two R 3 replace;

[0041] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0042] Another embodiment of the present invention relates to compounds of formula (I), wherein

[0043] A is A2b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing three to four nitrogens; and wherein A2b is independently substituted by one or two R 3 replace;

[0044] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0045] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from the group consisting of pyridyl, pyrazinyl, pyrazolyl, isothiazolyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 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 and wherein A3 is independently substituted with one or two R 3 replace;

[0046] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0047] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a radical A4 of the group consisting of pyridyl, pyrazinyl, pyrazolyl, isothiazolyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl and pyrazolo[1,5-b]pyridazinyl; and wherein A4 is independently substituted by one or two R 3 replace;

[0048] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0049] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from the group consisting of pyridyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl and pyrazolo[1,5-b]pyridazinyl; and wherein A5 is independently substituted by one or two R 3 replace;

[0050] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0051] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A6 consisting of pyridyl and pyrazolo[1,5-b]pyridazinyl; and wherein A6 is independently substituted by one or two R 3 replace;

[0052] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0053] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from the group consisting of: pyridyl; and wherein A is independently substituted by one or two R 3 replace;

[0054] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0055] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from the group consisting of: pyrazolo[1,5-b]pyridazinyl; and wherein A8 is independently substituted by one or two R 3 replace;

[0056] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0057] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A9 consisting of:

[0058]

[0059]

[0060] A9 is independently connected to one or two R 3 replace;

[0061] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0062] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A10 consisting of:

[0063]

[0064] A10 is independently connected to one or two R 3 replace;

[0065] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0066] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A11 consisting of:

[0067]

[0068] A11 is independently connected to one or two R 3 replace;

[0069] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0070] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A12 consisting of:

[0071]

[0072] A12 is independently connected to one or two R 3 replace;

[0073] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0074] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A13 consisting of:

[0075]

[0076] A13 is independently connected to one or two R 3 replace;

[0077] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0078] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A14 consisting of:

[0079]

[0080] A14 is independently connected to one or two R 3 replace;

[0081] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0082] Another embodiment of the present invention relates to compounds of formula (I), wherein A is selected from a group A15 consisting of:

[0083]

[0084] A15 is independently connected to one or two R 3 replace;

[0085] and substituent R 1 , R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0086] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 R1b is a group selected from H, H3C-, H3CH2C-, H3CH2CH2C-, (H3C)2HC-, Cl and F;

[0087] and substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0088] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 R1c is selected from the group consisting of H, H3C- and F;

[0089] and substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0090] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 R1d is selected from the group consisting of H;

[0091] and substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0092] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 R1e is selected from the group consisting of F;

[0093] and substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0094] Another embodiment of the present invention relates to compounds of formula (I), wherein R 1 R1f is selected from the group consisting of H3C- and F;

[0095] and substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0096] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 Selected from H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 - a group R2b consisting of an alkyl group;

[0097] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0098] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 Choose from H, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl group R2c;

[0099] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0100] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 R2d is selected from the group consisting of H, H3C-, and F3C-;

[0101] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0102] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2is selected from the group R2e consisting of H;

[0103] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0104] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 R2f is selected from the group consisting of H3C- and F3C-;

[0105] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0106] Another embodiment of the present invention relates to compounds of formula (I), wherein R 2 Selected from F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 -alkyl group R2g;

[0107] and substituents A and R 1 , R 3 and R 4 is as defined in any of the previous embodiments.

[0108] Another embodiment of the present invention relates to compounds of formula (I),

[0109] Where R 3 Selected from H, halogen, C 1-4 -alkyl, C 3-4 -Cycloalkyl, F 1-9 -Fluoro-C 1-4 -alkyl, C 1-4 -alkoxy, C 3-4 -cycloalkoxy and pyrazolyl, The group R3b composed of

[0110] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0111] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 Selected from H, F, Cl, H3C, (H3C)3C-, H3C-O-, F3C-,

[0112] The group R3c is composed of;

[0113] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0114] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 Selected from H, F, Cl, H3C, (H3C)3C-, H3C-O-, F3C- and The group R3d is composed of;

[0115] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0116] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 Select from H, H3C-O-, The group R3e is composed of;

[0117] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0118] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 R3f is selected from the group consisting of H, H3C, (H3C)3C-, H3C-O- and F3C-;

[0119] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0120] Another embodiment of the present invention relates to compounds of formula (I), wherein R 3 R3g is selected from the group consisting of H, F and Cl;

[0121] and substituents A and R 1 , R 2 and R 4 is as defined in any of the previous embodiments.

[0122] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 Selected from H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 - an alkyl group R4b;

[0123] and substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0124] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 Choose from H, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 - an alkyl group R4c;

[0125] and substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0126] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 R4d is selected from the group consisting of H, H3C-, and F3C-;

[0127] and substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0128] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 is selected from the group R4e consisting of H;

[0129] and substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0130] Another embodiment of the present invention relates to compounds of formula (I), wherein R 4 R4f is selected from the group consisting of H3C- and F3C-;

[0131] and substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0132] Another embodiment of the present invention relates to compounds of formula (I) above, which have the formula (Ia)

[0133]

[0134] The substituents A and R 1 , R 2 , R 3and R 4 is as defined in any of the previous embodiments. Another embodiment of the present invention relates to compounds of formula (I) above, which have formula (Ib)

[0135]

[0136] The substituents A and R 1 , R 2 and R 3 is as defined in any of the previous embodiments.

[0137] Another embodiment of the present invention relates to compounds of formula (I) above, which have the formula (Ic)

[0138]

[0139] The substituents A and R 2 and R 3 is as defined in any of the previous embodiments.

[0140] Another embodiment of the present invention relates to compounds of formula (I) above, which have the formula (Id)

[0141]

[0142] The substituents A and R 2 , R 3 and R 4 is as defined in any of the previous embodiments. Another embodiment of the present invention relates to compounds of formula (I) above, which have formula (Ie)

[0143]

[0144] The substituents A and R 2 and R 3 is as defined in any of the previous embodiments.

[0145] Another embodiment of the present invention relates to compounds of formula (I) above, which have the formula (If)

[0146]

[0147] The substituent R 2 , R 3 and R 4 is as defined in any of the previous embodiments.

[0148] Further preferred embodiments of the compounds of the formula (I) are contained in the following Table 1 as embodiments (EMB-1) to (EMB-20), wherein the above definitions of substituents apply.

[0149] Table 1: Other preferred embodiments

[0150]

[0151]

[0152] For example, the compounds of embodiment EMB-1 are directed to R 1 The generic group R1e having the generic group as defined above is combined with the other generic groups for the other substituents in formula (I) as defined in the same column of the table. The same applies to the other variables incorporated in the general formula.

[0153] Particularly preferred are compounds according to formula (I) selected from the group consisting of:

[0154]

[0155]

[0156]

[0157]

[0158] 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, as described below in the Examples.

[0159] 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, as described below in the Examples.

[0160] 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, as described below in the Examples.

[0161] The present invention provides novel piperidinylpyridinylcarbonitrile derivatives of formula (I) which are surprisingly potent QPCT / L inhibitors.

[0162] Another aspect of the invention relates to compounds according to formula (I) which surprisingly have potent inhibition of QPCT / L in cells associated with (but not limited to) lung diseases or cancer.

[0163] Another aspect of the invention relates to compounds according to formula (I), which surprisingly act as potent QPCT / L inhibitors of cells with suitable membrane permeability and low in vitro efflux.

[0164] Another aspect of the invention relates to pharmaceutical compositions containing at least one compound according to formula (I), optionally together with one or more inert carriers and / or diluents.

[0165] Another aspect of the invention relates to compounds according to formula (I) for use in the prevention and / or treatment of disorders associated with QPCT / L inhibition.

[0166] Another aspect of the invention relates to methods of making the compounds of the invention.

[0167] Other aspects of the present invention will become apparent to those skilled in the art directly from the foregoing and following descriptions and examples. DETAILED DESCRIPTION

[0168] Terms and definitions used

[0169] General Definition

[0170] Terms not specifically defined herein shall have the meanings given to them by those skilled in the art based on the present disclosure and context. However, as used in this specification, unless otherwise specified to the contrary, the following terms have the meanings indicated by the present invention and follow the following conventions.

[0171] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, e.g. 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, one skilled in the art can see the radical attachment point to the molecule from the free valence of the group itself. For a combined group containing two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C 1-3 "-alkylene" means bonded to C 1-3 -aryl to an alkyl group, the former being bound to the core or to the group to which the substituent is attached.

[0172] Where compounds of the invention are depicted both in the form of chemical names and as formulas, the formula will control if there is any conflict. Asterisks may be used in subformulas to indicate bonds to a defined core molecule.

[0173] The numbering of the atoms of a substituent begins with the atom closest to the core or group to which the substituent is attached.

[0174] For example, the term "3-carboxypropyl" refers to the following substituents:

[0175]

[0176] wherein the carboxyl group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group refers to the following groups:

[0177]

[0178] Asterisks may be used in subformulas to indicate the bond to the defined core molecule.

[0179] As used herein, the term "substituted" means that one or more hydrogens on the designated atom are replaced with a group selected from a 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. Likewise, the term "substituted" may be used in conjunction with chemical moieties rather than individual atoms, such as "substituted alkyl," "substituted aryl," or the like.

[0180] Unless expressly indicated otherwise, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates and mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures in which any of these isomers and enantiomers are present in the aforementioned forms, and solvates thereof (such as, for example, hydrates).

[0181] Unless expressly indicated otherwise, a "pharmaceutically acceptable salt" as also defined in more detail below, shall include solvates thereof (such as, for example, hydrates).

[0182] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separation of the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. Methods for preparing optically active forms are known in the art, such as by resolution of racemic forms or by synthesis, for example starting from optically active starting materials and / or by using chiral reagents.

[0183] Enantiomerically pure compounds or intermediates of the invention may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates, which may be separated by known methods (e.g. by chromatographic separation or crystallization) and / or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliary agents.

[0184] Furthermore, the person skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on a chiral stationary phase; or by resolution of the racemic mixtures using suitable resolving agents, for example by means of formation of diastereomeric salts with an optically active acid or base, subsequent resolution of the salts and liberation of the desired compound from the salts; or by derivatization of the corresponding racemic compounds with an optically active chiral auxiliary reagent, subsequent separation of the diastereomers and removal of the chiral auxiliary group; or by kinetic resolution of the racemates (for example by enzymatic resolution); by enantioselective crystallization from clusters of enantiomeric crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0185] The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0186] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds disclosed herein, wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and the like.

[0187] For example, these 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. Other pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminodiethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0188] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally speaking, these salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof).

[0189] Salts of acids other than those mentioned above, such as trifluoroacetate salts, which are useful for purifying or isolating the compounds of the invention, also form part of the present invention.

[0190] The term halogen denotes fluorine, chlorine, bromine and iodine.

[0191] The term "C 1-n -alkyl", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6, alone or in combination with another group, represents a non-cyclic saturated branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5 -Alkyl groups include the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)2-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0192] The term "C 3-k -cycloalkyl", wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, alone or in combination with another group, means a cyclic saturated unbranched hydrocarbon group having 3 to k C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0193] The term "halo" added to an "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsaturated) defines an alkyl, alkylene or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine (preferably fluorine and chlorine, particularly preferably fluorine). Examples include: H2FC-, HF2C-, F3C-.

[0194] The term "monoheteroaryl ring" means a monocyclic aromatic ring system consisting of 5 to 6 ring atoms containing one or more heteroatoms selected from N or S.

[0195] The term "monoheteroaryl ring" is intended to include all possible isomeric forms.

[0196] Thus, the term "monoheteroaryl ring" includes the following exemplary structures (not depicted as radicals because each form may be optionally attached via a covalent bond to any atom as long as proper valence is maintained):

[0197]

[0198] The term "fused bicyclic heteroaryl ring" means a bicyclic aromatic ring system consisting 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 because each form may be optionally attached to any atom via a covalent bond as long as proper valence is maintained):

[0199]

[0200] The term pyridyl refers to a group having the following ring:

[0201] The term pyrazinyl refers to a group having the following ring:

[0202] The term pyrazolyl refers to a group having the following ring:

[0203] The term isothiazolyl refers to a group having the following ring:

[0204] The term imidazo[1,2-a]pyrimidinyl refers to a group having the following ring:

[0205]

[0206] The term pyrazolo[3,4-b]pyridinyl refers to a group having the following ring:

[0207]

[0208] The term [1,2,4]triazolo[4,3-a]pyrimidinyl refers to a group having the following ring:

[0209] The term pyrazolo[1,5-b]pyridazinyl refers to a group having the following ring:

[0210]

[0211] The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to a group having the following ring:

[0212] The term 2H-[1,2,3]triazolo[4,5-b]pyridinyl refers to a group having the following ring:

[0213] The term 1H-[1,2,3]triazolo[4,5-b]pyridinyl refers to a group having the following ring:

[0214] The term 1H-imidazo[4,5-b]pyridinyl refers to a group having the following ring:

[0215]

[0216] Many of the terms given above may be used repeatedly in the definitions of formulae or radicals and in each case independently of one another have one of the meanings given above.

[0217] Biological analysis

[0218] Evaluation of the inhibitory activity against QPCT and QPCTL

[0219] Analysis A: Biochemical QPCT and QPCTL Activity Assay

[0220] The activity of the compounds of the present invention can be demonstrated using the following biochemical enzyme activity assays:

[0221] 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 into clear 1,536-well microtiter plates. Enzymatic reactions were set up in assay buffer containing 20 mM Tris pH 7.5, 0.1 mM TCEP, 0.01% BSA, and 0.001% Tween 20. 2.5 μL of 2x concentrated QPCTL (in-house) or QPCT (Origine #TP700028) enzyme in assay buffer (0.5 nM final concentration, rows 1 to 23) or normal assay buffer (row 24) was added to each well. The plates were incubated at 24°C for 10 min in a humidified incubator. 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 plates were mixed at 1,000 rpm for 30 seconds and then incubated at 24°C in a humidified incubator for 40 min. After incubation, 1 μL of a stable isotope-labeled internal standard peptide was added. 19 [Pyr]LLFN(K)TKSVEFTFC 33The enzymatic reaction was stopped by adding 4% paraformaldehyde (final concentration 4.0 μM) and SEN177 (final concentration 10 μM). The plates were sealed with adhesive foil, mixed at 1,000 rpm for 30 s and stored at room temperature until the preparation of MALDI target plates. MALDI target plates were prepared as described previously. The products were tracked using a rapifleX MALDI-TOF / TOF instrument ( 19 [Pyr]LLFNKTKSVEFTFC 33 , m / z 1,787.9037) and internal standard ( 19 [Pyr]LLFN(K)TKSVEFTFC 33 , m / z 1,795.9179) peptide signal to acquire a mass spectrum. QPCT or QPCTL activity was monitored by calculating the ratio between the product and internal standard signals, followed by normalization to high (100% activity) and low (0% activity) controls. Determination of compound potency was obtained by fitting the dose-response data to a four-parameter logistic equation.

[0222] Table 2: Biological data of compounds of the invention as obtained in Assay A.

[0223]

[0224]

[0225] Table 3: Biological data of prior art compounds as obtained in Assay A.

[0226]

[0227] Analysis B: SIRPα signaling analysis (using Raji or A549 cells)

[0228] The activity of the compounds of the invention can be demonstrated using the following SIRPα signaling assay, which measures SIRPα engagement induced by CD47 presented via cell-cell interactions. Two cell types were used independently: the Raji cell line (a lymphoblastoid human cell line derived from B lymphocytes from a patient with Burkitt's lymphoma in 1963) and A549 cells (adenocarcinoma human alveolar basal epithelial cells).

[0229] Test compounds were dissolved in 100% DMSO and serially diluted into white 384-well microtiter cell culture plates (PerkinElmer #60076780 in the case of the Raji assay; Greiner #781945, PDL-coated plates in the case of the A549 assay). 5000 Raji cells (ATCC #CC86) or 5000 A549 cells (ATCC #CCL-185) in assay whole cell seeding reagent 30 (DiscoverX 93-0563R30B) were added per well. The assay plates were incubated for 48 h at 37° C., 95% humidity and 5% CO2. 15,000 reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93-1135C19) were added to each well and the plates were incubated for 5 h at 37° C., 95% humidity and 5% CO2. Bioassay Reagent 1 of the PathHunter Bioassay Detection Kit (DiscoverX 93-0001) was added to each well of the plate using a multichannel pipette, followed by incubation at room temperature for 15 min. Bioassay Reagent 2 was then added, followed by incubation at room temperature for 60 min (incubation in the dark).

[0230] Data were analyzed using luminescence signals generated by β-galactosidase in PathHunter reporter cell lines. Luminescence measurements were performed using a Pherastar multimode reader. Dose-response curves and IC were calculated using a 4-parameter sigmoidal dose-response equation. 50 data.

[0231] Table 4: Biological data of compounds of the invention as obtained in Assay B.

[0232]

[0233]

[0234] Table 5: Biological data of prior art compounds as obtained in Assay B.

[0235]

[0236] Permeability assessment

[0237] Assay C: Permeability in CACO-2 cells

[0238] Caco-2 cells (1 to 2 x 105 cells / 1 cm2 area) are seeded onto filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days. The compound is dissolved in an appropriate solvent (such as DMSO, 1 to 20 mM stock solution). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x 7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare a transport solution (0.1 to 300 μM compound, final DMSO <= 0.5%). The transport solution (TL) was applied to the apical or basolateral donor side for measuring AB or BA permeability, respectively (3 filtration replicates). Samples were collected from the donor at the beginning and end of the experiment and also from the receiver side at various time intervals for up to 2 hours for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiver volume was replaced with fresh receiver solution.

[0239] Efflux ratio (ER) = Permeability BA / Permeability AB

[0240] Table 7: Biological data of compounds of the invention as obtained in Assay C.

[0241]

[0242]

[0243] Table 8: Biological data of prior art compounds as obtained in assay C.

[0244]

[0245] Assessment of microsomal clearance

[0246] Microsomal clearance:

[0247] The metabolic degradation of the test compound was analyzed at 37°C with mixed liver microsomes from various species. The final culture volume of 60 μl at each time point contained TRIS buffer (0.1M) at room temperature pH 7.6, magnesium chloride (5mM), microsomal protein (1mg / mL for humans and dogs, 0.5mg / mL for other species) and a test compound at a final concentration of 1 μm. After a short pre-culture at 37°C, the reaction was started by adding the β nicotinamide adenine dinucleotide phosphate of the reduced form (NADPH, 1mM), and the reaction was terminated by transferring aliquots to the solvent after different time points. After centrifugation (10000g, 5min), the amount of the parent compound in the aliquots of the supernatant was analyzed by LC-MS / MS. The half-life was determined by the slope of the semi-logarithmic graph of the concentration-time curve.

[0248] The intrinsic clearance (CL_intrinsic) was calculated by taking into account the amount of protein in the culture:

[0249] CL_intrinsic [μl / min / mg protein] = (Ln 2 / (half-life [min]*protein content [mg / ml]))*1000

[0250] CL_intrinsic_in vivo [ml / min / kg] = (CL_intrinsic [μL / min / mg protein] x MPPGL [mg protein / g liver] x liver factor [g / kg body weight]) / 1000

[0251] Qh[%]=CL[ml / min / kg] / liver blood flow[ml / min / kg])

[0252] Hepatocellular, human: 120x10e6 cells / g liver

[0253] Hepatic factor, human: 25.7 g / kg body weight

[0254] Blood flow, human: 21ml / (min x kg)

[0255] Assessment of hepatocyte clearance

[0256] Hepatocyte clearance

[0257] Metabolic degradation of test compounds was analyzed in human hepatocyte suspensions. After recovery from cryopreservation, human hepatocytes were diluted in Dulbecco's modified Eagle's medium (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, 5% human serum) to obtain 1.0×10 6 The final cell density was 10 cells / mL.

[0258] After pre-incubation for 30 min in a cell culture incubator (37° C., 10% CO 2 ), the test compound solution was spiked into the hepatocyte suspension resulting in a final test compound concentration of 1 μM and a final DMSO concentration of 0.05%.

[0259] The cell suspension was cultured at 37°C (cell culture incubator, horizontal shaker) and samples were removed from the culture after 0, 0.5, 1, 2, 4 and 6 hours. The samples were quenched with acetonitrile (containing internal standard) and pelleted by centrifugation. The supernatant was transferred to a 96-deep well plate and prepared for analysis of the reduction of the parent compound by HPLC-MS / MS.

[0260] The percentage of residual test compound was 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 were plotted against incubation time, and the absolute value of the slope obtained by linear regression analysis was used to estimate the in vitro half-life (T1 / 2).

[0261] In vitro intrinsic clearance (CLint) was calculated from the in vitro T1 / 2 and scaled to whole liver using a hepatocyte population of 120 x 106 cells / g liver, a human liver per body weight of 25.7 g liver / kg and in vitro culture parameters, applying the following equation:

[0262] CL_intrinsic_in vivo [mL / min / kg] = (CL_intrinsic [μL / min / 106 cells] x hepatocytes [106 cells / g liver] x hepatocytes [g / kg body weight]) / 1000

[0263] Prediction of hepatic in vivo blood clearance (CL) based on a well-stirred liver model taking into account a mean hepatic blood flow (QH) of 20.7 mL / min / kg:

[0264] CL [mL / min / kg] = CL_intrinsic_in vivo [mL / min / kg] x liver blood flow [mL / min / kg] / (CL_intrinsic_in vivo [mL / min / kg] + liver blood flow [mL / min / kg])

[0265] The results are expressed as a percentage of liver blood flow:

[0266] QH[%]=CL[mL / min / kg] / liver blood flow[mL / min / kg])

[0267] Assessment of plasma protein binding

[0268] The approximate in vitro partial binding of the test compounds to plasma proteins was determined using the equilibrium dialysis technique using Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consisted of a donor and an acceptor compartment separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. A stock solution of each test compound was prepared at 1 mM in DMSO and serially diluted to obtain a final test concentration of 1 μM. The dialysis solution was then prepared in plasma (supplemented with NaEDTA as an anticoagulant) and an aliquot of 200 μl of the test compound dialysis solution in plasma was distributed into the donor (plasma) compartment. An aliquot of 200 μl of dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7% dextran) was distributed into the buffer (acceptor) compartment. The incubation was carried out for 2 hours at 37° C. under rotation for establishment of equilibrium.

[0269] At the end of the dialysis period, aliquots obtained from the donor and acceptor compartments, respectively, were transferred into reaction tubes and processed for HPLC-MS / MS analysis.The analyte concentrations in aliquots of the samples were quantified by HPLC-MS / MS against a calibration curve.

[0270] Calculate the percentage limits using the following formula:

[0271] % binding = (plasma concentration - buffer concentration / plasma concentration) x 100

[0272] Solubility Assessment

[0273] Saturated solution is prepared in a well plate (form depends on the automatic operation device) by adding a selected aqueous medium of appropriate volume (usually in the range of 0.25 to 1.5 ml) to each hole containing a known amount of solid bulk drug (usually in the range of 0.5 to 5.0 mg). The hole is vibrated or stirred for a predetermined time period (usually in the range of 2 to 24 h) and then filtered using an appropriate filter membrane (usually 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 bulk drug is determined by UV spectroscopy. In addition, the pH of the saturated aqueous solution is measured using a glass electrode pH meter.

[0274] Assessment of metabolism in human hepatocytes in vitro

[0275] Metabolic pathways of test compounds were studied using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes were cultured 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.

[0276] After pre-incubation for 30 min in a cell culture incubator (37°C, 10% CO2), the test compound solution was spiked into the hepatocyte suspension to obtain a concentration of 1.0*10 6 Up to 4.0*10 6 The cells were cultured at a final cell density of 10 cells / ml (depending on the metabolic turnover of the compound observed with primary human hepatocytes), a final test compound concentration of 10 μM, and a final DMSO concentration of 0.05%.

[0277] Cells were cultured in a cell culture incubator on a horizontal shaker for six hours, and samples were removed from the cultures after 0, 0.5, 1, 2, 4, or 6 hours, depending on metabolic turnover. Samples were quenched with acetonitrile and pelleted by centrifugation. Supernatants were transferred to 96-deep well plates, evaporated under nitrogen, and resuspended before bioanalysis by liquid chromatography-high resolution mass spectrometry for identification of putative metabolites.

[0278] Based on Fourier transform-MS n Data are provisionally assigned structure. Metabolites are reported as percentage of the parent in human hepatocyte culture with a threshold value of ≥4%.

[0279] Evaluation of pharmacokinetic properties

[0280] The test compound is administered intravenously or orally to the respective test species. Blood samples are collected at several time points after administration of the test compound, anticoagulated and centrifuged.

[0281] The concentration of analyte (administered compound and / or metabolite) in plasma samples was quantified. PK parameters were calculated using a non-compartmental approach. AUC and Cmax were dose normalized to 1 μmol / kg.

[0282] Treatment

[0283] The present invention relates to compounds of general formula (I), which are suitable for preventing and / or treating diseases and / or disorders associated with or regulated by QPCT / L activity, including (but not limited to) treating and / or preventing cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney disease.

[0284] The compounds of general formula (I) are suitable for preventing and / or treating the following:

[0285] (1) Pulmonary fibrosis diseases, such as pneumonia or interstitial pneumonia associated with collagen degeneration (e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis, and dermatomyositis), idiopathic interstitial pneumonia, such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis associated with interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, proteinosis), Lambda-cell histiocytosis, pleural parenchymal elastosis, interstitial lung disease of known cause, such as interstitial pneumonia due to occupational exposure, such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon farmer's lung (birds), or other occupational air pollutant triggers (such as metal dust or mycobacteria), or interstitial pneumonia caused by treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy), or injections. For granulomatous diseases, such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis or interstitial pneumonitis caused by different origins (e.g., inhalation, inhalation of toxic gases, vapors), bronchitis or pneumonia or interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, M. boeck's sarcoid or sarcoidosis, granulomatosis, cystic fibrosis or muco-obstructive disease or alpha 1-antitrypsin deficiency.

[0286] (2) Other fibrotic diseases, such as bridging fibrosis of the liver, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, atherosclerosis, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, osteomyelitis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive cystitis; spontaneous acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, previous exacerbation and drugs.

[0287] (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's lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid cancer, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, stomach cancer cancer), intestinal 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, teratoma, liver cancer, kidney cancer, bladder cancer, urothelial carcinoma, bile duct cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell malignancy, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma (bone 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, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colorectal 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.

[0288] (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperresponsive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, 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 disease, such as Crohn's disease (Crohn's disease), 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 (e.g., necrotizing, cutaneous, and allergic vasculitis) or erythemanodosum.

[0289] (5) Neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy or prion disease.

[0290] Therefore, the present invention relates to compounds of general formula (I) or pharmaceutically acceptable salts thereof for use as medicaments.

[0291] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or disorders which are associated with or modulated by QPCT / L activity.

[0292] In addition, the present invention relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition for treating and / or preventing cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney disease.

[0293] In addition, the present invention relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition for treating and / or preventing the following: (1) pulmonary fibrosis diseases, such as pneumonia or interstitial pneumonia associated with collagen degeneration (e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis and dermatomyositis), idiopathic interstitial pneumonia, such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis associated with interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangiomyoma, alveolar proteinosis, Lambda-cell histiocytosis, pleural parenchymal elastosis, interstitial lung diseases of known causes, such as those caused by occupational exposure; Interstitial pneumonia caused by asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon farmer's lung (birds) or other occupational air pollutant triggers (such as metal dust or mycobacteria), or interstitial pneumonia caused by treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapy), or for granulomatous diseases such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis or interstitial pneumonia caused by different origins (e.g., inhalation, inhalation of toxic gases, vapors), bronchitis or pneumonia or interstitial pneumonia caused by heart failure, X-rays, radiation, chemotherapy, Burke's sarcoid or sarcoidosis, granulomatosis, cystic fibrosis or muco-obstructive disease or alpha 1-antitrypsin deficiency.

[0294] (2) Other fibrotic diseases, such as bridging fibrosis of the liver, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, atherosclerosis, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, osteomyelitis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive cystitis; spontaneous acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis or induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, previous exacerbation and drugs.

[0295] (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's lymphoma, multiple myeloma (MM), myeloid dysplasia syndrome, solid cancer, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, intestinal 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, teratoma, liver cancer, kidney cancer, bladder cancer Bladder cancer, urothelial carcinoma, bile duct cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal carcinoma, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell malignancy, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma Glioblastoma, neurothecoma, glioblastoma or sarcoma, gastrointestinal cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colorectal 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.

[0296] (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperresponsive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Dove's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, 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 (e.g., necrotizing, cutaneous and allergic vasculitis) or erythema nodosum.

[0297] (5) Neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy or prion disease.

[0298] In another aspect, the present invention relates to a compound of 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 or disorders.

[0299] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing the above-mentioned diseases or disorders.

[0300] In another aspect of the present invention, the present invention relates to a method for treating or preventing the above-mentioned diseases or disorders, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a human.

[0301] Combination therapy

[0302] 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 suitable for treating the diseases or conditions described above, in particular diseases or conditions associated with cancer, fibrotic diseases, Alzheimer's disease, atherosclerosis, infectious diseases, chronic kidney disease and autoimmune diseases.

[0303] Suitable additional therapeutic agents for use in these combinations include, in particular, those which, for example, enhance the therapeutic effect of one or more active substances with respect to one of the indications mentioned herein and / or allow a reduction in the dosage of one or more active substances.

[0304] 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, radiation therapy, anti-fibrotic agents, antitussive agents, anti-inflammatory agents, anti-atopic dermatitis and bronchodilators.

[0305] Chemotherapy is a cancer treatment using one or more chemical anticancer drugs such as cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances and the like. Examples include folic acid (folate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, azacytidine, gemcitabine, alkylating agents, antimitotic agents, taxanes and other current state-of-the-art or standard of care compounds.

[0306] 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 therapies include agents such as 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, such as HER2, HER3, HER4) and hepatocyte growth factor), inhibitors of tyrosine kinases, KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinases, or MDM2.

[0307] Cancer immunotherapy is a therapy 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, which 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 immunotherapy also includes 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 immunotherapy also includes STING-targeting agents, or T cell engagers, such as blinatumomab.

[0308] Antifibrotic agents are, for example, nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors such as roflumilast or specific PDE4b inhibitors such as BI1015550, autotoxin 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 Lanariumab (Lanalumab), α-V / β-6 blocking inhibitors (such as BG-00011 / STX-100), recombinant penetratin-2 (PTX-2) (such as PRM-151); c-Jun-N-terminal kinase (JNK) inhibitors (such as CC-90001); galectin-3 inhibitors (such as TD-139); G-protein coupled 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 (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 (such as SM-04646); LD4 / PDE3 / 4 inhibitors (such as Tipelukast); recombinant immunomodulatory domains of histidyl tRNA synthetase (HARS) (such as ATYR-1923), prostaglandin synthase inhibitors (such as ZL-2102 / SAR-191801); 15-hydroxy-eicosapentaenoic acid (15-HEPE, for example DS-102); lysine acyl oxidase-like 2 (LOXL2) inhibitors (such as 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 βI (TGF-βI) small interfering RNA (such as TRKZSO / BNC-1021); or lysophosphatidic acid receptor antagonists (such as BMS986278).

[0309] The dosage for the above-mentioned combination partners is usually 1 / 5 of the usually recommended lowest dosage to up to 1 / 1 of the usually recommended dosage.

[0310] Therefore, in a further aspect, the invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents as described hereinbefore and in the following for the treatment of a disease or disorder which can affect or is mediated by QPCT / L, in particular a disease or disorder as described hereinbefore and in the following.

[0311] In another aspect, the present invention relates to a method for treating a disease or condition that can be affected by inhibiting QPCT / L in a patient, comprising the step of 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.

[0312] In another 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 treating a disease or condition that can be affected by inhibition of QPCT / L in a patient in need thereof.

[0313] 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 the step of administering to a patient (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents as described hereinabove and hereinbelow.

[0314] The use of the combination of a compound according to the invention and an additional therapeutic agent may be carried out simultaneously or at staggered times.

[0315] The compounds according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, such as a tablet or capsule, or separately in two identical or different formulations, such as as a so-called kit-of-parts.

[0316] Thus, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and one or more additional therapeutic agents as described hereinabove and infra, optionally together with one or more inert carriers and / or diluents.

[0317] Other features and advantages of the invention will be apparent from the following more detailed embodiments, which illustrate by way of example the principles of the invention.

[0318] preparation

[0319] The compounds according to the invention and intermediates thereof can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis. Preferably, these compounds are obtained in a manner similar to the preparation methods explained more fully below, particularly as described in the experimental section. In some cases, the order in which the reaction steps are carried out can be changed. Variants of the reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0320] Those skilled in the art who study the following schemes will appreciate the general method for preparing compounds according to the present invention. Conventional protecting groups may be used to protect any functional group in the starting material or intermediate. These protecting groups may be cleaved again at a suitable stage in the reaction sequence using methods familiar to those skilled in the art.

[0321] The compounds according to the invention are prepared by the synthetic methods described below, wherein the general substituents have the meanings previously given herein. These methods are intended to illustrate the present invention without limiting the scope of its subject matter and the compounds claimed to these embodiments. Where the preparation of the starting compounds is not described, these compounds can be purchased or can be prepared similarly to the known compounds or methods described herein. The materials described in the literature are prepared according to the disclosed synthetic methods. Abbreviations are as defined in the Examples section.

[0322] Examples 1 to 25 can be prepared as shown in Scheme I below.

[0323] Option I:

[0324]

[0325] 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 run at ambient temperature or at elevated temperatures (up to 110°C) in the presence of a base (e.g., diisopropylethylamine). The intermediate (C) is then subjected to Suzuki cross coupling with a heteroaryl boronic acid derivative in the presence of a suitable catalyst (e.g., Pd(dppf)Cl2) and a suitable base at elevated temperatures (e.g., 100°C) to provide compounds of general formula (I).

[0326] Intermediate I can be prepared as shown in Scheme II below:

[0327] Option II:

[0328]

[0329] Compounds of formula (A) with Z = CF, C-Me, CH can be prepared from the corresponding piperidinyl esters (R = Me, Et) (D) with suitable protecting groups (PG, such as BOC) by treatment with a suitable hydrazine source (e.g. N2H4*H2O) at elevated temperature (e.g. 50°C). The obtained hydrazide (E) is then activated with DMF / DMA at elevated temperature (e.g. 50°C) and subsequently treated with methylamine at elevated temperature (e.g. 90°C) to produce the triazole derivative (F). Compounds of formula (A) can be obtained by cleavage of the protecting group under suitable conditions (e.g. 4M HCl in dioxane for PG = BOC). The obtained hydrochloride salt of (A) is treated with ammonia and passed through a Biotage SNAP cartridge KP-NH column to release the free amine (A). Compounds of formula (A) with Z = CH and C-Me can also be obtained as hydrochloride salts from commercial sources.

[0330] Intermediate II can be prepared as shown in Scheme III below:

[0331] Option III:

[0332]

[0333] In the case of 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) at ambient temperature using a suitable combination of reagents (e.g., 1,1'-carbonyldiimidazole and ammonia). The compound of formula (B) is then obtained by treating (H) with a suitable dehydrating agent (e.g., Burgess reagent) at ambient temperature. In the case of R = Me or CF3, pyridine (J) is deprotonated at low temperature (e.g., -65 ° C) and quenched with DMF to produce the corresponding aldehyde (K). In the case of R = Me, aldehyde (K) can be directly converted to nitrile (B) at ambient temperature by using a combination of ammonia and a suitable oxidant (e.g., iodine). In the case of R = CF3, aldehyde (K) can be converted to amide (H) at ambient temperature using a suitable reagent (e.g., phenyltrimethylammonium tribromide) and further converted to nitrile (B) as described above for R = H.

[0334] Example

[0335] preparation

[0336] The compounds according to the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature, for example, using "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, these compounds are obtained by preparation methods similar to those explained more fully below, particularly as described in the experimental section. In some cases, the order for carrying out the reaction scheme can be changed. Variants of these reactions known to those skilled in the art but not described in detail herein can also be used. Once those skilled in the art have studied the following scheme, the general method for preparing the compounds according to the present invention will be clear. The starting compound can be purchased or can be prepared by the methods described in the literature or herein, or can be prepared in a similar or similar manner. Before carrying out the reaction, any corresponding functional group in the starting compound can be protected using a known protecting group. These protecting groups can be cleaved off again at an appropriate stage in the reaction sequence using methods familiar to the person 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 GM 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., for example between 19 and 24° C.

[0337] abbreviation:

[0338]

[0339]

[0340] Preparation of intermediates

[0341] Intermediate I.1

[0342]

[0343] tert-Butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate

[0344] 4-fluoropiperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (160g, 0.58mol) was suspended in ethanol (640mL) in a round-bottom flask. Hydrazine hydrate (70.6mL, 1.16mol) was added to the mixture at ambient temperature. The reaction mixture was heated to 50°C and stirred for 12h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to produce 80% purity of 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylic acid tert-butyl ester.

[0345] C 11 H 20 FN3O3 (M=261.3g / mol)

[0346] ESI-MS:284.2[M+Na]+

[0347] Rt(HPLC):0.62min(Method A)

[0348] tert-Butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

[0349] 4-Fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylic acid tert-butyl ester (135 g, 0.413 mol, 80% purity) was mixed with dioxane (945 mL) in a round-bottom flask. N,N-dimethylformamide-dimethylacetal (137 mL, 1.03 mol) was added to the mixture at ambient temperature. The reaction mixture was heated to 50 ° C and stirred for 1 h. A solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) were added to the mixture. The resulting reaction mixture was heated to 90 ° C and stirred for 11 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc gradient 20: 1 to 0: 1) to obtain 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0350] C 13 H 21 FN4O2 (M=284.3g / mol)

[0351] ESI-MS: 285.1[M+H] +

[0352] Rt(HPLC):0.77min(Method A)

[0353] Intermediate I.1: 4-Fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine

[0354] 4-Fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (90 g, 0.32 mol) was combined with methanol (90 mL) in a round bottom flask. A solution of HCl (4M in MeOH, 450 mL, 1.8 mol) was slowly added at ambient temperature. The resulting reaction mixture was stirred for 12 h at ambient temperature. The desired product was collected by filtration, washed with methanol, and dried to produce 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride.

[0355] The hydrochloride salt (13.5 g) was 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).

[0356] 8H 13 FN4 (M=184.2g / mol)

[0357] ESI-MS: 185[M+H] +

[0358] Rt(HPLC):0.20min(Method B)

[0359] 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 suppliers. The hydrochloride salts were converted to the free piperidine or piperazine according to the procedure described for Int. I.

[0360] Intermediate II.1

[0361]

[0362] 2-Bromo-3-fluoropyridine-4-carboxamide

[0363] 2-Bromo-3-fluoropyridine-4-carboxylic acid (25.0 g, 0.114 mol) was suspended in THF (250 mL) and 1,1'-carbonyldiimidazole (22.1 g, 0.136 mol) was added in several small portions. The reaction mixture was stirred at ambient temperature for 3 h, then a solution of ammonia (32% in H2O, 64.8 mL, 0.938 mol) was slowly added. The resulting reaction mixture was stirred at ambient temperature for another 3 h. The mixture was concentrated and the residue was loaded into The product was purified by column chromatography (SiO 2 , DCM / MeOH 9:1) to give 2-bromo-3-fluoropyridine-4-carboxamide.

[0364] C6H4BrFN2O (M=219.0g / mol)

[0365] ESI-MS: 219 / 221[M+H] +

[0366] Rt(HPLC): 0.28min(Method C)

[0367] Intermediate II.1: 2-Bromo-3-fluoropyridine-4-carbonitrile

[0368] 2-Bromo-3-fluoropyridine-4-carboxamide (17.4 g, 79.5 mmol) was added to dichloromethane (250 mL). Burgess reagent (CAS: 29684-56-8, 22.0 g, 89.5 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 16 h. The mixture was concentrated to half of the original volume and purified by column chromatography (SiO2, DCM) to produce 2-bromo-3-fluoropyridine-4-carbonitrile.

[0369] C6H2BrFN2 (M=201.0g / mol)

[0370] ESI-MS: mass not detected

[0371] Rt(HPLC): 0.41min(Method F)

[0372] 1H NMR (400MHz, DMSO-d6) δppm 8.52 (d, J = 4.9 Hz, 1H), 8.05 (t, J = 4.8 Hz, 1H).

[0373] Intermediate II.2

[0374]

[0375] 2-Chloro-3-fluoropyridine-4-carboxamide

[0376] 2-Chloro-3-fluoropyridine-4-carboxylic acid (1.00 g, 5.41 mmol) was suspended in THF (25 mL) and 1,1'-carbonyldiimidazole (1.05 g, 6.49 mmol) was added in several small portions. The reaction mixture was stirred at ambient temperature for 2 h, then a solution of ammonia (32% in H2O, 3.09 mL, 44.6 mmol) was slowly added. The resulting reaction mixture was stirred for an additional 2 h at ambient temperature. The mixture was concentrated and the residue was loaded into Upload and purified by column chromatography (SiO2, CyH / EtOAc gradient 1:0 to 1:1) to give 2-chloro-3-fluoropyridine-4-carboxamide.

[0377] C6H4ClFN2O (M=174.6g / mol)

[0378] ESI-MS: 174[MH] -

[0379] Rt(HPLC): 0.11min(Method B)

[0380] Intermediate II.2: 2-Chloro-3-fluoropyridine-4-carbonitrile

[0381] 2-Chloro-3-fluoropyridine-4-carboxamide (748 mg, 4.29 mmol) was added to DCM (20 mL). Burgess reagent (CAS: 29684-56-8, 1.26 g, 3.64 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 16 h. The mixture was concentrated to half of the original volume and purified by column chromatography (SiO2, CyH / EtOAc gradient 1:0 to 7:3) to produce 2-chloro-3-fluoropyridine-4-carbonitrile.

[0382] C6H2ClFN2 (M=156.5g / mol)

[0383] ESI-MS: No mass detected

[0384] Rt(HPLC):0.41min(Method C)

[0385] 1 H NMR (400MHz, DMSO-d6) δppm 8.53 (d, J=4.9Hz, 1H), 8.06 (t, J=4.7Hz, 1H)

[0386] Intermediate II.3

[0387]

[0388] 2-Bromo-3-fluoro-6-methylpyridine-4-carbaldehyde

[0389] 2-Bromo-3-fluoro-6-methylpyridine (1.00 g, 5.16 mmol) was added to THF (50 mL) under argon atmosphere and the resulting mixture was cooled to -65 °C. A solution of lithium diisopropylamide (1 M in THF, 5.42 mL, 5.42 mmol) was added dropwise and the mixture was stirred for another 30 min at -65 °C. A solution of DMF (476 μL DMF in 3 mL THF, 6.19 mmol) was added dropwise. The mixture was stirred for 20 min at -65 °C and then allowed to warm to ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and Me-THF. The phases were separated, the organic phase was washed with water, dried over MgSO4 and concentrated to give 2-bromo-3-fluoro-6-methylpyridine-4-carbaldehyde.

[0390] C7H5BrFNO (M=218.0g / mol)

[0391] ESI-MS: mass not detected

[0392] Rt(HPLC): 0.41min(Method C)

[0393] 1 H NMR (400MHz, DMSO-d6) δppm 10.16 (s, 1H), 7.64 (d, J = 4.6Hz, 1H), 2.53 (d, J = 1.0Hz, 3H)

[0394] Intermediate II.3: 2-Bromo-3-fluoro-6-methylpyridine-4-carbonitrile

[0395] 2-Bromo-3-fluoro-6-methylpyridine-4-carbaldehyde (460 mg, 2.11 mmol) was added to THF (4.6 mL) and a solution of ammonia (28% in H2O, 4.6 mL) and iodine (580 mg, 2.28 mmol) were added. The resulting reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous NH4Cl solution. The organic phase was concentrated and loaded into The product was purified by column chromatography (SiO 2 , CyH / EtOAc gradient 1:0 to 4:1) to give 2-bromo-3-fluoro-6-methylpyridine-4-carbonitrile.

[0396] C7H4BrFN2(M=215.0g / mol)

[0397] ESI-MS: 215 / 217[M+H] +

[0398] Rt(HPLC):0.40min(Method C)

[0399] Intermediate II.4

[0400]

[0401] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde

[0402] Under an argon atmosphere, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine (1.00 g, 4.1 mmol) was added to THF (25 mL), and the resulting mixture was cooled to -70 ° C. A solution of lithium diisopropylamide (1 M in THF, 4.51 mL, 4.51 mmol) was added dropwise, and the mixture was stirred at -70 ° C for 45 min. DMF (0.378 mL, 4.92 mmol) was added dropwise. The mixture was stirred for another 30 min at -70 ° C. The reaction was quenched by adding acetic acid (800 μL) and diluted with water and ethyl acetate. The organic phase was separated, dried over MgSO4, and concentrated. The residue was purified by column chromatography (SiO2, CyH / EtOAc gradient 1:0 to 4:1) to produce 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde.

[0403] C7H2BrF4NO (M=272.0g / mol)

[0404] ESI-MS: mass not detected

[0405] Rt(HPLC):0.48min(Method E)

[0406] 1 H NMR (400MHz, DMSO-d6) δppm 10.19 (s, 1H), 8.26 (d, J = 4.3Hz, 1H).

[0407] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide

[0408] Ammonium acetate (5.53 g, 71.8 mmol) and 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde (2.17 g, 7.18 mmol) were mixed and acetonitrile (44 mL) was added. Phenyltrimethylammonium tribromide (5.57 g, 14.4 mmol) was added in small portions and the resulting reaction mixture was stirred at ambient temperature for 72 h. The mixture was filtered and the residue was washed with acetonitrile and purified by column chromatography (dry loaded SiO2, CyH / EtOAc gradient 1:0 to 7:3) to give the desired product.

[0409] C7H3BrF4N2O (M=287.0g / mol)

[0410] ESI-MS: 285 / 287[MH] -

[0411] Rt(HPLC):0.50min(Method B)

[0412] Intermediate II.4: 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbonitrile

[0413] The product of the previous step, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide (975 mg, 3.40 mmol), was suspended in dichloromethane (80 mL) and Burgess reagent (CAS: 29684-56-8, 1.25 g, 5.10 mmol) was added at ambient temperature. The resulting reaction mixture was stirred for 40 h and then purified by column chromatography (dry loaded SiO 2 , CyH / EtOAc gradient 1:0 to 9:1) was directly purified to give the desired product.

[0414] C7HBrF4N2(M=268.9g / mol)

[0415] ESI-MS: 268 / 270[M+H] +

[0416] Rt(HPLC):0.59min(Method C)

[0417] General procedure for the synthesis of intermediate III

[0418]

[0419] 2-Bromo-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile

[0420] Int.II.1 (500 mg, 2.49 mmol) and Int.I.1 (687 mg, 3.73 mmol) were suspended in DMSO (5.0 mL), and DIPEA (861 μL, 4.98 mmol) was added at ambient temperature. The resulting mixture was stirred for 72 h at ambient temperature. The mixture was diluted with water (0.1 mL), and the precipitate was collected by filtration, washed with water, and dried to give 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 was used in the next step without further purification.

[0421] C 14 H 14 BrFN6 (M=365.2g / mol)

[0422] ESI-MS: 365 / 367[M+H] +

[0423] Rt(HPLC): 0.42min(Method C)

[0424]

[0425]

[0426] Intermediate IV.1

[0427]

[0428] 4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride (180 mg, 0.89 mmol), 3-fluoro-4-iodopropionitrile (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 3) to give the desired product along with a side product resulting from iodine displacement.

[0429] C 14 H 15 IN6 (M=394.2g / mol)

[0430] ESI-MS: 395[M+H] +

[0431] Rt(HPLC): 0.38min(Method C)

[0432]

[0433]

[0434] Intermediate V.1

[0435]

[0436] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine

[0437] 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 19.8 mmol) was suspended in toluene (23 mL) and tert-butyl acetate (26.6 mL, 198 mmol) was added. Methanesulfonic acid (1.3 mL, 19.8 mmol) was slowly added. The resulting reaction mixture was heated to 80 ° C and stirred for 1 h. After cooling to ambient temperature, methanesulfonic acid (1.3 mL, 19.8 mmol) was added and the reaction mixture was heated to 80 ° C and stirred for 1 h. After cooling to ambient temperature, the reaction mixture was concentrated and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to produce 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine.

[0438] C 10 H 12 BrN3 (M = 254.1 g / mol)

[0439] ESI-MS: 254 / 256[M+H] +

[0440] Rt(HPLC):0.50min(Method C)

[0441] Intermediate V.1

[0442] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.50 g, 3.87 mmol), bis(pinacolato)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 by passing a stream of argon through the mixture for 10 min. [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2*CH2Cl2, CAS: 95464-05-4) (190 mg, 0.232 mmol) was added, and the mixture was degassed for another 3 min. The mixture was then heated to 110° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, the mixture was concentrated and the residue was dissolved in 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.

[0443] C 10 H 14 BN3O2 (M=219.1g / mol)

[0444] ESI-MS: 220[M+H] +

[0445] Rt(HPLC): 0.27min(Method C)

[0446] Intermediate V.2

[0447]

[0448] 6-Bromo-3-tert-butyl-[1,2,4]triazolo[4,3-a]pyrimidine

[0449] 5-Bromo-2-hydrazinopyrimidine (200 mg, 1.01 mmol) and pivaloyl chloride (985 mg, 8.09 mmol) were added to a microwave vial, which was then sealed. The mixture was heated to 120 °C and stirred at this temperature for 22 h. Water and ACN were added, and the mixture was concentrated. The residue was dissolved in ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired compound.

[0450] C9H 11 BrN4 (M = 255.1 g / mol)

[0451] ESI-MS: 255 / 257[M+H] +

[0452] Rt(HPLC):0.46min(Method C)

[0453] Intermediate V.2

[0454] 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 by passing a stream of argon through the mixture for 15 min. Bis(triphenylphosphine)palladium(II) dichloride (CAS: 13965-03-2; 20.4 mg, 0.029 mmol) was added and the mixture was further degassed for 3 min. The resulting reaction mixture was heated to 60 °C and stirred at this temperature for 20 h. After cooling to ambient temperature, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated and taken up with a mixture of ACN, water and TFA. It was then purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to yield the desired compound.

[0455] C9H 13 BN4O2 (M=220.0g / mol)

[0456] ESI-MS: 221[M+H] +

[0457] Rt(HPLC): 0.34min(Method C)

[0458] Intermediate V.3

[0459]

[0460] 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine

[0461] 2-Amino-5-bromopyrimidine (250 mg, 1.41 mmol) and 1-chloropinacolone (285 μL, 2.11 mmol) were added to ethanol (2.0 mL), and the resulting reaction mixture was stirred for 96 h at 90° C. After cooling to ambient temperature, the mixture was diluted with ACN and purified by column chromatography (SiO 2 , DCM / MeOH gradient 1: 0 to 9: 1) to give the desired product.

[0462] C 10 H 12 BrN3 (M = 254.1 g / mol)

[0463] ESI-MS: 254 / 256[M+H] +

[0464] Rt(HPLC):0.28min(Method C)

[0465] Intermediate V.3

[0466] 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 by passing a stream of argon through the mixture for 10 min. Bis(triphenylphosphine)palladium(II)dichloride (CAS: 13965-03-2; 39.8 mg, 56.7 μmol) was added and the mixture was further degassed for 3 min. The resulting reaction mixture was heated to 90° C. and stirred at this temperature for 5 h. After cooling to ambient temperature, the mixture was concentrated. The residue was dissolved in 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.

[0467] C 10 H 14 BN3O2 (M = 219.1 g / mol)

[0468] ESI-MS: 220[M+H] +

[0469] Rt(HPLC):0.25min(Method C)

[0470] Intermediate V.4

[0471]

[0472] 6-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine

[0473] 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 charged to It was then purified by column chromatography (SiO2, DCM / MeOH gradient 1:0 to 9:1) to give the desired product.

[0474] C7H3BrF3N3 (M=266.0g / mol)

[0475] ESI-MS: 266 / 268[M+H] +

[0476] Rt(HPLC): 0.38min(Method C)

[0477] Intermediate V.4

[0478] 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) were added to 1,4-dioxane (1.0 mL). The mixture was degassed by passing a stream of argon through the mixture for 10 min. Bis(triphenylphosphine)palladium(II)dichloride (98.4 mg, 0.140 mmol) was added and the mixture was further degassed for 3 min. The resulting reaction mixture was heated to 90 °C and stirred at this temperature for 5 h. After cooling to ambient temperature, the mixture was concentrated. The residue was dissolved 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.

[0479] C7H5BF3N3O2 (M=230.9g / mol)

[0480] ESI-MS: 232[M+H] +

[0481] Rt(HPLC):0.29min(Method C)

[0482] Intermediate VI.1

[0483]

[0484] 5-Bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine

[0485] 5-Bromo-2-fluoropyridin-3-ol (3.00 g, 15.3 mmol) was added to DCM (40 mL) and DIPEA (5.3 mL, 31 mmol) was added. 2-(Trimethylsilyl)ethoxymethyl chloride (3.15 mL, 16.8 mmol) was added dropwise and the resulting reaction mixture was stirred at ambient temperature for 90 min. The mixture was concentrated and charged to and purified by column chromatography (SiO2, CyH / EtOAc 1:0 to 3:1) to give the desired product.

[0486] C 11 H 17 BrFNO2Si (M=322.2g / mol)

[0487] ESI-MS: 322 / 324[M+H] +

[0488] Rt(HPLC): 0.84min(Method C)

[0489] (6-Fluoro-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-3-yl)boronic acid

[0490] Under argon atmosphere, 1,4-dioxane (30 mL) was 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 was degassed by passing a stream of argon through the mixture for 10 min. [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2*CH2Cl2, CAS: 95464-05-4) (545 mg, 0.745 mmol) was added and the mixture was further degassed for 3 min. The mixture was then heated to 80° C. and stirred at this temperature for 18 h. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The organic phase was separated, dried over MgSO4 and concentrated.The residue was purified by preparative HPLC (XBridge C18, ACN / water gradient) to give the desired product in 80% purity.

[0491] C 11 H 19 BFNO4Si (M=287.2g / mol)

[0492] ESI-MS: 288[M+H] +

[0493] Rt(HPLC): 0.60min(Method C)

[0494] 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

[0495] Under argon atmosphere, 1,4-dioxane (3.0 mL) was 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% purity, 519 mg, 1.44 mmol) and tetrakis(triphenylphosphine)palladium(0) (66.8 mg, 0.058 mmol). The suspension was degassed by passing a stream of argon through the mixture for 10 min. A solution of cesium carbonate (2 M in H2O, 867 μL, 1.73 mmol) was added, and the mixture was degassed again for 3 min. The reaction mixture was then heated to 80°C and stirred at this temperature for 8 h. After cooling to ambient temperature, the mixture was concentrated. The residue was dissolved in ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product.

[0496] C 25 H 31 F2N7O2Si (M=527.6g / mol)

[0497] ESI-MS: 528[M+H] +

[0498] Rt(HPLC): 0.67min(Method C)

[0499] Intermediate VI.1

[0500] 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) was added to dichloromethane and a solution of hydrochloric acid (4M in dioxane, 563 μL, 2.25 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 2 h. The mixture was diluted with MTBE and the precipitated solid was collected by filtration, washed with MTBE, and dried to give the desired product.

[0501] C 19 H 17 F2N7O (M=397.4g / mol)

[0502] ESI-MS: 398[M+H] +

[0503] Rt(HPLC): 0.39min(Method C)

[0504] Intermediate VI.2

[0505]

[0506] 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

[0507] Under 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 (2M in water, 2.74 mL, 5.48 mmol) are added to 1,4-dioxane (30 mL). The mixture is degassed by passing a stream of argon through the mixture for 10 min. [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (200 mg, 0.274 mmol) is then added, and the mixture is further degassed for 3 min. The reaction mixture is then heated to 100° C. and stirred at this temperature for 1 h. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The organic phase was separated, dried over sodium sulfate, and concentrated. The residue was dissolved in DMF and purified by preparative HPLC (ZORBAX StableBond C18, ACN / water gradient containing 0.1% TFA) to give the desired product.

[0508] C 20 H 17 F2N7O (M=409.4g / mol)

[0509] ESI-MS: 410[M+H] +

[0510] Rt(HPLC): 0.73min(Method G)

[0511] Intermediate VI.2

[0512] 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) were added to DMSO (20 mL). Sodium azide (212 mg, 3.22 mmol) was then added in small portions at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 1 h and then diluted with half-saturated aqueous sodium chloride solution. The organic phase was extracted with EtOAc (3x), and the combined organic layers were dried over sodium sulfate and concentrated to give the desired product, which was used in the next step without further purification.

[0513] C 20 H 17 FN 10 O (M=432.4g / mol)

[0514] ESI-MS: 433[M+H] +

[0515] Rt(HPLC): 0.66min(Method G)

[0516] Preparation of final compounds

[0517] Example 1

[0518]

[0519] Under 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 by passing a stream of argon through the solution for 15 min. [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (286 mg, 0.392 mmol) is added, and the mixture is further degassed for 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. The filtrate was concentrated and purified via preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% NH3) to give the desired compound.

[0520] C 19 H 17 F2N7 (M = 381.4 g / mol)

[0521] ESI-MS: 382[M+H] +

[0522] Rt(HPLC):0.40min(Method C)

[0523] 1 H NMR(400MHz,DMSO-d6)δppm:8.54(d,J=4.9Hz,1H),8.50(d,J=2.3Hz,1H),8.48(s,1H),8.25(td,J=8.2,2.5Hz,1H ),7.82(d,J=4.8Hz,1H),7.34(dd,J=8.4,2.6Hz,1H),3.73(d,J=1.6Hz,3H),3.15-3.28(m,4H),2.09-2.27(m,4H)

[0524] Example of program synthesis similar to that described for Example 1

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531] Analytical Data of Synthetic Examples

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Embodiment 26

[0540]

[0541] Intermediate VI.1 (90.0 mg, 0.207 mmol) and cesium carbonate (135.2 mg, 0.414 mmol) were added to DMF (2.0 mL) and (iodomethyl)cyclopropane (56.6 mg, 0.311 mmol) was added. The resulting reaction mixture was heated to 80 °C and stirred at this temperature for 8 h. After cooling to ambient temperature, it was 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.

[0542] C 23 H 23 F2N7O (M=451.5g / mol)

[0543] ESI-MS: 452[M+H] +

[0544] Rt(HPLC): 0.52min(Method C)

[0545] 1 H NMR(400MHz,DMSO-d6)δppm 8.53(s,1H),8.51-8.53(m,1H),8.52(d,J=4.8Hz,1H),7.94(t,J=1.6Hz,1H),7.88(dd,J=10.1,1.8Hz,1H),7.82(d,J=4.9Hz,1H),3.99 (d,J=7.1Hz,2H),3.74(d,J=1.6Hz,3H),3.15-3.32(m,4H),2.09-2.30(m,4H),1.20-1.33(m,1H),0.52-0.65(m,1H),0.30-0.42(m,2H).

[0546] Example of a program synthesis similar to that described for Example 26

[0547]

[0548]

[0549] Analytical Data of Synthetic Examples

[0550]

[0551] Embodiment 29

[0552]

[0553] Under argon atmosphere, intermediate VI.2 (20.0 mg, 0.046 mmol) and iron (II) bromide (2.0 mg, 9.5 μmol) were suspended in DMSO (1.0 mL). 1,1,1-Trifluoro-2-methyl-propan-2-amine hydrochloride (11.3 mg, 0.069 mmol) was added, and the resulting reaction mixture was heated to 120 ° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, the mixture was diluted with water and purified by preparative HPLC (ZORBAX StableBond C18, water / ACN gradient containing 0.1% TFA) to give the desired product.

[0554] C 24 H 23 F4N9 (M=513.5g / mol)

[0555] ESI-MS: 514[M+H] +

[0556] Rt(HPLC): 0.65min(Method L)

[0557] 1 H NMR(400MHz,DMSO-d6)δppm 8.95(s,1H),8.92(d,J=2.2Hz,1H),8.56(d,J=4.8Hz,1H),8.49(s,1H),8.41(d,J=2.2Hz,1H),7 .81(d,J=4.8Hz,1H),3.71(d,J=1.3Hz,3H),3.23-3.28(m,4H),2.15-2.30(m,4H),2.03(s,6H).

[0558] Example synthesized similarly to the procedure described for Example 29

[0559]

[0560]

[0561] Analytical Data of Synthetic Examples

[0562]

[0563]

[0564] Analytical HPLC method

[0565] Method A

[0566]

[0567] Analytical column: Kinetex EVO C18_2.1x30mm_5μm; Column temperature: 40℃

[0568] Method B

[0569]

[0570] Device description: Waters Acquity; Analytical column: XBridge (Waters) BEH C18_2.1x 30mm_2.5μm; Column temperature: 60°C

[0571] Method C

[0572]

[0573] Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1x 30mm_1.7μm; Column temperature: 60°C

[0574] Method D

[0575]

[0576] Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0577] Method E

[0578]

[0579] Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH Phenyl_2.1x 30mm_1.7μm; Column temperature: 60°C

[0580] Method F

[0581]

[0582] Device description: Agilent 1200; Analytical column: XBridge (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0583] Method G

[0584]

[0585] Device description: Agilent 1200; Analytical column: Zorbax (Agilent) StableBond C18_3.0x 30mm_1.8μm; Column temperature: 60°C

[0586] Method H

[0587]

[0588] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0589] Method I

[0590]

[0591] Device description: Waters Acquity; Analytical column: XBridge (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0592] Method J

[0593]

[0594] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0595] Method K

[0596]

[0597]

[0598] Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0599] Method L

[0600]

[0601] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x 30mm_2.5μm; Column temperature: 60°C

[0602] Method M

[0603]

[0604] Apparatus description: Agilent 1260 Infinity II SFC; Column: Chiral ART (YMC) cellulose SC_4.6x250 mm_1.7 μm; Column temperature: 40°C.

Claims

1. A compound of formula (I), in 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 monoheteroaryl ring containing one nitrogen or containing two heteroatom members, one of which is nitrogen and the second is selected from nitrogen or sulfur; or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing one to four nitrogen atoms; and wherein A1a or A1b is independently substituted by one or two R 3 replace; R 1 Choose from H, C 1-4 - A group R1a consisting of an alkyl group and a halogen group; R 2 Selected from halogen, H, C 1-4 -alkyl, C 3-4 -Cycloalkyl and F 1-9 -Fluoro-C 1-4 -alkyl group R2a; R 3 Selected from H, halogen, C 1-4 -alkyl, C 3-4 -cycloalkyl, C 3-4 -Fluorinated cycloalkyl, F 1-9 -Fluoro-C 1-4 -alkyl, C 1-4 -alkoxy, C 3-4 -cycloalkoxy and pyrazolyl, and The group R3a composed of R 4 Selected from halogen, H, C 1-4 -alkyl, C 3-4 -Cycloalkyl and F 1-9 -Fluoro-C 1-4 - a group R4a consisting of an alkyl group; or a salt thereof.

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

3. The compound of formula (I) according to claim 1, wherein A is selected from the group A9 consisting of: and A9 is independently connected to one or two R 3 replace; or a salt thereof.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R 2 Selected from H, F, Cl, C 1-4 -Alkyl and F 1-9 -Fluoro-C 1-4 - a group R2b consisting of an alkyl group; or a salt thereof.

5. A compound of formula (I) according to any one of claims 1 to 4, wherein R 3 Selected from H, halogen, C 1-4 -alkyl, C 3-4 -Cycloalkyl, F 1-9 -Fluoro-C 1-4 -alkyl, C 1-4 -alkoxy, C 3-4 -cycloalkoxy and pyrazolyl, and The group R3b composed of or a salt thereof.

6. A compound of formula (I) according to any one of claims 1 to 5, which has formula (Ia) or a salt thereof.

7. A compound of formula (I) according to any one of claims 1 to 5, which has formula (Ib) or a salt thereof.

8. The compound of formula (I) according to claim 1, which is selected from the group consisting of: and or a salt thereof.

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

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

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

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 any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use as a medicament.

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

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

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