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

Abstract

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

Description

[Technical Field]

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

[0002] Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyze intramolecular cyclization of the N-terminal glutamine (Q) residue to pyroglutamic acid (pE), releasing ammonia. [Stephan Schilling et al., “Identification of Human Glutaminyl Cyclase as a Metalloenzyme POTENT INHIBITION 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 Anett Stephan et al., “Mammalian Glutaminyl Cyclases and Their Isoenzymes Have Identical Enzymatic Characteristics,” FEBS Journal 276, no. 22 (2009): 6522-36, https: / / doi.org / 10.1111 / j.1742-4658.2009.07337.x.QPCT is a secreted protein, while QPCTL is retained within the Golgi complex. Both enzymes share high homology and similar catalytic specificity at their active sites. Due to the high homology at the active sites, inhibition of the active site blocks the enzymatic activity of both enzymes: QPCT and QPCTL. Therefore, the term "QPCT / L" refers to both enzymes at once. Differences in the relevance of biological substrate modification have been reported due to their localization in different cells. Known substrates of intracellular QPCTLs and / or extracellular QPCTLs include CD47 [Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612-19, https: / / doi.org / 10.1038 / s41591-019-0356-z.], various chemokines (e.g., CCL2 and 7 or CX3CL1) [Rosa Barreira da Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology 23, no. 4 (2022): 568-80]. https: / / doi.org / 10.1038 / s41590-022-01153-x; Astrid Kehlen et al., “N-Terminal Pyroglutamate Formation in CX3CL1 Is Essential for Its Full Biologic Activity,” Bioscience Reports 37, no. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.], amyloid-β peptide [Cynis et al.These include hormones such as TRH [Andreas Becker et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery.”] or 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 in the substrate to pyroglutamate has functional consequences for the protein and can affect various pathological mechanisms in several diseases. CD47 is expressed on the cell surface of virtually all cells in the body, including apoptotic 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 alpha (SIRPα), an inhibitory transmembrane receptor found in myeloid cells such as macrophages, monocytes, neutrophils, and dendritic cells. QPCTL-mediated modification of the N-terminal pyroglutamate in CD47 is required for SIRPα binding [Deborah Hatherley et al., “Paired Receptor Specificity Explained by Structures of Signal Regulatory Proteins Alone and Complexed with CD47,” Molecular Cell 31, no.2 (2008): 266-77, https: / / doi.org / 10.1016 / j.molcel.2008.05.026; Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612-19, https: / / doi.org / 10.1038 / s41591-019-0356-z.] This signaling axis induces the “Don’t Eat Me signal,” preventing macrophages from phagocytosing CD47-expressing cells. Therefore, high expression of CD47 is associated with cancer [Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47- SIRPα Axis and a Target for Cancer Immunotherapy,” 2019; Meike EW Logtenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “The CD47-SIRPα Immune Checkpoint,” Immunity 52, no. 5 (2020): 742-52, https: / / doi.org / 10.1016 / j.immuni.2020.04.011.], COVID-19[Katie-May McLaughlin et al., “A Potential Role of the CD47 / SIRPalpha Axis in COVID-19 Pathogenesis,” Current Issues in Molecular Biology 43, no. 3 (2021): 1212-25, [https: / / doi.org / 10.3390 / cimb43030086.], pulmonary fibrosis [Gerlinde Wernig et al.], “Unifying Mechanism for Different Fibrotic Diseases,” Proceedings of the National Academy of Sciences 114, no. 18 (2017): 4757-62, https: / / doi.org / 10.1073 / pnas.1621375114; Lu Cui et al., “Activation of JUN in Fibroblasts Promotes Pro-Fibrotic Programme and Modulates Protective Immunity,” Nature Communications 11, no. 1 (2020): 2795, https: / / doi.org / 10.1038 / s41467-020-16466-4.], systemic sclerosis [Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases”; Tristan Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma,” [JCI Insight 5, no. 16 (2020): e140458, https: / / doi.org / 10.1172 / jci.insight.140458.] and liver fibrosis [Taesik Gwag et al., “Anti-CD47 Antibody Treatment Attenuates Liver Inflammation and Fibrosis in Experimental Non-alcoholic Steatohepatitis Models,” Liver International 42, no. 4 (2022): 829-41, https: / / doi.org / 10.1111 / liv.15182.] are linked to the pathogenesis of these conditions. Increased CD47 expression blocks the clearance of apoptotic cells, leading to pro-fibrotic stimulation and the development of apoptotic lung epithelial cells that accelerate lung inflammation and scaring [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 the half-life and function of CD47 are primarily dependent on QPCTL enzyme activity, QPCT and QPCTL inhibition are used as treatments for pulmonary fibrosis, such as IPF or SSC-ILD [Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma.”], either alone or in conjunction with current standards of care 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 as a future treatment 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] This may be a suitable mechanism. CD47 expression allows cancer cells to evade destruction by the immune system, or to evade immune surveillance by, for example, phagocytosis by immune cells [Stephen B. Willingham et al., “The CD47-Signal Regulatory Protein Alpha (SIRPa) Interaction Is a Therapeutic Target for Human Solid Tumors,” Proceedings of the National Academy of Sciences 109, no. 17 (2012): 6662-67, https: / / doi.org / 10.1073 / pnas.1121623109].

[0003] In addition to CD47, chemokines such as CCL2 and CX3CL1 have been identified as QPCTL and / or QPCT substrates [Holger Cynis et al., “The Isoenzyme of Glutaminyl Cyclase Is an Important Regulator of Monocyte Infiltration under Inflammatory Conditions,” EMBO Molecular Medicine 3, no. 9 (2011): 545-58, https: / / doi.org / 10.1002 / emmm.201100158]. N-terminal pGlu formation has been shown to increase in vivo activity by both conferring resistance to aminopeptidases and increasing their ability to induce chemokine receptor signaling. The two main monocyte chemotaxis, CCL2 and CCL7, are insensitive to DPP4-inactivation in vivo due to the intracellular mechanism of N-terminal cyclization mediated by the Golgi-associated enzyme QPCTL. QPCTLs have been shown to be important regulators of monocyte migration into solid tumors [Kaspar Bresser et al., “QPCTL Regulates Macrophage and Monocyte Abundance and Inflammatory Signatures in the Tumor Microenvironment,” Oncoimmunology 11, no. 1 (2022): 2049486, https: / / doi.org / 10.1080 / 2162402x.2022.2049486; Rosa Barreira da Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology, 2022, 1-13, https: / / doi.org / 10.1038 / s41590-022-01153-x].Chemokine targeting has been pursued as a potential strategy for modulating cell transport in various disease states.

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

[0005] [ka] It is disclosed that (supplementary information) SEN177 has an IC of 53 nM relative to isolated hQC and 13 nM relative to isolated QPCTL. 50 It is disclosed that it has (Supplementary Information), SEN180 has ICs of 170nM for hQC and 58nM for QPCTL. 50 It is disclosed that it has [this feature].

[0006] Pozzi, C, et al, Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226 (hereinafter referred to as "P, JBIC 2018") further discloses the binding mode of SEN177 and hQC within the cavity. There, SEN177 is found to bind to isolated hQC with 20 nM K i It is disclosed that it has [this feature].

[0007] International Publication No. 2018 / 178384 discloses a QPCTL inhibitor of general formula ABDE, which includes Examples 1094 and 1095 (Formula (XIIa) on page 123 and Table on page 125).

[0008] [ka] International Publication No. 2018 / 178384 does not disclose the biological data for either Example 1094 or 1095. International Publication No. 2022 / 086920 is a general formula [ka] The present invention discloses QPCTL inhibitors, which include compounds 3 and 6. [ka]

[0009] The chemical name of compound 3 is disclosed in International Publication No. 2022 / 086920 as "1-(1-(6'-chloro-[3,3'-bipyridine]-2-yl)piperidine-4-yl)-1H-1,2,3-triazole-4-amine," which does not correspond to the chemical structure disclosed therein, but corresponds to an alternative structure in which the fluorine atom is replaced by a chlorine atom.

[0010] [ka]

[0011] Compounds 3 (including alternative compound 3) and 6 in International Publication No. 2022 / 086920 are

[0343] and IC for isolated QPCTLs. 50 It is disclosed to have inhibitory activity of <1 μM.

[0012] Chinese Patent Application Publication No. 114874186 is a general formula [ka] This document discloses glutamine acylcyclase isoenzyme inhibitors, which include Examples 21 and 23 (table on page 17). [ka] In Chinese Patent Application Publication No. 114874186, IC 50For Examples 21 and 23, the values ​​are shown as 29.22 nM and 11.26 nM, respectively. [Overview of the project]

[0013] The present invention discloses a novel phenylpiperidine derivative of formula (I) that is an inhibitor of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL) possessing appropriate pharmacological and pharmacokinetic properties, enabling its use as a pharmaceutical for treating conditions and / or diseases treatable by inhibition of QPCT / L.

[0014] [ka] (I)

[0015] The compounds of the present invention can offer several advantages, such as improved potency, cellular efficacy, high metabolic and / or chemical stability, high selectivity, safety and tolerability, improved solubility, improved permeability, desirable plasma protein binding, improved bioavailability, a suitable pharmacokinetic profile, and the possibility of forming stable salts. [Modes for carrying out the invention]

[0016] The compound of the present invention The present invention provides a novel phenylpiperidine derivative which is, surprisingly, a potent inhibitor of QPCT and QPCTL (Assay A), and furthermore, a potent inhibitor of QPCT / L in cells, not limited to those associated with lung disease or cancer (Assay B). Furthermore, this novel phenylpiperidine derivative exhibits appropriate membrane permeability and low in vitro efflux (Assay C). As a result, the compounds of the present invention have a high probability of being used in humans. The compounds of the present invention structurally differ from SEN177 and SEN180 in JS, NCB 2015 in that the phenyl ring is attached to a piperidinyl ring instead of a pyridyl ring. Furthermore, the carbonitrili substituent is attached to the ortho position of the phenyl ring relative to the piperidinyl ring attachment site. Moreover, the phenyl ring, including the attached piperidinyl ring, is entirely tetrasubstituted. Furthermore, R 1 A is not limited to hydrogen, and A represents a substituted heterocyclic ring system beyond pyridinyl.

[0017] The compounds of the present invention structurally differ from Examples 1094 and 1095 in International Publication No. 2018 / 178384 in that the phenyl ring is attached to a piperidinyl ring instead of a pyridyl ring. Furthermore, the carbonitrile substituent is attached to the ortho position of the phenyl ring relative to the piperidinyl ring attachment site. Furthermore, the phenyl ring, including the attached piperidinyl ring, is entirely tetrasubstituted. 1 A is not limited to hydrogen, and A represents a heterocyclic ring system beyond pyridinyl. Furthermore, the 5-membered heterocyclic ring attached to the piperidinyl ring at the 4-position relative to the piperidinyl nitrogen is an aminothiazolyl ring in Example 1094, an aminothiadiazolyl ring in Example 1095, while in the compound of the present invention, this is a 3-substituted-4-methyl-4H-1,2,4-triazolyl ring.

[0018] The compounds of the present invention differ structurally from compounds 3 (including alternative compound 3) and 6 in International Publication No. 2022 / 086920 in that the phenyl ring is attached to a piperidinyl ring instead of a pyridinyl ring. Furthermore, the carbonitrili substituent is attached to the ortho position of the phenyl ring relative to the piperidinyl ring attachment site. Furthermore, the phenyl ring, including the attached piperidinyl ring, is entirely tetrasubstituted. 1Furthermore, A is not limited to hydrogen, and A represents a heterocyclic ring system beyond pyridinyl. Moreover, in the general formula of International Publication No. 2022 / 086920, the 5-membered heterocyclic ring "M" is a positional isomer of the 3-substituted 4-methyl-4H-1,2,4-triazolyl ring in the compound of the present invention in compound 3, and in compound 4, the 5-membered heterocyclic ring "M" is the same as the compound of the present invention except that it possesses an amino group.

[0019] The compounds of the present invention differ structurally from compounds 21 and 23 in Chinese Patent Application Publication No. 114874186 in that the central sulfonamide portion linking the piperidinyl ring to the phenyl ring is replaced by a direct bond. Furthermore, the carbonitrile substituent is attached to the ortho position of the phenyl ring relative to the piperidinyl ring attachment site. Moreover, the phenyl ring, including the piperidinyl ring attached to it, is entirely tetrasubstituted. Furthermore, the compounds of the present invention do not contain an aminolinker between the phenyl ring and any further cyclic rings. These structural differences between the compounds of the present invention and the prior art unexpectedly result in an effective combination of (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells associated with lung disease or cancer (but not limited to the above), and (iii) appropriate membrane permeability and low in vitro efflux.

[0020] The compounds of the present invention are therefore superior to those disclosed in the prior art in terms of the following combination of parameters: • Potent inhibition of QPCT and QPCTL (Assay A) • Potent inhibition of QPCT / L in cells associated with lung disease or cancer (Assay B), but not limited to the following. • Appropriate membrane permeability and low in vitro efflux (Assay C)

[0021] The present invention provides a novel compound of formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

[0022]

Chemical Structure

[0023] Another embodiment of the present invention relates to a compound of formula (I), wherein A is A2, which is a 5 or 6-membered monoheteroaryl ring containing one or two heteroatom members selected from nitrogen. Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is a six-membered monoheteroaryl ring containing one or two heteroatom members selected from nitrogen, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), where A is A4, which is a 9 or 10-membered condensed bicyclic heteroaryl ring containing 2 to 4 heteroatom members selected from nitrogen. Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments.

[0024] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from A5 groups consisting of pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyrimidinyl and imidazo[1,2-a]pyrimidinyl. Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from A6 groups consisting of pyridinyl, pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyrimidinyl, and imidazo[1,2-a]pyrimidinyl. Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0025] [ka] Selected from A7 groups consisting of, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0026] [ka] Selected from the A8 group consisting of, substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0027] [ka] ; Selected from A9 groups consisting of, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0028] [ka] ; Selected from A10 units, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0029] [ka] ; Selected from A11 units consisting of, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0030] [ka] ; Selected from A12 units, Substituent R 1 , R 2 , R 3 and R 4is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein A is

[0031]

Chemical formula

[0032] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1b consisting of H, H3C-, Cl and F, and substituents A, R 2 , R 3 and R 4 are defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1c consisting of H and F, and substituents A, R 2 , R 3 and R 4 are defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1d consisting of H, and substituents A, R 2 , R 3 and R 4 are defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1e consisting of F, and substituents A, R 2 , R 3 and R 4 are defined as in any of the preceding embodiments.

[0033] Another embodiment of the present invention relates to a compound of formula (I), R 2 H, Halo, C 1-4 -alkyl, C 3-4 -Cycloalkyl, F 1-9 -Fluoro-C 1-6 -alkyl, 1-methyl-C 3-6 -Cycloalkyl, C 1-4 -Alkyloxy and C 3-4 - R2b consists of a cycloalkyloxy. Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2c consists of H, Cl, F, methyl, i-propyl, t-butyl, cyclopropyl, trifluoromethyl, 1-methyl-cyclopropyl, methyloxy and cyclopropyloxy. Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2d consists of H, Cl, F, methyl, t-butyl, cyclopropyl, trifluoromethyl, 1-methyl-cyclopropyl, methyloxy and cyclopropyloxy. Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 H, Cl, F, i-propyl, t-butyl, trifluoromethyl, methyloxy and

[0034] [ka] ; R2e consists of substituents A and R 1 , R 3 and R4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 H, Cl, F, t-butyl, trifluoromethyl, methyloxy and

[0035] [ka] ; R2f consists of substituents A and R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2g consists of H, F, i-propyl, t-butyl and trifluoromethyl, Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2h consists of H, F, t-butyl and trifluoromethyl, Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2j is composed of i-propyl, t-butyl, and trifluoromethyl. Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments.

[0036] Another embodiment of the present invention relates to a compound of formula (I), R 2 This is R2k, which consists of t-butyl and trifluoromethyl. Substituent A, R 1 , R 3 and R4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 R2m is selected from i-propyl and t-butyl, Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 2 This is R2n selected from t-butyl, Substituent A, R 1 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 3 The R3b group is selected from H, methyl, trifluoromethyl, F, and Cl. Substituent A, R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 3 It is selected from R3c groups consisting of H, methyl, F, and Cl. Substituent A, R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments.

[0037] Another embodiment of the present invention relates to a compound of formula (I), R 3 It is selected from R3d groups consisting of H, methyl, and Cl. Substituent A, R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 3 It is selected from R3e groups consisting of H and C-1, Substituent A, R1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 4 is, Haro, -CN, C 1-4 -alkyl, C 3-6 -Cycloalkyl, C 1-6 -alkyloxy, C 1-6 -alkyl-OC(O)-, F 1-9 -Fluoro-C 1-4 -alkyl, F 1-9 -Fluoro-C 1-4 -alkyloxy, C 3-6 -Cycloalkyloxy, C 3-6 A selection of R4b groups consisting of -cycloalkyl-H2C-O-, benzyloxy, (HO)(H3C)2-C- and HO-C(H3C)2H2CH2C-O-, Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments.

[0038] Another embodiment of the present invention relates to a compound of formula (I), R 4 is, Haro, -CN, C 1-4 -alkyl, C 3-6 -Cycloalkyl, C 1-6 -alkyloxy, C 1-6 -alkyl-OC(O)-, F 1-9 -Fluoro-C 1-4 -alkyl, F 1-9 -Fluoro-C 1-4 -alkyloxy, C 3-6 -Cycloalkyloxy, C 3-6 Selected from R4c groups consisting of -cycloalkyl-H2C-O-, benzyloxy, and HO-C(H3C)2H2CH2C-O-, Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R4 is fluoro, chloro, -CN, C 1-4 -alkyl, C 3-6 -Selected from R4d groups consisting of cycloalkyl, methoxy, (H3C)2HC-O-, H3CO-C(O)-, F2HC-, H3C-F2C-, trifluoromethyl, F2HC-O-, cyclopropyl-H2C-O-, benzyloxy, (HO)(H3C)2-C- and HO-C(H3C)2H2CH2C-O-, Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments.

[0039] Another embodiment of the present invention relates to a compound of formula (I), R 4 is fluoro, chloro, -CN, C 1-4 -alkyl, C 3-6 -Selected from the R4e group consisting of cycloalkyl, methoxy, (H3C)2HC-O-, H3CO-C(O)-, F2HC-, H3C-F2C-, trifluoromethyl, F2HC-O-, cyclopropyl-H2C-O-, benzyloxy and HO-C(H3C)2H2CH2C-O-, Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 4 The R4f group is selected from fluoro, chloro, -CN, methyl, cyclopropyl, methoxy, (H3C)2HC-O-, H3CO-C(O)-, F2HC-, H3C-F2C-, trifluoromethyl, F2HC-O-, cyclopropyl-H2C-O-, benzyloxy, (H3C)2HC-O- and HO-C(H3C)2H2CH2C-O-. Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments.

[0040] Another embodiment of the present invention relates to a compound of formula (I), R4 The R4g group is selected from fluoro, chloro, -CN, methyl, cyclopropyl, methoxy, (H3C)2HC-O-, H3CO-C(O)-, F2HC-, H3C-F2C-, trifluoromethyl, F2HC-O-, cyclopropyl-H2C-O-, benzyloxy and HO-C(H3C)2H2CH2C-O-. Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 4 The R4h group is selected from fluoro, chloro, -CN, methyl, cyclopropyl, methoxy, F2HC-, H3C-F2C-, trifluoromethyl, and F2HC-O-. Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments.

[0041] Another embodiment of the present invention relates to a compound of formula (I), R 4 The R4j group is selected from fluoro, chloro, methyl, cyclopropyl, methoxy, and trifluoromethyl groups. Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 4 The R4k group is selected from fluoro, chloro, methoxy, and trifluoromethyl groups. Substituent A, R 1 , R 2 and R 3 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ia),

[0042] [ka] (Ia) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ib),

[0043] [ka] (Ib) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ic),

[0044] [ka] (I C) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Id),

[0045] [ka] (Id) Substituent R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ie),

[0046] [ka] (Ie) Substituent R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (If),

[0047] [ka] (If) Substituent R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to the compound of formula (I) above having formula (Ig),

[0048] [ka] (Ig) Substituent R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ih),

[0049] [ka] (Ih) Substituent R 1 , R 2 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ij),

[0050] [ka] (Ij) Substituent R 1 , R 2 and R 4This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Ik),

[0051] [ka] (Ik) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (Im),

[0052] [ka] (Im) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of the above formula (I) having formula (In),

[0053] [ka] (In) Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments. Further preferred embodiments of the compound of formula (I) are included below as embodiments (EMB-1) through (EMB-10) in Table 1, using the above substituent definitions.

[0054] [Table 1]

[0055] For example, the compound of embodiment EMB-1 is R 2 Therefore, it has the R2c type group defined above, in combination with other types of groups as other substituents in formula (I) defined in the same row of the table. The same applies to other variable parts incorporated into the general formula.

[0056] [ka] [ka] [ka] [ka] [ka] [ka] Compounds according to formula (I), selected from the group consisting of the above, are particularly preferred.

[0057] Compounds according to formula (I) selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 16, 18, 19, 22, 24, 25, 29, 31, and 36, as described in the following examples, are particularly preferred. Compounds according to formula (I) selected from the group consisting of Examples 1, 2, 4, 7, 16, 18, 19, 25, 31, and 36, as described in the following examples, are particularly preferred. Compounds according to formula (I), selected from the group consisting of Examples 1, 4, 7, 16, and 18, as described in the following examples, are particularly preferred.

[0058] The present invention provides a novel phenylpiperidine derivative of formula (I) that is a surprisingly potent QPCT / L inhibitor. Another aspect of the present invention refers to a compound according to formula (I) that unexpectedly exhibits potent inhibition of QPCT / L in cells, which is associated with lung disease or cancer, but is not limited to the following. Another aspect of the present invention refers to a compound according to formula (I) as a surprisingly potent QPCT / L inhibitor of cells that have appropriate membrane permeability and low in vitro efflux. Another aspect of the present invention refers to a pharmaceutical composition containing at least one compound according to formula (I) together with one or more inert carriers and / or diluents. Further aspects of the present invention refer to compounds according to formula (I) for use in preventing and / or treating disorders associated with QPCT / L inhibition. Another aspect of the present invention refers to a method for producing the compound of the present invention. Further aspects of the present invention will become apparent directly to those skilled in the art from the above and below description and examples.

[0059] Terms and definitions used General definition Terms not specifically defined herein should be given the meanings that a person skilled in the art would assign to them in light of this disclosure and the context. However, the following terms used herein shall have the meanings given unless otherwise specified, and the following arrangements shall be observed.

[0060] In the groups, radicals, or parts defined below, the number of carbon atoms is often specified prior to the group, for example, C 1-6 Alkyl refers to an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., those skilled in the art can refer to the radical attachment site to the molecule from the free valence of the group itself. In combined groups containing two or more subordinate groups, the last designated subordinate group is the radical attachment site, for example, the substituent "aryl-C". 1-3 Alkylene (aryl-C)1-3 -alkylene) is C 1-3 This refers to an aryl group bonded to an alkyl group, where the latter is bonded to the nucleus or group to which the substituent is attached. Where the compounds of this invention are described in both chemical noun form and formula form, in case of any inconsistency, the formula form shall prevail. An asterisk may be used in a subform to indicate a bond leading to the defined nuclear molecule. The numbering system for substituent atoms begins with the atom closest to the nucleus or group to which the substituent is attached. For example, the term "3-carboxypropyl group" refers to the following substituents:

[0061] [ka] The carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" group refer to the following groups:

[0062] [ka] The asterisk can be used in sub-formulas to indicate a bond leading to a defined nuclear molecule. As used herein, the term “substituted” means that one or more hydrogen atoms on a given atom are replaced by a group selected from the defined groups of the substituent, provided that the substitution does not exceed the normal valency of the given atom and that the substitution results in a stable compound. Similarly, the term “substituted” may be used in reference to a chemical moiety, such as “substituted alkyl,” “substituted aryl,” etc., instead of a single atom. Unless otherwise specifically indicated throughout this specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereoisomers, E / Z isomers) and their racemic compounds, as well as mixtures of different proportions of other enantiomers, mixtures of diastereoisomers, or any of the aforementioned forms in which such isomers and enantiomers exist, and their solvates, e.g., hydrates.

[0063] Unless otherwise specified, the term "pharmaceutically acceptable salt," as defined in more detail below, shall also include its solvate, such as hydrate. In general, substantially pure stereoisomers can be obtained by using stereochemically pure starting materials, for example by separation of the corresponding mixtures, and / or by stereoselective synthesis, according to synthetic principles known to those skilled in the art. Methods for preparing optically active compounds are known in the art, such as by resolution of racemates or by synthesis, for example, by starting with optically active starting materials and / or by using chiral reagents.

[0064] The enantiomerically pure compounds of the present invention or intermediates can be prepared via asymmetric synthesis, for example, by the preparation of suitable diastereoisomer compounds or intermediates that can be separated by known methods (e.g., by chromatographic separation or crystallization) and / or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries, and subsequent separation. Furthermore, methods for preparing enantiomerically pure compounds from a corresponding racemic mixture are known to those skilled in the art, for example, by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by resolution of the racemic mixture using a suitable resolving agent, for example, by the formation of diastereoisomer salts of the racemic compound using an optically active acid or base, subsequent resolution of the salts and release of the desired compound from the salts; or by derivatization of the corresponding racemic compound using an optically active chiral additive reagent, subsequent separation of diastereoisomers and removal of chiral auxiliary groups; or by kinetic resolution of the racemic compound (e.g., by enzymatic resolution); by enantioselective crystallization from an aggregate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral additive.

[0065] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition and / or dosage form suitable for use in contact with human tissue, provided that it is within the bounds of medical common sense and provides a reasonable benefit-to-risk ratio without excessive toxicity, irritation, allergic response or other problems or complications. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound is modified by an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues, such as inorganic or organic salts of amines; and acidic residues, such as alkali or organic salts of carboxylic acids. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Further pharmaceutically acceptable salts may be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0066] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic 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. Other salts of acids useful for purifying or separating the compounds of the present invention (e.g., trifluoroacetate), other than those mentioned above, also constitute part of the present invention. The term halogen refers to fluorine, chlorine, bromine, and iodine.

[0067] n is an integer selected from 2, 3, 4, 5, or 6, preferably 4, 5, or 6, and is either a single radical or combined with another radical called "C". 1-n The term "-alkyl" refers to an acyclic, saturated, branched, or linear hydrocarbon radical having 1 to n carbon atoms. For example, C 1-5 The term alkyl encompasses the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-. "C 2-m The term "-alkynyl" is "C 2-m The term is used for an alkyl group (wherein m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6) in which at least two carbon atoms are bonded to each other by a triple bond.

[0068] k is an integer selected from 3, 4, 5, 7, or 8, preferably 4, 5, or 6, and is either a single radical or combined with another radical called "C". 3-k The term "cycloalkyl" refers to a cyclic, saturated, unbranched hydrocarbon radical having 3 to k carbon atoms. For example, C 3-7 - The term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0069] The term "halo" attached 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, preferably selected from fluorine, chlorine, or bromine, with fluorine being particularly preferred. Examples include H2FC-, HF2C-, and F3C-. The term "mono-heteroaryl ring" refers to a monocyclic aromatic ring system containing one or more heteroatoms selected from N, O, or S, consisting of 5 to 6 ring atoms. The term "mono-heteroaryl ring" is intended to encompass all possible isomeric forms. Therefore, the term "mono-heteroaryl ring" includes the following exemplary structures (each form is not described as a radical, as it can be arbitrarily attached to any atom via covalent bonds, as long as the valence is maintained).

[0070] [ka] The term "condensed bicyclic heteroaryl ring" refers to a bicyclic aromatic ring system consisting of 9 to 10 ring atoms, containing one or more heteroatoms selected from N, O, or S. The term "condensed bicyclic heteroaryl ring" is intended to include all possible isomeric forms. Therefore, the term "bicyclic heteroaryl ring" includes the following exemplary structures (each form is not described as radical, as it can be arbitrarily attached to any atom through covalent bonds, as long as the valence is maintained):

[0071] [Chemistry] The term "pyridyl" refers to the radicals of the following rings.

[0072] [Chemistry] . The term "pyridazinyl" refers to the radicals of the following rings.

[0073] [Chemistry] . The term "pyrimidyl" refers to the radicals of the following rings. [Chemistry] . The term "pyrazolyl" refers to the radicals of the following rings.

[0074] [Chemistry] . The term "thiazolyl" refers to the radicals of the following rings. [Chemistry] . The term "oxazolyl" refers to the radicals of the following rings.

[0075] [Chemistry] . The term "isoxazolyl" refers to the radicals of the following rings. [Chemistry] . The term "3H-imidazo[4,5-b]pyridyl" refers to the radicals of the following rings.

[0076] [Chemistry] . The term imidazo[1,2-a]pyrimidinyl refers to the radical of the following ring. [Chemistry] . The term 2H-pyrazolo[3,4-b]pyridyl refers to the radical of the following ring.

[0077] [Chemistry] . The term 1H-[1,2,3]triazolo[4,5-b]pyridyl refers to the radical of the following ring. [Chemistry] . The term [1,2,4]triazolo[4,3-a]pyrimidinyl refers to the radical of the following ring.

[0078] [Chemistry] . The term 1H-pyrazolo[4,3-c]pyridyl refers to the radical of the following ring. [Chemistry] . The term [1,2,5]oxadiazolo[3,4-b]pyridyl refers to the radical of the following ring.

[0079] [Chemistry] . The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to the radical of the following ring. [Chemistry] . The term [1,2,5]thiadiazolo[3,4-b]pyridyl refers to the radical of the following ring.

[0080] [ka] . The term imidazo[1,2-a]pyrimidinyl refers to the radical of the following ring. [ka] . The term pyrazolo[1,5-b]pyridazinyl refers to the radical of the following ring:

[0081] [ka] . The term 1,8-naphthilidinyl refers to the radical of the following ring:

[0082] [ka] . Many of the terms presented above may be used repeatedly in the definitions of formulas or bases, and in each case, independently of each other, have one of the meanings presented above.

[0083] Biological assays Evaluation of inhibitory activity against QPCT and QPCTL Assay A: Biochemical QPCT and QPCTL activity assay The activity of the compounds of the present invention can be demonstrated using the following biochemical enzyme activity assay.

[0084] QPCT or QPCTL-dependent conversion of the N-terminal glutamine of CD47 to pyroglutamate was monitored via MALDI-TOF MS. The test compound was dissolved in 100% DMSO and serially diluted in a clear 1,536-well microtiter plate. The enzymatic reaction was set up in assay buffer containing 20 mM Tris pH 7.5, 0.1 mM TCEP, 0.01% BSA, and 0.001% Tween 20. 2.5 μL of 2× concentrated QPCTL (in-house) or QPCT (Origine #TP700028) enzyme in assay buffer (0.5 nM final concentration, columns 1-23) or plain assay buffer (column 24) was added to each well. The plate was incubated for 10 minutes in a humidified incubator at 24°C. Subsequently, 2.5 μL of CD47 peptide substrate substitute was added. 19 QLLFNKTKSVEFTFC 33 The ) was added to each well (final concentration: 10 μM for QPCTL / 20 μM for QPCT). The plate was mixed at 1,000 rpm for 30 seconds, followed by incubation in a humidified incubator at 24°C for 40 minutes. After incubation, the stable isotope-labeled internal standard peptide was added. 19 [Pyr]LLFN(K)TKSVEFTFC 33 The enzymatic reaction was stopped by adding 1 μL containing (final concentration 4.0 μM) and SEN177 (final concentration 10 μM). The plate was sealed with adhesive foil, mixed at 1,000 rpm for 30 seconds, and stored at room temperature until the preparation of the MALDI target plate. The MALDI target plate was prepared as previously described. The 1-mass spectrum was obtained from the product ( 19 [Pyr]LLFNKTKSVEFTFC 33 , m / z 1,787.9037) and internal standards ( 19 [Pyr]LLFN(K)TKSVEFTFC 33The signal of the peptide (m / z 1,795.9179) was tracked using a rapifleX MALDI-TOF / TOF instrument. QPCT or QPCTL activity was monitored by calculating the ratio between the product signal and the internal standard signal, followed by standardization against high (100% activity) and low (0% activity) controls. The potency of the compound was determined by fitting the dose-response data to a 4-parameter logistic equation.

[0085] [Table 2]

[0086] [Table 3]

[0087] Assay B: SIRPα signal transduction assay (using Raji or A549 cells) The activity of the compounds of the present invention can be demonstrated using the following SIRPα signaling assay, which measures SIRPα association induced by CD47 presented via cell-cell interactions. Two cell types are used independently: the Raji cell line (a lymphoblastoid human cell line derived from B lymphocytes of Burkitt lymphoma patients in 1963) and A549 cells (human alveolar basal epithelial adenocarcinoma cells).

[0088] The test compounds were dissolved in 100% DMSO and serially diluted in white 384-well microtiter cell culture plates (PerkinElmer #60076780 for the Raji assay; Greiner #781945 PDL-coated plate for the A549 assay). 5000 Raji cells (ATCC #CC86) or 5000 A549 cells (ATCC #CCL-185) from Assay Complete Cell Plating reagent 30 (DiscoverX 93-0563R30B) were added to each well. The assay plates were incubated at 37°C, 95% humidity, and 5% CO2 for 48 hours. 15000 reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93-1135C19) were added to each well, and the plates were incubated at 37°C, 95% humidity, and 5% CO2 for 5 hours. Bioassay reagent 1 from the PathHunter Bioassay Detection Kit (DiscoverX 93-0001) was added to each well of the plate using a multichannel pipette, followed by incubation at room temperature for 15 minutes. Then, bioassay reagent 2 was added, followed by incubation at room temperature for 60 minutes (incubated in the dark).

[0089] Data analysis was performed using the luminescence signal generated by beta-galactosidase in the PathHunter reporter cell line. Luminescence measurements were performed using a Pherastar multimode reader. Dose-response curves & IC50 50 The data was calculated using a 4-parameter sigmoid dose-response equation.

[0090] [Table 4]

[0091] [Table 5]

[0092] Evaluation of permeability Assay C: Permeability in CACO-2 cells Caco-2 cells (1-2 × 10⁵ cells / 1 cm² area) were seeded into filter inserts (Costar transwell polycarbonate or PET filter, 0.4 μm pore size) and cultured for 10-25 days (DMEM).

[0093] Dissolve the compound in a suitable solvent (such as DMSO, a 1-20 mM stock solution). Dilute the stock solution 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 × 7H2O, 0.41 mM NaH2PO4 × H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare a transport solution (0.1-300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) is applied to the apical or basal-outside donor side, respectively, to measure AB or BA permeability (using a triple filter). Samples are collected from the donor at the beginning and end of the experiment, and from the receiver at various time intervals for up to 2 hours, for concentration measurement by HPLC-MS / MS or scintillation counting. The collected receiver volume is replaced with a fresh receiver solution. Efflux ratio (ER)=permeability BA / permeability AB

[0094] [Table 6]

[0095] [Table 7]

[0096] Evaluation of microsomal clearance Microsome clearance: Metabolic degradation of the test compound was assayed at 37°C using pooled liver microsomes from various species. Each 60 μl final incubation volume at each time point contained TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / mL in humans and dogs, 0.5 mg / mL in other species), and the test compound at a final concentration of 1 μM at room temperature. Following a short pre-incubation period at 37°C, the reaction was initiated by adding reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated at various time points by transferring aliquots to the solvent. After centrifugation (10000 g, 5 min), the supernatant aliquots were assayed for the amount of the parent compound by LC-MS / MS. Half-life was determined by the slope of the semi-logarithmic plot of the concentration-time profile. Intrinsic clearance (CL_INTRINSIC) is calculated by taking into account the amount of protein in incubation: CL_INTRINSIC[μl / min / mg protein]=(Ln2 / (half-life [min] × protein content [mg / ml]))×1000 CL_INTRINSIC_INVIVO[ml / min / kg]=(CL_INTRINSIC[μL / min / mg protein]×MPPGL[mg protein / g liver]×liver factor[g / kg body weight]) / 1000 Qh[%]=CL[ml / min / kg] / hepatic blood flow [ml / min / kg]) Solid liver cells, human: 120 × 10⁶ e⁶ cells / g liver Liver factor, human: 25.7 g / kg body weight Blood flow, human: 21 ml / (min × kg)

[0097] Evaluation of hepatocyte clearance Liver cell clearance Metabolic degradation of the test compound is assayed in a human hepatocyte suspension. After recovery from cryopreservation, human hepatocytes are diluted in Dulbecco's modified Eagle medium (3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, supplemented with 5% human serum) and measured in 1.0 × 10⁶ units. 6 The final cell density was obtained (cells / mL). Following a 30-minute pre-incubation in a cell culture incubator (37°C, 10% CO2), the test compound solution was spiked in a hepatocyte suspension to obtain a final concentration of 1 μM of the test compound and a final concentration of 0.05% of DMSO.

[0098] The cell suspension was incubated at 37°C (cell culture incubator, horizontal shaker), and the sample was removed from incubation after 0, 0.5, 1, 2, 4, and 6 hours. The sample was quenched with acetonitrile (containing an internal standard) and pelletized 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. The percentage of the remaining test compound is calculated using the peak area ratio at each incubation time point (test compound / internal standard) relative to the peak area ratio at time point 0. The logarithmically transformed data is plotted against incubation time, and the absolute value of the slope obtained by linear regression analysis is used to estimate the in vitro half-life (T1 / 2).

[0099] In vitro intrinsic clearance (CLint) is calculated from in vitro T1 / 2 and scaled to the whole liver using the following equation: hepatic liver (120 × 10⁶ cells / g liver), human liver (25.7 g liver / kg body weight), and in vitro incubation parameters. CL_INTRINSIC_IN VIVO[mL / min / kg]=(CL_INTRINSIC[μL / min / 1 cell]×hepatocellularity[10 6 [Cells / g liver] × [Liver factor [g / body weight]] / 1000 Hepatic in vivo blood clearance (CL) is predicted according to a well-agitated liver model, taking into account a mean hepatic blood flow (QH) of 20.7 mL / min / kg: CL[mL / min / kg]=CL_INTRINSIC_IN VIVO[mL / min / kg]×hepatic blood flow [mL / min / kg] / (CL_INTRINSIC_IN VIVO[mL / min / kg]+hepatic blood flow [mL / min / kg]) The results are expressed as a percentage of hepatic blood flow. QH[%]=CL[mL / min / kg] / hepatic blood flow [mL / min / kg])

[0100] Evaluation of plasma protein binding Equilibrium dialysis technique is used with a Dianorm Teflon dialysis cell (micro 0.2) to determine the approximate in vitro fractional binding of test compounds to plasma proteins. Each dialysis cell consists of donor and acceptor chambers separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. Stock solutions of each test compound are prepared in 1 mM DMSO and serially diluted to achieve a final test concentration of 1 μM. Subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as an anticoagulant), and aliquots of 200 μl of the test compound dialysis solution in plasma are dispensed into the donor (plasma) chamber. Aliquots of 200 μl of dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7% dextran) are dispensed into the buffer (acceptor) chamber. To establish equilibrium, incubation is performed at 37°C for 2 hours with rotation. At the end of the dialysis period, aliquots obtained from the donor and acceptor chambers were transferred to a reaction tube and processed for HPLC-MS / MS analysis. The concentration of the sample was quantified in the aliquot by HPLC-MS / MS against the calibration curve. The combined percentage is calculated using the following formula: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) x 100

[0101] Evaluation of solubility Saturated solutions are prepared in a well plate (formatted by robot) by adding an appropriate volume of selected aqueous medium (typically in the range of 0.25–1.5 ml) to each well containing a known amount of solid active pharmaceutical ingredient (typically in the range of 0.5–5.0 mg). The wells are shaken or stirred for a predetermined period (typically in the range of 2–24 hours), and then filtered using a suitable filter membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter absorption is avoided by discarding the first few drops of the filtrate. The amount of dissolved active pharmaceutical ingredient is determined by UV spectroscopy. Furthermore, the pH of the saturated aqueous solution is measured using a glass-electrode pH meter.

[0102] Evaluation of metabolism in human hepatocytes in vitro The metabolic pathway of the test compound will be investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes will be incubated in Dulbecco's Eagle medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg hydrocortisone / 500 ml. Following a 30-minute pre-incubation in a cell culture incubator (37°C, 10% CO2), the test compound solution was spiked in a hepatocyte suspension to obtain 1.0 × 10⁶ 6 ~4.0×10 6 Achieve a final cell density of cells / ml (depending on the turnover rate of the compound observed in primary human hepatocytes), a final concentration of 10 μM of the test compound, and a final DMSO concentration of 0.05%.

[0103] Cells are incubated in a cell culture incubator on a horizontal shaker for 6 hours, and the sample is removed from incubation after 0, 0.5, 1, 2, 4, or 6 hours, depending on the turnover rate. The sample is quenched with acetonitrile and pelletized by centrifugation. The supernatant is transferred to a 96-deep well plate, evaporated under nitrogen, and resuspended before biological analysis by liquid chromatography-high-resolution mass spectrometry to identify the estimated metabolites. The structure is Fourier-transform-MS n Assignments are made provisionally based on the data. Metabolites are reported as parental percentages in human hepatocyte incubations with a threshold of ≥4%.

[0104] Evaluation of pharmacokinetic properties The test compounds are administered intravenously or orally to each test species. Blood samples are taken at several time points after the application of the test compounds, treated with anticoagulants, and centrifuged. The concentrations of the administered compound and / or metabolites in the subject are quantified in the plasma sample. PK parameters are calculated using a non-compartmental method. AUC and Cmax are standardized to a dose of 1 μmol / kg.

[0105] Treatment method The present invention relates to compounds of general formula (I) that are useful for preventing and / or treating diseases and / or conditions related to or modulated by QPCT / L activity, including but not limited to cancer, fibrous diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, and chronic kidney disease. Compounds of general formula (I) are useful for the prevention and / or treatment of the following: (1) Pulmonary fibrosis, such as connective tissue diseases, including lupus erythematosus, systemic sclerosis, rheumatoid arthritis, pneumonitis or interstitial pneumonitis associated with polymyositis and dermatomyositis, idiopathic interstitial pneumonia, such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and idiopathic organic pneumonia (cryptogenic organic pneumonia). Pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, alveolar proteinosis, Langerhans cell histioproliferative disorder, pleural parenchymal fibroelasticity, interstitial lung diseases of known causes, such as occupational exposure, e.g., asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon lover's lung (birds), or other occupational airborne triggers, e.g., metals Bronchitis, pneumonitis, or interstitial pneumonitis caused by powder or mycobacteria, or by treatment, such as radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy, or by granulomatous diseases, such as polyangiitis, granulomatosis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or by other causes, such as inhalation of toxic gases, vapors, or heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis, or alpha-I-antitrypsin deficiency. (2) Other fibrotic diseases, such as hepatic fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endocardial fibrosis, old myocardial infarction, gliocarcinoma, arterial wall sclerosis, arthral fibrosis, Dupuytren's contracture, keloids, scleroderma / systemic scleroderma, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; pulmonary fibrosis and progressive pulmonary fibrosis, or spontaneous acute exacerbations induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, prior exacerbations and drugs. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid tumors, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer Cancer, intestinal cancer, small intestine cancer, large intestine cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, urogenital cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, seminoma, teratoma, liver cancer, kidney cancer, bladder cancer, urothelial carcinoma, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma Sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, Schwann cell tumor, glioblastoma, or sarcoma, gastrointestinal cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin lymphoma (NHL), urothelial carcinoma, or peritoneal cancer. (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjögren'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 hypersensitivity vasculitis), or erythema nodosum. (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion disease. Therefore, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0106] Furthermore, the present invention relates to the use of compounds of general formula (I) for treating and / or preventing diseases and / or conditions associated with or modulated by QPCT / L activity.

[0107] Furthermore, the present invention relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment and / or prevention of cancer, fibrous diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, and chronic kidney diseases.

[0108] Furthermore, the present invention relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for treating and / or preventing the following: (1) Pulmonary fibrosis diseases, such as connective tissue diseases, including lupus erythematosus, systemic sclerosis, rheumatoid arthritis, pneumonitis or interstitial pneumonitis with polymyositis and dermatomyositis, idiopathic interstitial pneumonia, such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, idiopathic organic pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, alveolar proteinosis, Langerhans cell histiocytosis, pleural parenchymal fibroelasticity, interstitial lung diseases of known causes, such as occupational exposure, such as asbestosis, silicosis, coal miner's lung (coal dust), As a result of farmer's lung (hay and mold), pigeon lover's lung (birds), or other occupational airborne triggers, such as metal dust or mycobacteria, or as a result of treatments, such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapy, or granulomatous diseases, such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, interstitial pneumonitis in hypersensitivity pneumonitis, or interstitial pneumonitis caused by other causes, such as inhalation of toxic gases, vapors, or heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatous diseases, cystic fibrosis or cystic fibrosis, or alpha-I-antitrypsin deficiency. (2) Other fibrotic diseases, such as hepatic fibrous bridging, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endocardial fibrosis, old myocardial infarction, gliocarcinoma, arterial wall sclerosis, arthral fibrosis, Dupuytren's contracture, keloids, scleroderma / systemic scleroderma, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; pulmonary fibrosis and progressive pulmonary fibrosis, or spontaneous acute exacerbations induced by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, prior exacerbations and drugs. (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid Lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, stomach cancer, intestinal cancer, small intestine cancer, colorectal 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, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, Schwann cell tumor, glioblastoma, or sarcoma; gastrointestinal cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC); breast cancer, colorectal cancer, intestinal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer; leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin lymphoma (NHL), urothelial carcinoma, or peritoneal cancer. (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonitis, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjögren'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 hypersensitivity vasculitis), or erythema nodosum. (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, or prion disease.

[0109] In further embodiments, the present invention relates to compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment and / or prevention of the diseases and conditions mentioned above. In a further embodiment, the present invention relates to the use of compounds of general formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preparing pharmaceuticals for treating and / or preventing the diseases and conditions mentioned above. In a further aspect of the present invention, the present invention relates to a method for treating or preventing the diseases and conditions mentioned above, comprising the step of administering to a human being an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0110] Combination therapy The compounds of the present invention may be further combined with one or more additional therapeutic agents, preferably one additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents described above, which are useful for treating diseases or conditions related to cancer, fibrous diseases, Alzheimer's disease, atherosclerosis, infectious diseases, chronic kidney disease, and autoimmune diseases. Suitable additional therapeutic agents for such combinations include, in detail, those that enhance the therapeutic effect of one or more active agents with respect to one of the symptoms mentioned, and / or those that reduce the dosage of one or more active agents. Therefore, the compounds of the present invention can be combined with one or more additional therapeutic agents selected from the group consisting of chemotherapy, cancer-targeted therapy, cancer immunotherapy, irradiation, antifibrotic agents, antitussives, anti-inflammatory agents, anti-atopic dermatitis agents, and bronchodilators.

[0111] Chemotherapy is a type of cancer treatment that uses one or more types of chemical anticancer drugs, such as cell division inhibitors or cytotoxic substances, cell proliferation inhibitors, and anti-angiogenic agents. Examples include folic acid (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, azacitidine, gemcitabine, alkylating agents, antimitotic agents, taxanes, and further advanced or standard-of-care compounds. Targeted therapy is a type of cancer treatment that uses drugs that target specific genes and proteins that help cancer cells survive and grow. Targeted therapy includes inhibitors of agonists, 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, e.g., HER2, HER3, HER4) and hepatocyte growth factor), tyrosine kinases, KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinases, or MDM2.

[0112] Cancer immunotherapy is a type of treatment that uses substances to stimulate or suppress the immune system to help the body fight cancer. Cancer immunotherapy includes therapeutic antibodies, such as anti-Her2 antibodies, anti-EGFR antibodies, and anti-PDGFR antibodies; and anti-GD2 (ganglioside G2) antibodies. Examples include dinutuximab, olaratumab, trastuzumab, pertuzumab, erzumaxomab, cetuximab, nesitumumab, nimotuzumab, panitumumab, or rituximab. Cancer immunotherapy also includes therapeutic antibodies that are checkpoint inhibitors, such as anti-PD1, anti-PD-L1 antibodies, or CTLA4 inhibitors. Examples include atezolizumab, avelumab, and durvalumab, ipilimumab, nivolumab, or pembrolizumab. Cancer immunotherapy includes agonists that target (inhibit) the CD47-SIRPα signaling axis, such as agonists 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 activators, such as blinatumomab.

[0113] Antifibrotic agents include, for example, nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors, such as roflumilast, or specific PDE4b inhibitors such as BI 1015550, autotaxin inhibitors, such as GLPG-1690 or BBT-877; connective tissue growth factor (CTGF) blocking antibodies, such as pamrebulumab; B-cell activator receptor (BAFF-R) blocking antibodies, such as ianarumab (Lanalumab); alpha-V / beta-6 blocking inhibitors, such as BG-00011 / STX-100; recombinant pentraxin-2 (PTX-2), such as PRM-151; c-Jun-N - Terminal kinase (JNK) inhibitors, e.g., CC-90001; galectin-3 inhibitors, e.g., TD-139; G protein-coupled receptor 84 (GPR84) inhibitors; G protein-coupled receptor 84 / G protein-coupled receptor 40 dual inhibitors, e.g., PBI-4050; Rho-related coiled-coil-containing protein kinase 2 (ROCK2) inhibitors, e.g., KD-025; heat shock protein 47 (HSP47) small interfering RNA, e.g., BMS-986263 / ND-L02- s0201; Wnt pathway inhibitors, e.g., SM-04646; LD4 / PDE3 / 4 inhibitors, e.g., tipercast; recombinant immunomodulatory domain of histidyl tRNA synthetase (HARS), e.g., ATYR-1923; prostaglandin synthase inhibitors, e.g., ZL-2102 / SAR-191801; 15-hydroxy-eicosapentaenoic acid (15-HEPE, e.g., DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors, e.g., PAT-1251, PXS-5382 / PXS-5338; phosphoinositide 3-kinase (PI3K) / rapamycin mammalian target (mTOR) dual inhibitors, e.g., HEC-68498; calpain inhibitors, e.g., BLD-2660; mitogen-activated protein kinase kinase kinase (MAP3K19) inhibitors, e.g., MG-S-2525; chitinase inhibitors, e.g., OATD-01; mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) inhibitors, e.g., MMI-0100;These include transforming growth factor beta-I (TGF-beta-I) small interfering RNAs, such as TRKZSO / BNC-1021; or lysophosphatidic acid receptor antagonists, such as BMS986278.

[0114] The dosage of the combination partners mentioned above is typically between 1 / 5 of the minimum dose usually recommended and 1 / 1 of the maximum dose usually recommended. Therefore, in another aspect, the present invention relates to the use of the compounds according to the present invention in combination with one or more additional therapeutic agents described above and below for treating diseases or conditions that may be affected or mediated by QPCT / L, more particularly the diseases or conditions described above and below.

[0115] In a further embodiment, the present invention relates to a method for treating a disease or condition in a patient that may be affected by inhibition of QPCT / L, comprising the step of administering to a patient requiring such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents. In a further embodiment, 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 may be affected by inhibition of QPCT / L in a patient in need thereof. In yet another aspect, the present invention relates to a method for treating a disease or condition mediated by QPCT / L activity in a patient, comprising the step of administering to a patient, preferably a human, in need of such treatment, a therapeutically effective amount of the compound of the present invention in combination with one or more therapeutically effective amounts of the additional therapeutic agents described above and below.

[0116] The compounds according to the present invention may be used in combination with additional therapeutic agents, either simultaneously or at staggered intervals. The compounds and one or more additional therapeutic agents according to the present invention may all be present together in a single formulation, for example, a tablet or a capsule, or separately in two identical or different formulations, for example, as a so-called kit of parts. As a result, in another embodiment, the present invention relates to a pharmaceutical composition comprising the compound according to the present invention and one or more additional therapeutic agents described above and below, together with one or more inert carriers and / or diluents. Other features and advantages of the present invention will become apparent from the examples illustrating the principle of the present invention and further detailed below.

[0117] preparation The compounds and intermediates according to the present invention are obtained using synthetic methods known to those skilled in the art and described in the literature on organic synthesis. Preferably, the compounds are obtained by methods relating to the preparation methods described more fully below, in detail in the experimental section. In some cases, the order in which the reaction steps are carried out may vary. Variations of reaction methods known to those skilled in the art but not described in detail here may also be used.

[0118] A general method for preparing the compounds according to the present invention will be apparent to those skilled in the art who study the following scheme. Any functional groups in the starting material or intermediate can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art. The compounds according to the present invention are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings shown above. These methods are intended as illustrations of the invention and do not limit the subject matter and scope of the claimed compounds to these examples. Where the preparation of the starting compounds is not described, they may be commercially available or prepared according to known compounds or methods described herein. Substances described in the literature are prepared according to the published synthetic methods. Abbreviations are as defined in the Examples section. The compound of formula (I) can be prepared as shown in scheme I below. Scheme I:

[0119] [ka] In scheme I, N-methyltriazolylpiperidine (R1=H, F)(A) undergoes nucleophilic aromatic substitution using an aryl fluoride (B, X=Cl, Br). The reaction can typically be carried out at high temperatures (100-130°C). The intermediate (C) is then subjected to Suzuki-cross coupling with a heteroarylboronic acid derivative at high temperatures (e.g., 100°C) in the presence of a suitable catalyst (e.g., Pd(dppf)Cl2)) and a suitable base (e.g., aqueous K2CO3) to obtain the compound of general formula (I). Scheme II:

[0120] [ka] Alternatively, as described in Scheme II, heteroarylboronic acid derivatives can be prepared from the corresponding bromide (Het(Ar)-Br) and a suitable boronating agent (e.g., bis(pinacolate)diborone) in the presence of a suitable catalyst (e.g., Pd(dppf)Cl2*CH2Cl2) and a suitable base (e.g., KOAc) at a high temperature (e.g., 100°C). The heteroarylboronic acid derivative (Het(Ar)-B(OR)2) can be isolated as a pinacolate boronic acid ester (R=CMe2, where both Rs form a 5-membered ring with O, B, O) or as a boronic acid (R=H), depending on the stability of the boronic acid ester, or used in a subsequent Suzuki coupling by adding (X=Cl, C having Br), a suitable catalyst (e.g., Pd(dppf)Cl2*CH2Cl2), and a suitable base (e.g., an aqueous Na2CO3 solution). If isolated, the boronic acid derivative can be converted to the examples of General Formula I described in Scheme I. Scheme III:

[0121] [ka] Compounds of formula (A) with R1=F can be prepared from the corresponding piperidinyl ester (D) equipped with a suitable protecting group (PG, e.g., BOC) by treatment with a suitable hydrazine source (e.g., N2H4*H2O) at a high temperature (e.g., 50°C). The resulting hydrazide (E) is then activated with DMF / DMA at an increasing temperature (e.g., 50°C), followed by treatment with methylamine at an increasing temperature (e.g., 90°C) to obtain the triazole derivative (F). Compounds of formula (A) with R1=F are obtained by cleaving the protecting group under suitable conditions (e.g., 4N HCl in dioxane for PG=BOC). Compounds of formula (A) with R1=H are obtained from commercial sources. (R1=H: CAS No: 297172-18-0). [Examples]

[0122] preparation The compounds and intermediates according to the present invention are obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis, for example, using the methods described in “Comprehensive Organic Transformations”, 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010, and “March's Advanced Organic Chemistry”, 7th Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained according to the preparation methods described more fully below, in detail in the experimental section. In some cases, the sequence employed in carrying out the reaction scheme may be varied. Variations of these reactions, known to those skilled in the art but not described in detail herein, may also be used. The general method for preparing the compounds according to the present invention will be apparent to those skilled in the art who are studying the subsequent schemes. The starting compounds may be commercially available or prepared by methods described in the literature or herein, or by similar or equivalent methods. Before carrying out the reaction, any corresponding functional groups in the starting compounds may be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art and described in the literature, e.g., “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 specify a temperature of about 20°C, e.g., 19–24°C.

[0123] [Table 8] Preparation of intermediates TIFF2026510266000071.tif243149 Synthesis of intermediate I

[0124] [ka]

[0125] tert-butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (160 g, 0.58 mol) is suspended in ethanol (640 mL) in a round-bottom flask. Hydrazine hydrate (70.6 mL, 1.16 mol) is added to the mixture at ambient temperature. The reaction mixture is heated to 50 °C and stirred for 12 hours. After cooling to ambient temperature, the mixture is concentrated under reduced pressure to obtain tert-butyl 4-fluoro-4-(hydrazine carbonyl)piperidine-1-carboxylate with 80% purity. C 11 H 20 FN3O3 (M=261.3g / mol) ESI-MS:284.2[M+Na]+ Rt(HPLC): 0.615 min (Method I)

[0126] tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-carboxylate Mix tert-butyl 4-fluoro-4-(hydrazine carbonyl)piperidine-1-carboxylate (135 g, 0.413 mol, 80% purity) with dioxane (945 mL) in a round-bottom flask. Add N,N-dimethylformamide-dimethylacetal (137 mL, 1.03 mol) to the mixture at ambient temperature. Heat the reaction mixture to 50°C and stir for 1 hour. Add a solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) to the mixture. Heat the resulting reaction mixture to 90°C and stir for 11 hours. Concentrate the mixture under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 20:1 to 0:1) to obtain tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-carboxylate. C 13 H 21 FN4O2 (M=284.3g / mol) ESI-MS:285.1[M+H] + Rt(HPLC): 0.766 min (Method I)

[0127] Intermediate I.1: 4-Fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine 90 g, 0.316 mol of tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-carboxylate is combined with methanol (90 mL) in a round-bottom flask. A solution of HCl (4 M in MeOH, 450 mL, 1.79 mol) is slowly added at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 12 hours. The desired product is filtered, washed with methanol, and dried to obtain 4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine hydrochloride. The hydrochloride salt (13.5 g) was added to a solution of ammonia in methanol (7N, 150 mL) and purified by chromatography (Biotage SNAP cartridge KP-NH, gradient DCM / MeOH 4:1~7:3). C8H 13 FN4 (M=184.2g / mol) ESI-MS:185[M+H]+ Rt(HPLC): 0.20 min (Method D) 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (MFCD09055373, CAS:297172-18-0) is obtained from commercial vendors. The hydrochloride is converted to free piperidine or piperazine according to the procedure described for Int. I. Intermediate II.1

[0128] [ka] A solution of 3-chloro-2-fluorobenzonitrile (100 mg, 0.43 mmol) and intermediate I (80 mg, 0.43 mmol) in DMSO (1 mL) is stirred at 100°C for 18 hours. The reaction mixture is diluted with acetonitrile and water, and purified directly via preparative HPLC (Xbridge C18, acetonitrile / water gradient containing 0.1% TFA) to obtain intermediate II.1. C 16 H 14 ClF4N5 (M=387.8g / mol) ESI-MS:389[M+H]+ Rt(HPLC): 0.58 min (Method A)

[0129] [Table 9-1] [Table 9-2] [Table 9-3] Synthesis of intermediates II.5 and II.6

[0130] [ka]

[0131] 3-Bromo-2-fluoro-4-methoxybenzonitrile 3-Bromo-2-fluoro-4-methoxybenzaldehyde (500 mg, 2.06 mmol), sodium formate (303 mg, 4.41 mmol), and hydroxylamine hydrochloride (168 mg, 2.37 mmol) are added to formic acid (2.5 mL). The resulting mixture is stirred and heated under reflux for 30 hours. After cooling to ambient temperature, it is diluted with a semi-saturated sodium chloride solution. The resulting precipitate is filtered, washed with water, and dried to obtain the desired product. C8H5BrFNO (M=230.0g / mol) ESI-MS:229 / 231(M*+) Rt(HPLC): 0.61 min (Method A)

[0132] Intermediate II.5 3-Bromo-2-fluoro-4-methoxybenzonitrile (2.00 g, 8.69 mmol) is added to DMSO (20 mL), and 4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine (3.47 g, 20.9 mmol) is added. The resulting mixture is heated at 100°C for 30 hours. After cooling to ambient temperature, the mixture is concentrated, and the residue is purified by preparative HPLC (Sunfire C18, MeCN / water gradient containing 0.1% TFA) to obtain the desired product together with the demethylated analog Int.II.5a. Intermediate II.5: C 16 H 18 BrN5O (M=376.3g / mol) ESI-MS:376 / 378[M+H]+ Rt(HPLC): 0.72 min (Method C) Intermediate II.5a: C 15 H 16 BrN5O (M=362.2g / mol) ESI-MS:362 / 364[M+H]+ Rt(HPLC): 0.64 min (Method C)

[0133] Intermediate II.6 3-Bromo-2-fluoro-4-methoxybenzonitrile (200 mg, 869 μmol) is added to DMSO (4 mL), and intermediate I (384 mg, 2.09 mmol) is added. The resulting mixture is heated at 100 °C for 22 hours. After cooling to ambient temperature, the mixture is concentrated, and the residue is purified by preparative HPLC (X-Bridge C18, MeCN / water gradient containing 0.1% TFA, followed by X-Bridge C18, MeCN / water gradient containing 0.1% NH3) to obtain the desired product. C 16 H 17 BrFN5O (M=394.2g / mol) ESI-MS:394 / 396[M+H]+ Rt(HPLC): 0.53 min (Method D) Intermediate II.7

[0134] [ka] Intermediate II.5a (70.0 mg, 0.193 mmol) and cyclopropanol (17.4 μL, 0.290 mmol) are added to degassed THF (1.0 mL). Triphenylphosphine (102 mg, 0.387 mmol) and diisopropyl azodicarboxylate (81.0 μL, 0.387 mmol) are added. The mixture is stirred at 70°C for 2 hours. Another batch of triphenylphosphine (102 mg, 0.387 mmol), diisopropyl azodicarboxylate (81.0 μL, 0.387 mmol), and cyclopropanol (17.4 μL, 0.290 mmol) is added, and the mixture is stirred again at 70°C for 4 hours. After cooling to ambient temperature, the solution is diluted with MeCN and water, acidified with TFA, and purified by preparative HPLC (Sunfire C18, MeCN / water gradient containing 0.1% TFA) to obtain the desired product. C 18 H 22 BrN5O (M=404.3g / mol) ESI-MS:404 / 406[M+H]+ Rt(HPLC): 0.78 min (Method C) 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1 H), 7.69 (d, J=8.7 Hz, 1 H), 7.04 (d, J=9.0 Hz, 1 H), 4.80 (spt, J=6.0 Hz, 1 H), 3.79 (s, 3 H), 3.38 - 3.51 (m, 2 H), 3.27 - 3.36 (m, 2 H), 3.16 - 3.27 (m, 1 H), 1.89 - 2.07 (m, 4 H), 1.32 (d, J=6.0 Hz, 6 H).

[0135] [Table 10] Intermediate II.10

[0136] [ka] Intermediate II.5a (75 mg, 0.207 mmol) is added to a mixture of DMF and water (9:1, 1.0 mL). Potassium carbonate (143 mg, 1.04 mmol) and sodium chlorodifluoroacetate (189 mg, 1.24 mmol) are added, the mixture is stirred, and the mixture is heated at 90°C for 10 hours. After cooling to ambient temperature, the addition of potassium carbonate (143 mg, 1.04 mmol) and sodium chlorodifluoroacetate (189 mg, 1.24 mmol) is repeated. The mixture is then stirred again at 90°C for 10 hours. After cooling to ambient temperature, the mixture is concentrated, and the residue is purified by preparative HPLC (Sunfire C18, MeCN / water gradient containing 0.1% TFA) to obtain the desired product. C 16 H 16 BrF2N5O (M=412.2g / mol) ESI-MS:412 / 414[M+H]+ Rt(HPLC): 0.53 min (Method C) Synthesis of Intermediate II.12

[0137] [ka] Intermediate II.12a 5-Bromo-3-chloro-2-fluorobenzonitrile (1.20 g, 4.96 mmol) and 4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine (956 mg, 5.46 mmol) are suspended in DMF (10 mL), and diisopropylethylamine (954 μL, 5.46 mmol) is added. The resulting reaction mixture is stirred at ambient temperature for 18 hours. This is then added dropwise to water, and the precipitated solid is collected by filtration and subsequently purified by column chromatography (SiO2, siRNA / MeOH gradient) to obtain the desired product. C 15 H 15 BrClN5 (M=380.7g / mol) ESI-MS:380 / 382[M+H]+ Rt(HPLC): 0.77 min (Method C)

[0138] Intermediate II.12 Intermediate II.12a (700 mg, 1.84 mmol), palladium(II) acetate (64.8 mg, 0.288 mmol), 1,1'-bis(diphenylphosphino)ferrocene (80.0 mg, 0.144 mmol), and sodium acetate (400 mg, 4.88 mmol) are suspended in a mixture of methanol (20 mL) and 1,4-dioxane (20 mL). The mixture is subjected to three vacuum cycles and purged with carbon monoxide. After the third purging cycle, a pressure of 8 bar is applied and the mixture is stirred at 60°C for 18 hours. The mixture is then concentrated, and the residue is purified by column chromatography (SiO2, siRNA / MeOH gradient) to obtain the desired product. C 17 H 18 ClN5O2 (M=359.8g / mol) ESI-MS:360[M+H]+ Rt(HPLC): 0.74 min (Method C) Synthesis of Intermediate II.18

[0139] [ka] Intermediate II.18 To a mixture of intermediate II.15 (40.0 mg, 0.100 mmol) in acetonitrile (1.0 mL), a solution of sodium methoxide in MeOH (30%, 28.2 μL, 0.151 mmol) is added. The resulting mixture is stirred at ambient temperature for 1 hour, and then at 50°C for 18 hours. A second solution of sodium methoxide in MeOH (30%, 28.2 μL, 0.151 mmol) is added. The resulting mixture is stirred at 50°C for 4 hours. After cooling to ambient temperature, the mixture is neutralized by adding acetic acid and diluted with water. This is purified by preparative HPLC (Sunfire C18, acetonitrile / water gradient containing 0.1% TFA) to obtain the desired product. C 16 H 17 BrFN5O (M=394.2g / mol) ESI-MS:394 / 396[M+H]+ Rt(HPLC): 0.92 min (Method E) Synthesis of Intermediate II.19

[0140] [ka] Intermediate II.19 To a mixture of 3-methyl-1,3-butanediol (52.2 mg, 0.502 mmol) in THF (1 mL), sodium hydride (55%, 17.5 mg, 0.401 mmol) is added, and the resulting mixture is stirred at ambient temperature for 1 hour. A solution of intermediate II.15 (40.0 mg, 0.100 mmol) in acetonitrile (1 mL) is added, and the resulting reaction mixture is heated to 50°C. After stirring at this temperature for 18 minutes, the mixture is cooled to ambient temperature, neutralized by adding acetic acid, and diluted with water. This is purified by preparative HPLC (Sunfire C18, acetonitrile / water gradient containing 0.1% TFA) to obtain the desired product. C 20 H 25 BrFN5O2 (M=466.3g / mol) ESI-MS:466 / 468[M+H]+ Rt(HPLC): 0.71 min (Method J) Synthesis of Intermediate III.1

[0141] [ka] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine To a mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.00 g, 19.8 mmol) in toluene (23 mL), tert-butyl acetate (26.6 mL, 198 mmol) and methanesulfonic acid (1.3 mL, 19.8 mmol) are added. After stirring at 80°C for 1 hour, the reaction is treated with additional methanesulfonic acid (1.3 mL, 19.8 mmol). The reaction mixture is cooled to ambient temperature, concentrated, redissolved in MeCN / H2O, and purified via preparative HPLC (Xbridge C18, acetonitrile / water gradient containing 0.1% TFA) to obtain 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine. C 10 H 12 BrN3 (M=254.1g / mol) ESI-MS:254 / 256[M+H]+ Rt(HPLC): 0.50 min (Method A)

[0142] Intermediate III.1 A solution of 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.50 g, 3.87 mmol), bis(pinacolato)diborone (1.20 g, 4.78 mmol), and potassium acetate (763 mg, 7.77 mmol) in 1,4-dioxane (15 mL) is purged with Ar for 10 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (190 mg, 0.23 mmol). After stirring at 110°C for 4 hours, the mixture was cooled to ambient temperature, concentrated, redissolved in MeCN / H2O, and purified via preparative HPLC (Xbridge C18, acetonitrile / water gradient containing 0.1% TFA) to obtain Int.III.1. C 10 H14 BN3O2 (M=219.0g / mol) ESI-MS:220[M+H]+ Rt(HPLC): 0.27 min (Method A) Synthesis of Intermediate III.2

[0143] [ka] 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine 5-tert-butyl-4H-1,2,4-triazole-3-amine (400 mg, 2.71 mmol) and 2-bromopropanedial (646 mg, 4.07 mmol) were added to acetic acid (5 mL). After stirring at 60°C for 3 hours, the reaction mixture was concentrated, neutralized with a saturated aqueous solution of NaHCO3, and extracted three times by DCM. The combined organic phase was dried (Na2SO4), concentrated, and purified by column chromatography (SiO2, cyclohexane / siRNA gradient) to obtain the title compound. C9H 11 BrN4 (M=255.1g / mol) ESI-MS:255 / 257[M+H]+ Rt(HPLC): 0.84 min (Method C)

[0144] Intermediate III.2 A solution of 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg, 0.63 mmol), bis(pinacolato)diborone (260 mg, 1.02 mmol), and potassium acetate (240 mg, 2.45 mmol) in 1,4-dioxane (4 mL) was purged with Ar for 15 minutes, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (55 mg, 0.08 mmol). After stirring at 60°C for 24 hours, the mixture was cooled to ambient temperature, diluted with ethyl acetate, and filtered through a silica plug. The filtrate was concentrated, redissolved in MeCN / H2O / TFA, and purified by preparative HPLC (SunFire C18, MeCN / H2O gradient containing 0.1% TFA) to obtain intermediate III.2. C9H 13 BN4O2 (M=220.0g / mol) ESI-MS:221[M+H]+ Rt(HPLC): 0.34 min (Method A) Synthesis of Intermediate III.3

[0145] [ka] 6-Bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine Ethanol (2 mL) is added to a mixture of 2-amino-5-bromopyrimidine (1.00 g, 5.63 mmol) and 1-chloro-3,3,3-trifluoroacetone (889 μL, 8.45 mmol). The resulting mixture is stirred at 90°C for 5 days. After cooling to ambient temperature, the mixture is packed onto EXtrelut® and purified by column chromatography (SiO2, DCM / MeOH gradient) to obtain the desired product. C7H3BrF3N3 (M=266.1g / mol) ESI-MS:266 / 268[M+H]+ Rt(HPLC): 0.38 min (Method A)

[0146] Intermediate III.3 6-Bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine (82 mg, 0.308 mmol) is added to 1,4-dioxane (1.0 mL). Bis(pinacorato)diborone (117 mg, 462 mmol) and potassium acetate (90.6 mg, 0.925 mmol) are added, and the resulting mixture is degassed by passing it through an argon stream. Pd(PPh3)2Cl2 (21.6 mg, 0.031 mmol) is added, and the reaction mixture is heated to 90°C and stirred for 5 hours. After cooling to ambient temperature, the mixture is concentrated, resuspended in a mixture of water and ACN, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired product. C7H5BF3N3O2 (M=230.9g / mol) ESI-MS:232[M+H]+ Rt(HPLC): 0.29 min (Method A) Synthesis of Intermediate III.4

[0147] [ka] 5-Bromo-2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.00 g, 3.93 mmol) is added to acetonitrile (15 mL), and N-chlorosuccinimide (0.58 g, 4.33 mmol) is added at ambient temperature. The resulting reaction mixture is stirred at 85°C for 12 hours. After cooling to ambient temperature, the mixture is concentrated and resuspended in water. This is extracted with ELISA (3×). The combined organic extract is dehydrated with Na₂SO₄, filtered, and concentrated. The residue is purified by column chromatography (SiO₂, PE / ELISA gradient) to obtain the desired product. C 10 H 11 BrClN3 (M=288.6g / mol) ESI-MS:288 / 290[M+H]+ Rt(HPLC): 0.80 min (Method L)

[0148] Intermediate III.4 A solution of 5-bromo-2-tert-butyl-3-chloropyrazolo[3,4-b]pyridine (0.80 g, 2.77 mmol), bis(pinacolato)diborone (0.92 g, 3.61 mmol), and potassium acetate (815 mg, 8.32 mmol) in 1,4-dioxane (16 mL) is purged with N2 for 10 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (202 mg, 0.23 mmol). After stirring at 100°C for 12 hours, the mixture is cooled to ambient temperature, concentrated, and resuspended in water. This is extracted with ELISA (3×), dehydrated with Na2SO4, and concentrated. The residue is purified via preparative HPLC (Welch Xtimate C18, acetonitrile / water gradient containing 10 mM NH4HCO3) to obtain Int.III.4. C 10 H 13 BClN3O2 (M=253.5g / mol) ESI-MS:254[M+H]+ Rt(HPLC): 0.71 min (Method M) Synthesis of Intermediate III.5

[0149] [ka] 6-Bromo-2-(1-methylcyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine A solution of 5-bromo-2-hydrazinopyrimidine (2.0 g, 2.1 mmol) and 1-methylcyclopropanecarboxylic acid (1.1 g, 2.1 mmol) in phosphoryl chloride (20 mL) is stirred at 100°C for 12 hours. After cooling to ambient temperature, the mixture is concentrated, resuspended in a saturated aqueous solution of Na2CO3, and extracted with siRNA (3×). The combined organic extract is dehydrated with Na2SO4, filtered, and concentrated. The resulting crude product is used without further purification. C9H9BrN4 (M=253.1g / mol) ESI-MS:253 / 255[M+H]+ Rt(HPLC): 0.56 min (Method L)

[0150] Intermediate III.5 To a solution of 6-bromo-2-(1-methylcyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine (0.50 g, 2.0 mmol) in 1,4-dioxane (5 mL), bis(pinacolato)diborone (0.60 g, 2.4 mmol), potassium acetate (0.58 g, 3.5 mmol), and [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (0.14 g, 0.19 mmol) were added. After stirring at 100 °C for 12 hours, the mixture was cooled to ambient temperature, diluted with water, and extracted with SiO(3×). The combined organic layer was dehydrated with Na2SO4 and concentrated. Further purification by column chromatography (SiO2, PE / Ã gradient, followed by DCM / MeOH gradient) yields Int.III.5. C9H 11 BN4O2 (M=218.0g / mol) ESI-MS:219[M+H]+ Rt(HPLC): 0.42 min (Method L) Synthesis of Intermediate III.6

[0151] [ka] 5-Bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine To a stirred solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (6.00 g, 28.8 mmol) in DMF (200 mL), sodium hydride (1.50 g, 34.5 mmol, 55% in mineral oil) was added at 0°C. After stirring for 30 minutes, the reaction mixture was treated with dibromodifluoromethane (8.3 mL, 86.3 mmol) and warmed to ambient temperature. The resulting mixture was stirred for 18 hours, diluted with MeCN / H2O, and directly purified via preparative HPLC (Xbridge C18, MeCN / water gradient containing 0.1% TFA) to obtain 5-bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine. C7H3Br2F2N3 (M=326.9g / mol) ESI-MS:326 / 328 / 330[M+H]+ Rt(HPLC): 0.56 min (Method A)

[0152] 5-Bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine A solution of 5-bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (2.1 g, 6.4 mmol) and silver tetrafluoroborate (2.5 g, 12 mmol) in DCM (40 mL) is stirred at 50°C for 18 hours. The reaction mixture is concentrated, redissolved in DCE (40 mL), and stirred at 80°C for 18 hours. The resulting mixture is concentrated, packed onto EXtrelut®, and purified by column chromatography (SiO2, DCM / MeOH gradient 100 / 0~1 / 1) to obtain the title compound. C7H3BrF3N3 (M=266.0g / mol) ESI-MS:266 / 268[M+H]+ Rt(HPLC): 0.47 min (Method A)

[0153] Intermediate III.6 To a stirred solution of 5-bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (741 mg, 1.39 mmol) in 1,4-dioxane (10 mL), bis(pinacorato)diborone (529 mg, 2.09 mmol) and potassium acetate (409 mg, 4.18 mmol) are added. The resulting mixture is purged with Ar for 10 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (102 mg, 0.14 mmol). After stirring at 90°C for 5 hours, the mixture is cooled to ambient temperature, concentrated, redissolved in H2O / MeCN, and purified via preparative HPLC (Xbridge C18, MeCN containing 0.1% TFA / water gradient) to obtain Int.III.6. C7H5BF3N3O2 (M=230.9g / mol) ESI-MS:232[M+H]+ Rt(HPLC): 0.30 min (Method A) Synthesis of intermediate IV

[0154] [ka] 3-Bromo-5-chloro-2-fluorobenzamide 3-Bromo-5-chloro-2-fluorobenzoic acid (1.00 g, 3.75 mmol) and HATU (1.49 g, 3.94 mmol) are suspended in DMF (10 mL), and a solution of ammonia in THF (0.5 M, 37.5 mL, 18.7 mmol) is added. The resulting mixture is stirred at ambient temperature for 18 hours. Another aliquot of the ammonia solution in THF (0.5 M, 37.5 mL, 18.7 mmol) is added, and the mixture is stirred for a further 4 hours. After completion, this is diluted with ethyl acetate and a semi-saturated NH4Cl solution. The organic phase is further washed with aqueous sat.NaHCO3 and aqueous sat.NaCl solutions, dehydrated with Na2SO4, and concentrated to obtain the desired product. C7H4BrClFNO(M=252.5g / mol) ESI-MS: Not detected Rt(HPLC): 0.76 min (Method B) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (dd, J=5.6, 2.7 Hz, 1 H), 7.92 - 7.98 (m, 1 H), 7.83 (br s, 1 H), 7.64 (dd, J=5.4, 2.7 Hz, 1 H)

[0155] Intermediate IV 3-Bromo-5-chloro-2-fluorobenzamide (850 mg, 3.37 mmol) is added to dichloromethane (20 mL), and Burgess's reagent (1.61 g, 6.73 mmol) is added. The resulting mixture is stirred at ambient temperature for 1.5 hours, and a second batch of Burgess's reagent (1.61 g, 6.73 mmol) is added. The mixture is stirred at ambient temperature for a further 4 hours. This is then washed with an aqueous solution of sat.NaCl, the organic phase is dehydrated with Na2SO4, and the mixture is concentrated to obtain the desired product. C7H2BrClFN (M=234.4g / mol) EI-MS:233 / 235[M*]+ Rt(HPLC): 0.97 min (Method B) Intermediate V

[0156] [ka] 3-Cyano-5-(6-Fluoropyridine-3-yl)-4-[4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]-benzoic acid This compound is obtained as a byproduct of the mixture during the synthesis of Example 15. C 21 H 19 FN6O2 (M=406.4g / mol) ESI-MS:405(MH)- Rt(HPLC): 0.63 min (Method C)

[0157] Intermediate V 3-Cyano-5-(6-Fluoropyridine-3-yl)-4-[4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]benzoic acid (60.0 mg, 0.140 mmol) and HATU (56.0 mg, 0.148 mmol) were added to DMF (1.0 mL), and a solution of ammonia in THF (0.5 M, 1.40 mL, 0.701 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 18 hours. This was concentrated, and the residue was purified by preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the desired product. C 21 H 20 FN7O (M=405.4g / mol) ESI-MS:406[M+H]+ Rt(HPLC): 0.60 min (Method C) Preparation of the final compound

[0158] (Example 1) [ka] Potassium carbonate (2M in H2O, 0.13mL, 0.25 mmol) is added to a mixture of intermediate II.1 (50 mg, 0.13 mmol) and intermediate III.1 (33 mg, 0.15 mmol) in 1,4-dioxane (2 mL). The resulting mixture is purged with argon for 15 minutes, and [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (9.2 mg, 0.01 mmol) is added, and the mixture is further purged with argon for 3 minutes. The reaction mixture is heated to 100°C and stirred for 15 hours. After cooling to ambient temperature, the reaction mixture is diluted with MeCN / H2O and filtered. Example 1 is obtained by direct purification via preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% TFA). C 26 H 26 F4N8 (M=526.5g / mol) ESI-MS:527[M+H]+ Rt(HPLC): 0.59 min (Method A) 1H NMR (400 MHz, DMSO-d6) δ = 8.66 (d, J=2.3 Hz, 1 H), 8.63 (s, 1 H), 8.51 (s, 1 H), 8.29 (d, J=2.3 Hz, 1 H), 8.24 (dd, J=2.3, 0.6 Hz, 1 H), 7.85 - 7.88 (m, 1 H), 3.70 (d, J=1.6 Hz, 4 H), 3.25 - 3.34 (m, 2 H), 3.11 - 3.22 (m, 2 H), 2.12 - 2.29 (m, 4 H), 1.72 (s, 9 H) The following examples are prepared by slightly modifying the procedure of Example 1:

[0159] [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] Synthesis of Example 20

[0160] [ka]

[0161] Ethyl 1-(6-bromo-2-cyano-3-methoxyphenyl)piperidine-4-carboxylate A solution of 3-bromo-2-fluoro-6-methoxybenzonitrile (726 mg, 3.00 mmol), ethylpiperidine-4-carboxylate (1.2 mL, 7.5 mmol), and DIPEA (2.6 mL, 15 mmol) in DMSO (10 mL) was stirred at 100°C for 18 hours, followed by the addition of another ethylpiperidine-4-carboxylate (1.2 mL, 7.5 mmol). After stirring at 100°C for 72 hours, the resulting mixture was diluted with H2O and purified by preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the title compound. C 16 H 19 BrN2O3 (M=367.2g / mol) ESI-MS:367[M+H]+ Rt(HPLC): 1.13 min (Method E)

[0162] Ethyl 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carboxylate A 2M aqueous solution of ethyl 1-(6-bromo-2-cyano-3-methoxyphenyl)piperidine-4-carboxylate (310 mg, 0.84 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (CAS: 329214-79-1) (297 mg, 1.3 mmol), XPhos Pd G3 (40 mg, 0.08 mmol), and potassium phosphate (1.3 mL, 2.5 mmol) in 1,4-dioxane (10 mL) was purged with argon for 2 minutes, and then stirred at 90°C for 18 hours. After cooling to ambient temperature, the resulting mixture was filtered and subjected directly to preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the title compound. C 21 H 22 FN3O3 (M=383.4g / mol) ESI-MS:384[M+H]+ Rt(HPLC): 1.07 min (Method E)

[0163] 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carboxylic acid To a solution of ethyl 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carboxylate (240 mg, 0.63 mmol) in EtOH (10 mL), a 1 M aqueous solution of sodium hydroxide (0.75 mL, 0.75 mmol) is added. After stirring for 1 hour, the reaction is treated with an additional 1 M aqueous solution of sodium hydroxide (0.75 mL, 0.75 mmol), stirred for another 1 hour, and then a further 1 M aqueous solution of sodium hydroxide (0.75 mL, 0.75 mmol) is added. After stirring for 1 hour, the reaction mixture is acidified with acetic acid and diluted with H2O / siRNA. The aqueous phase is extracted twice more with siRNA. The combined organic phase is dried (Na2SO4), concentrated to obtain the title compound, which is used without further purification. C 19 H 18 FN3O3 (M=355.4g / mol) ESI-MS:356[M+H]+ Rt(HPLC): 0.96 min (Method C)

[0164] 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carbozide To a stirred solution of 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carboxylic acid (210 mg, 0.59 mmol) in DMF (10 mL), hydrazine hydrate (44 mg, 0.89 mmol) and DIPEA (0.2 mL, 1.2 mmol) were added. The resulting mixture was stirred for 2 minutes, treated with HATU (292 mg, 0.77 mmol), and stirred for a further 18 hours. The reaction was purified directly by preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the title compound. C 19 H 20FN5O2 (M=369.4g / mol) ESI-MS:370[M+H]+ Rt(HPLC): 0.81 min (Method C)

[0165] (Example 20) To a solution of 1-[2-cyano-6-(6-fluoropyridine-3-yl)-3-methoxyphenyl]piperidine-4-carbohydrazide (55 mg, 0.15 mmol) in 1,4-dioxane (1 mL), N,N-dimethylformamide dimethyl acetal (49 μL, 0.37 mmol) was added. After stirring at 50°C for 45 minutes, the mixture was treated with a 2 M solution of methylamine (0.37 mL, 0.74 mmol) and acetic acid (43 μL, 0.74 mmol) in THF, and further stirred at 90°C for 18 hours. Example 20 was obtained by direct purification by preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% TFA). C 21 H 21 FN6O (M=392.4g / mol) ESI-MS:393[M+H]+ Rt(HPLC): 0.81 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ = 8.98 (s, 1 H), 8.23 ​​(d, J=2.4 Hz, 1 H), 8.00 (td, J=8.2, 2.4 Hz, 1 H), 7.49 (d, J=8.6 Hz, 1 H), 7.28 (dd, J=8.5, 2.7 Hz, 1 H), 7.01 (d, J=8.7 Hz, 1 H), 3.94 (s, 3 H), 3.72 (s, 3 H), 3.15 - 3.25 (m, 2 H), 2.92 - 3.09 (m, 3 H), 1.78 - 1.87 (m, 2 H), 1.57 - 1.73 (m, 2H) Synthesis of Example 21

[0166] [ka]

[0167] (Example 21) Intermediate V (18 mg, 44 μmol) is added to pyridine (0.4 mL), and phosphoroxychloride (4.1 μL, 44 μmol) is added. The resulting reaction mixture is stirred at 60°C for 1 hour. After cooling to ambient temperature, it is concentrated, and the residue is purified by column chromatography (SiO2, HCl / MeOH gradient) and preparative HPLC (XBridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the desired product. C 21 H 18 FN7 (M=387.4g / mol) ESI-MS:388[M+H]+ Rt(HPLC): 0.60 min (Method F) 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (d, J=2.0 Hz, 1 H), 8.32 (d, J=2.4 Hz, 1 H), 8.31 (s, 1 H), 8.08 (td, J=8.2, 2.5 Hz, 1 H), 7.97 (d, J=2.2 Hz, 1 H), 7.35 (dd, J=8.5, 2.7 Hz, 1 H), 3.58 (s, 3 H), 3.32 - 3.38 (m, 2 H), 2.88 - 3.01 (m, 3 H), 1.63 - 1.84 (m, 4 H) (Example 23)

[0168] [ka] 5-chloro-3-methoxypyridazine (34.6 mg, 0.23 mmol), potassium acetate (30.4 mg, 0.31 mmol), and bis(pinacolato)diborone (58.9 mg, 0.23 mmol) are suspended in 1,4-dioxane (2 mL), and the resulting mixture is purged with argon for 15 minutes. [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloride DCM complex (Pd(dppf)Cl2*CH2Cl2, CAS:95464-05-4) (12.6 mg, 0.015 mmol) is added. The reaction mixture is heated to 100 °C and stirred for 4 hours. After cooling to ambient temperature, intermediate II.1 (60.0 mg, 0.15 mmol), Na2CO3 solution (2 M in H2O, 232 μL, 0.46 mmol), and (Pd(dppf)Cl2*CH2Cl2, CAS:95464-05-4) (12.6 mg, 0.015 mmol) are added. The mixture is purged again with argon for 3 minutes, heated to 100°C, and stirred at 100°C for 4 hours. After cooling to ambient temperature, the reaction is diluted with a water / ACN mixture, acidified with TFA, filtered, and purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C 21 H 19 F4N7O (M=461.4g / mol) ESI-MS:462[M+H]+ Rt(HPLC): 0.87 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ = 9.02 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 4.09 (s, 3H), 3.74 (d, J = 1.1 Hz, 3H), 3.32 - 3.16 (m, 4H), 2.26 - 2.08 (m, 4H) Analysis data of the synthesized examples

[0169] [Table 12-1] Table 12-2 Table 12-3 Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Analytical HPLC method

[0170] Table 13

[0171] Table 14

[0172] Table 15

[0173] Table 16

[0174] Table 17

[0175] Table 18

[0176] Table 19

[0177] Table 20

[0178] Table 21

[0179] Table 22

[0180] Table 23

[0181] Table 24

[0182] Table 25

[0183] Table 26

[0184] Table 27

Claims

1. Compounds of formula (I) or salts thereof, especially pharmaceutically acceptable salts thereof. 【Chemistry 1】 (I) (In the formula, A is a 5- or 6-membered mono-heteroaryl ring A1a containing one or two heteroatom members selected from the group consisting of nitrogen, oxygen, and sulfur, wherein at least one of the heteroatom members is nitrogen. Alternatively, A1b is a 9 or 10-membered condensed bicyclic heteroaryl ring containing 1 to 4 heteroatom members selected from the group consisting of nitrogen, oxygen, and sulfur, wherein at least two of the heteroatom members are nitrogen. R 1 H, C 1-4 - Selected from R1a groups consisting of alkyl and halo, R 2 is selected from the R2a group consisting of H, halo, hydroxy, C 1-6 -alkyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, 1-methyl-C 3-6 -cycloalkyl, F 1-9 -fluoro-C 1-6 -alkyl, HO-C 1-6 -alkyl, C 1-6 -alkyloxy, C 1-4 -alkyl-O-H 2 CH 2 C-O-, C 3-6 -cycloalkyloxy, C 3-6 -cycloalkyl-H 2 C-O-, F 1-9 -fluoro-C 1-4 -alkyloxy, C 1-6 -alkyl-O-C(O)-, H 2 N-C(O)- and C 1-6 -alkyl-NH-C(O)-, R 3 H, C 1-4 - Alkyl, F 1-9 -Fluoro-C 1-4 - Selected from R3a groups consisting of alkyl and halo, R 4 Hello, C 1-4 - Alkyl, C 3-6 -Cycloalkyl, -CN, C 1-6 -Alkyloxy, C 1-6 -Alkyl-O-C(O)-, F 1-9 -Fluoro-C 1-4 - Alkyl, F 1-9 -Fluoro-C 1-4 -Alkyloxy, C 3-6 -Cycloalkyloxy, C 3-6 -Cycloalkyl-H 2 C-O-, benzyloxy, (HO)(H 3 C) 2 -C- and HO-C(H 3 C) 2 H 2 CH 2 (Selected from R4a groups consisting of C-O-)

2. A compound of formula (I) or a salt thereof according to claim 1, wherein A is selected from five A groups consisting of pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyrimidinyl, and imidazo[1,2-a]pyrimidinyl.

3. R 2 However, H, Haro, C 1-4 - Alkyl, C 3-4 - Cycloalkyl, F 1-9 -Fluoro-C 1-6 -Alkyl, 1-methyl-C 3-6 - Cycloalkyl, C 1-4 - Alkyloxy and C 3-4 - A compound of formula (I) or a salt thereof according to claim 1 or 2, wherein R2b is a cycloalkyloxy.

4. R 4 However, halo, -CN, C 1-4 - Alkyl, C 3-6 - Cycloalkyl, C 1-6 -Alkyloxy, C 1-6 -Alkyl-O-C(O)-, F 1-9 -Fluoro-C 1-4 - Alkyl, F 1-9 -Fluoro-C 1-4 -Alkyloxy, C 3-6 -Cycloalkyloxy, C 3-6 -Cycloalkyl-H 2 C-O-, benzyloxy, (HO)(H 3 C) 2 -C- and HO-C(H 3 C) 2 H 2 CH 2 A compound of formula (I) or a salt thereof according to any one of claims 1 to 3, selected from R4b groups consisting of C-O-.

5. A compound of formula (I) or a salt thereof according to any one of claims 1 to 4, having formula (1-c). 【Chemistry 2】 (I C)

6. A compound of formula (I) or a salt thereof according to any one of claims 1 to 4, having formula (1-f). 【Transformation 3】 (If)

7. A compound of formula (I) or a salt thereof according to any one of claims 1 to 4, having formula (1-j). 【Chemistry 4】 (Ij)

8. A compound of formula (I) or a salt thereof according to any one of claims 1 to 4, having formula (1-n). 【Transformation 5】 (In)

9. A compound of formula (I) or a salt thereof according to claim 1, selected from the group consisting of the following: 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】 【Transformation 6-6】

10. A pharmaceutically acceptable salt of one or more of the compounds described in claims 1 to 9.

11. A pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof described in one or more of claims 1 to 9, together with one or more inert carriers and / or diluents.

12. A pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof described in one or more of claims 1 to 9, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

13. The pharmaceutical composition according to claim 12, wherein one or more additional therapeutic agents are selected from the group consisting of anticancer agents and antifibrotic agents.

14. A compound according to one or more of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

15. A method for a patient in need of a method for treating a disease, such as cancer or fibrous disease, and conditions associated with these diseases, characterized by administering to the patient one or more of the compounds or pharmaceutically acceptable salts thereof described in one or more of claims 1 to 9.

16. A compound or pharmaceutically acceptable salt thereof according to one or more of claims 1 to 9, for use in methods for treating cancer, fibrous disease, neurodegenerative disease, atherosclerosis, infectious disease, or chronic kidney disease.

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