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

Abstract

This disclosure provides certain piperidinylpyridinylcarbonile 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 piperidinylpyridinylcarbonitrate 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 discloses a general formula QPCTL inhibitor.

[0009] [ka] (The formula includes compounds 3 and 6)

[0010] [ka] 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 match the chemical structure disclosed herein, but corresponds to an alternative structure in which the fluorine atom is replaced by a chlorine atom.

[0011] [ka]

[0012] Compounds 3 (including alternative compound 3) and 6 in International Publication No. 2022 / 086920 are described therein as

[0343] , IC for isolated QPCTLs. 50 It is disclosed to have inhibitory activity of <1 μM. Chinese Patent No. 114874186 discloses a glutamine acylcyclase isoenzyme inhibitor of a general formula, which includes Examples 21 and 23 (Table on page 17).

[0013] [ka]

[0014] [ka] I C50 These values ​​are shown as 29.22 nM and 11.26 nM, respectively, for Examples 21 and 23 in Chinese Patent No. 114874186. [Overview of the project]

[0015] The present invention discloses novel piperidinylpyridinylcarbonite derivatives of formula (I) that are inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like proteins (QPCTL) possessing appropriate pharmacological and pharmacokinetic properties, enabling their use as pharmaceuticals to treat conditions and / or diseases treatable by inhibition of QPCT / L.

[0016] [ka] (I)

[0017] 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]

[0018] The compound of the present invention The present invention provides a novel piperidinylpyridinylcarbonate 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 piperidinylpyridinylcarbonite 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.

[0019] The compounds of the present invention are structurally different from SEN177 and SEN180 of J-S, NCB 2015 in that the pyridinyl ring attached to the piperidinyl ring contains a ring nitrogen at the meta-position relative to the piperidinyl ring attachment position. Further, the carbonitrile substituent is attached to the ortho-position relative to the piperidinyl ring attachment position of the said pyridinyl ring. Furthermore, R 1 、R 2 and R 3 are not limited to hydrogen or methyl, and A represents a heterocyclic ring system beyond pyridinyl. The compounds of the present invention are structurally different from Examples 1094 and 1095 in International Publication No. 2018 / 178384 in that the pyridinyl ring attached to the piperidinyl ring contains a ring nitrogen at the meta-position relative to the piperidinyl ring attachment position. Further, the carbonitrile substituent is attached to the ortho-position relative to the piperidinyl ring attachment position of the said pyridinyl ring. Furthermore, R 1 、R 2 and R 3 is not limited to hydrogen, and A represents a heterocyclic ring system beyond pyridinyl. Furthermore, the 5-membered heterocyclic ring attached to the piperidinyl ring at the 4-position relative to the piperidinyl nitrogen is an aminothiazolyl ring in Example 1094 and an aminothiadiazolyl ring in Example 1095, while in the compounds of the present invention, this is a 3-substituted-4-methyl-4H-1,2,4-triazolyl ring.

[0020] The compounds of the present invention are structurally different from Compound 3 (including Alternative Compound 3) and Compound 6 of International Publication No. 2022 / 086920 in that the pyridinyl ring attached to the piperidinyl ring contains a ring nitrogen at the meta-position relative to the piperidinyl ring attachment position. Further, the carbonitrile substituent is attached to the ortho-position relative to the piperidinyl ring attachment position of the said phenyl ring. Further, R 1 、R 2 and R 3Furthermore, A is not limited to hydrogen, and represents a heterocyclic ring system beyond pyridinyl. In addition, the 5-membered heterocyclic ring "M" in the general formula of International Publication No. 2022 / 086920 is a positional isomer of the 3-substituted 4-methyl-4H-1,2,4-triazolyl ring of the compound of the present invention in compound 3, and the 5-membered heterocyclic ring "M" in the general formula of International Publication No. 2022 / 086920 is a 3-substituted 4-methyl-4H-1,2,4-triazolyl ring like the compound of the present invention in compound 4, but this has an amino group.

[0021] The compounds of the present invention differ structurally from compounds 21 and 23 of Chinese Patent No. 114874186 in that the central sulfonamide portion linking the piperidinyl ring to the phenyl ring is replaced by a direct bond. Furthermore, the carbonitrili substituent is attached to the ortho position of the phenyl ring relative to the piperidinyl ring attachment position. 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.

[0022] The compounds of the present invention are therefore superior to those disclosed in the prior art in terms of the following combinations 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) The present invention provides novel compounds according to formula (I) or salts thereof, in particular pharmaceutically acceptable salts thereof.

[0023] [ka] (I) (In the formula, A is A1a, which is a 5 or 6-membered mono-heteroaryl ring containing one or two nitrogen atoms. Alternatively, A is A1b, which is a 9 or 10-membered condensed bicyclic heteroaryl ring containing 1 to 4 nitrogen atoms. A has one or two R 4 It may be replaced by, R 1 It is selected from R1a groups consisting of H and F, R 2 H, Halo, C 1-6 -Alkyl and F 1-9 -Fluoro-C 1-6 Selected from R2a groups consisting of alkyl groups, R 3 H, Halo, C 1-4 -alkyl, F 1-9 -Fluoro-C 1-4 -Alkyl and C 3-6 -Selected from R3a groups consisting of cycloalkyl groups, R 4 Hello, C 1-6 -alkyl, F 1-9 -Fluoro-C 1-6 -Alkyl and C 3-6 (Selected from R4a groups consisting of cycloalkyl groups)

[0024] Another embodiment of the present invention relates to a compound of formula (I), A is a 6-membered mono-heteroaryl ring A2 containing one or two nitrogen atoms, A2 independently has one or two R 4 It has been replaced with, 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 A3 groups consisting of 1H-[1,2,3]triazolo[4,5-b]pyridinyl, pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and 1H-imidazo[4,5-b]pyridinyl. A3 independently has one or two R 4 It has been replaced with, 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 A4 groups, A4 independently comprises one or two R 4 It has been replaced with, 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 A5 groups consisting of, A5 independently comprises one or two R 4 It has been replaced with, 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 A6 groups consisting of, A6 independently comprises one or two R 4 It has been replaced with, 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 A7 groups consisting of, A7 independently comprises one or two R 4 It has been replaced with, 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 A8 groups consisting of, A8 independently, one or two R 4 It has been replaced with, Substituent R 1 , R 2 , R 3 and R 4 This is defined as in any of the preceding embodiments.

[0030] Another embodiment of the present invention relates to a compound of formula (I), where A is A9, which is a 9-membered condensed bicyclic heteroaryl ring containing 1 to 4 nitrogen atoms. A is one or two R 4 It may be replaced by, 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 R 1 is R1b selected from F, substituent 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 2 is R2b selected from H, halo, C 1-4 -alkyl and F 1-3 -fluoro-C 1-4 -alkyl, substituent R 1 , R 3 and R 4 are defined as in any of the preceding embodiments.

[0031] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2c selected from H, Cl, H3C and F3C, substituent R 1 , 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 3 is R3b selected from H, chloro, fluoro, C 1-4 -alkyl, F 1-9 [[ID= fifty-two]]-fluoro-C 1-4 -alkyl and cyclopropyl, substituent R 1 , R 2 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 3 is R3c selected from H, chloro, fluoro, H3C, F3C, F2HC, H3CF2C and cyclopropyl, substituent R [[ID= six-nine]] 1 , R 2 It should be noted that there is a possible error in the original text "selected from of" in line 54, which should probably be "selected from". The translation is adjusted accordingly.and R 4 is defined as in any of the preceding embodiments.

[0032] Another embodiment of the present invention relates to a compound of formula (I) wherein R 3 is R3d selected from H, chloro, H3C, F3C, F2HC, H3CF2C and cyclopropyl, substituent R 1 , R 2 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 3 is selected from the group R3e consisting of halo, C 1-4 -alkyl, F 1-9 -fluoro-C 1-4 -alkyl and C 3-6 -cycloalkyl, substituent R 1 , R 2 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 4 is selected from the group R4b consisting of halo, C 1-4 -alkyl, F 1-9 -fluoro-C 1-4 -alkyl and C 3-6 -cycloalkyl, substituent R 1 , R[[ID=5�]] 2 and R 3 are defined as in any of the preceding embodiments.

[0033] Another embodiment of the present invention relates to a compound of formula (I) wherein R 4 is selected from the group R4c consisting of halo, C 1-4 -alkyl and F[[ID={65]] 1-3 -fluoro-C 1-4 -alkyl, substituent R 1 , R 2 and R 3 are defined as in any of the preceding embodiments. Another embodiment of the present invention relates to a compound of formula (I), R 4 is chloro, fluoro, C 1-4 -Alkyl and F 1-3 -Fluoro-C 1-4 Selected from R4d groups consisting of -alkyl groups, Substituent 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 R4e group is selected from chloro, fluoro, H3C, F3C, (H3C)3C, (H3C)2HC and F3C(H3C)2C. Substituent 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), A is A9, R 3 It is R3e, 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 (Ia),

[0034] [ka] (Ia) Substituent A, 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),

[0035] [ka] (Ib) Substituent A, R3 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),

[0036] [ka] (I C) Substituent R 5 is H or R 4 and substituent 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),

[0037] [ka] (Id) Substituent R 5 is H or R 4 and substituent 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 (Ie),

[0038] [ka] (Ie) Substituent 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 (If),

[0039] [ka] (If) Substituent R 3This is defined as in any of the preceding embodiments.

[0040] [ka] [ka] [ka] [ka] [ka] Compounds according to formula (I), selected from the group consisting of the above, are particularly preferred.

[0041] Compounds according to formula (I) selected from the group consisting of Examples 1, 2, 5, 28, 29, 31, 32, 33, 34, and 36, as described in the following examples, are particularly preferred.

[0042] The present invention provides a novel piperidinylpyridinylcarbonite derivative of formula (I), which 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.

[0043] 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.

[0044] 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:

[0045] [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:

[0046] [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.

[0047] Unless otherwise specified, the term "medically acceptable salt," as defined in more detail below, shall also include its solvates, such as hydrates. 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.

[0048] 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.

[0049] The phrase "medically 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 reactions 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 acid 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.

[0050] 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.

[0051] 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 1-5The 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)-.

[0052] "C 2-m The term "-alkynyl" is "C 2-m When used in an alkyl group, and at least two carbon atoms of the group are bonded to each other by a triple bond, m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6. 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.

[0053] The terms "halo" added to an "alkyl," "alkylene," or "cycloalkyl" group (saturated or unsaturated) define alkyl, alkylene, or cycloalkyl groups 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 through covalent bonding, as long as the valence is maintained).

[0054] [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):

[0055] [ka]

[0056] The term pyridyl refers to the radical of the following ring: [ka] The term 3H-imidazo[4,5-b]pyridyl refers to the radical of the following ring:

[0057] [ka] The term 2H-pyrazolo[3,4-b]pyridyl refers to the radical of the following ring:

[0058] [ka] The term 1H-[1,2,3]triazolo[4,5-b]pyridyl refers to the radical of the following ring:

[0059] [ka] The term [1,2,4]triazolo[4,3-a]pyrimidinyl refers to the radical of the following ring. [ka] The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to the radical of the following ring.

[0060] [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.

[0061] 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.

[0062] 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.

[0063] [Table 1]

[0064] [Table 2]

[0065] 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).

[0066] 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).

[0067] 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.

[0068] [Table 3] JPEG2026525745000039.jpg94142

[0069] [Table 4]

[0070] 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).

[0071] 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 outer 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

[0072] [Table 5]

[0073] [Table 6]

[0074] 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)

[0075] 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.

[0076] 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).

[0077] 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]×hepatocytic [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])

[0078] 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

[0079] 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.

[0080] 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%.

[0081] 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%.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] Furthermore, the present invention relates to the use of compounds of general formula (I), 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.

[0088] Furthermore, the present invention relates to the use of compounds of general formula (I), 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 airway, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonia, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous and hypersensitivity vasculitis), or erythema nodosum. (5) Neurological disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy or prion disease.

[0089] In a further aspect, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment and / or prevention of the diseases and conditions mentioned above.

[0090] In a further aspect, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament 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 an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0091] Combination therapy The compounds of the present invention can be further combined with one or more, preferably one additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful for the treatment of diseases or conditions related to those described above, specifically cancer, fibrotic diseases, Alzheimer's disease, atherosclerosis, infectious diseases, chronic kidney diseases and autoimmune diseases. Additional therapeutic agents suitable for such combinations include, for example, those that enhance the therapeutic effect of one or more substances for one of the mentioned symptoms and / or those that reduce the dosage of one or more substances. Thus, 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, anti-fibrotic agents, cough suppressants, anti-inflammatory agents, anti-atopic dermatitis and bronchodilators.

[0092] Chemotherapy is a type of cancer treatment that uses one or more chemotherapeutic anti-cancer drugs, such as cell division inhibitors or cytotoxic substances, cell growth inhibitors, anti-angiogenic substances, etc. Examples include folic acid (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, azacitidine, gemcitabine, alkylating agents, anti-mitotic agents, taxanes and further compounds of the state of the art or standard of care. 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 therapies include agents such as growth factors (e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4) and hepatocyte growth factor), tyrosine-kinase, inhibitors of KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinase or MDM2. <F

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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 in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents. In a further 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.

[0097] 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.

[0098] 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.

[0099] 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. Examples 1 to 41 can be prepared as shown in Scheme I below. Scheme I:

[0100] [ka] In scheme I, N-methyltriazolylpiperidine (Z=CH,CF)(A) undergoes nucleophilic aromatic substitution with heteroaryl fluoride (X=Cl,Br)(B). The reaction can typically be carried out at ambient temperature or at an elevated temperature (up to 110°C) in the presence of a base (e.g., diisopropylethylamine). The intermediate (C) is then subjected to Suzuki-cross coupling with a heteroarylboronic acid derivative at an elevated temperature (e.g., 100°C) in the presence of a suitable catalyst (e.g., Pd(dppf)Cl2) and a suitable base to obtain the compound of general formula (I). Intermediate I can be prepared as shown in Scheme II below: Scheme II:

[0101] [ka]

[0102] Compounds of formula (A) with Z=CF,CH can be prepared from the corresponding piperidinyl ester (D) equipped with a suitable protecting group (PG, e.g., benzyl) by treatment with a suitable hydrazine source (e.g., N2H4*H2O) at an increasing 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) can be obtained by cleaving the protecting group under suitable conditions (e.g., H2, Pd / C 10%, EtOH). Compounds of formula (A) with Z=CH can also be obtained from commercial sources. Intermediate II can be prepared as shown in Scheme III below: Scheme III:

[0103] [Chemical formula] In the case of R = H, the intermediate of formula (B) can be prepared from the corresponding carboxylic acid (G). The carboxylic acid moiety is converted to the corresponding amide (H) using a suitable combination of reagents, such as 1,1'-carbonyldiimidazole and ammonia, at ambient temperature. Subsequently, the compound of formula (B) is obtained by treatment of (H) with a suitable dehydrating agent, such as Burgess reagent, at ambient temperature. In the case of R = Me or CF3, the corresponding aldehyde (K) is obtained by deprotonation of pyridine (J) at low temperature (e.g., -65 °C) and quenching with DMF. In the case of R = CF3, the aldehyde (K) can be converted to the amide (H) using a suitable reagent, such as phenyltrimethylammonium tribromide, at ambient temperature, and furthermore, in the case of R = H, it can be converted to the nitrile (B) as described above. [Examples]

[0104] 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.

[0105] [Table 7] JPEG2026525745000047.jpg188157 Preparation of intermediate Synthesis of intermediate I.1

[0106] [ka]

[0107] 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): 0.62 min (Method A)

[0108] 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 20:1~0:1) 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): 0.77 min (Method A)

[0109] Intermediate I.1: 4-Fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine 90 g, 0.32 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, 1.8 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 (7 M, 150 mL), and purified by column chromatography (Biotage SNAP cartridge KP-NH 110 g, gradient DCM / MeOH 4:1~7:3) to obtain the title compound. C8H 13 FN4 (M=184.2g / mol) ESI-MS: 185[M+H] + Rt(HPLC): 0.20 min (Method B)

[0110] 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (MFCD09055373, CAS:297172-18-0) is available from commercial vendors.

[0111] Synthesis of Intermediate II.1 [ka]

[0112] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde Under an argon atmosphere, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine (3.08 g, 12.6 mmol) was added to THF (75 mL), and the resulting mixture was cooled to -70°C. A solution of lithium diisopropylamide (1 M in THF, 13.9 mL, 13.9 mmol) was added dropwise, and the mixture was stirred at -70°C for 90 minutes. DMF (1.17 mL, 15.1 mmol) was added dropwise. The mixture was further stirred at -70°C for 30 minutes. The reaction was quenched by adding semi-concentrated acetic acid (800 μL), and the mixture was diluted with water and ethyl acetate. The organic phase was separated, dehydrated with MgSO4, and concentrated. The residue was purified by column chromatography (SiO2, CyH / ethyl acetate gradient 1:0~4:1) to obtain 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde. C7H2BrF4NO (M=272.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.51 min (Method B) 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 8.26 (d, J=4.3 Hz, 1 H).

[0113] 2-Bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide Ammonium acetate (5.53 g, 71.8 mmol) and 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbaldehyde (2.17 g, 7.18 mmol) are mixed, and acetonitrile (44 mL) is added. Phenyltrimethylammonium tribromide (5.57 g, 14.4 mmol) is added little by little, and the resulting reaction mixture is stirred at ambient temperature for 72 hours. The mixture is filtered, the residue is washed with acetonitrile, and the mixture is purified by column chromatography (Celite® dry-packed, SiO2, CyH / siRNA gradient 1:0 to 7:3) to obtain the desired product. C7H3BrF4N2O (M=287.0g / mol) ESI-MS: 285 / 287 [MH] - Rt(HPLC): 0.50 min (Method B)

[0114] Intermediate II.1: 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carbonilicate The product from the previous step, 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxamide (975 mg, 3.40 mmol), is suspended in dichloromethane (80 mL), and Burgess's reagent (CAS: 29684-56-8, 1.25 g, 5.10 mmol) is added at ambient temperature. The resulting reaction mixture is stirred for 40 hours, and then directly purified by column chromatography (dry packing, SiO2, CyH / siRNA gradient 1:0-9:1) to obtain the title compound. C7HBrF4N2 (M=268.9g / mol) ESI-MS: 268 / 270[M+H]+ Rt(HPLC): 0.59 min (Method C)

[0115] Synthesis of Intermediate II.2 [ka] 2-Bromo-3-fluoropyridine-4-carboxamide 2-bromo-3-fluoropyridine-4-carboxylic acid (25.0 g, 0.114 mol) is suspended in THF (250 mL), and 1,1'-carbonyldiimazole (22.1 g, 0.136 mol) is added in several small portions. The reaction mixture is stirred at ambient temperature for 3 hours, and then a solution of ammonia (32% in H2O, 64.8 mL, 0.938 mol) is slowly added. The resulting reaction mixture is stirred at ambient temperature for another 3 hours. The mixture is concentrated, the residue is packed onto an Extrelut® sheet, and purified by column chromatography (SiO2, DCM / MeOH 9:1) to obtain 2-bromo-3-fluoropyridine-4-carboxamide. C6H4BrFN2O (M=219.0g / mol) ESI-MS: 219 / 221[M+H] + Rt(HPLC): 0.28 min (Method C)

[0116] Intermediate II.2: 2-bromo-3-fluoropyridine-4-carbonitrile 2-Bromo-3-fluoropyridine-4-carboxamide (17.4 g, 79.5 mmol) is added to dichloromethane (250 mL). Burgess reagent (CAS: 29684-56-8, 22.0 g, 89.5 mmol) is added, and the resulting reaction mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated to half its original volume and purified by column chromatography (SiO2, DCM) to obtain the title compound. C6H2BrFN2 (M=201.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.41 min (Method D) 1 H NMR (400 MHz, DMSO-d6) δ = 8.52 (d, J = 4.9 Hz, 1H), 8.05 (t, J = 4.8 Hz, 1H)

[0117] Synthesis of Intermediate II.3 [ka] 6-Bromo-2-chloro-3-fluoropyridine-4-carbaldehyde Under an argon atmosphere, 6-bromo-2-chloro-3-fluoropyridine (6.80 g, 30.7 mmol) was added to THF (30 mL), and the resulting mixture was cooled to -75°C. A solution of lithium diisopropylamide (1 M in THF, 30.7 mL, 30.7 mmol) was added dropwise, and the mixture was stirred at -75°C for 1 hour. DMF (2.83 mL, 36.8 mmol) was added dropwise. The mixture was stirred for a further 2 hours at -78°C. The reaction was quenched by the addition of acetic acid (2.64 mL), and diluted with water / brine 1 / 1 and ethyl acetate. The organic phase was separated, dehydrated with Na2SO4, and concentrated. The residue was purified by column chromatography (SiO2, CyH / siRNA gradient 1:0~1:1) to obtain 6-bromo-2-chloro-3-fluoropyridine-4-carbaldehyde. C6H2BrClFNO (M=238.4g / mol) ESI-MS: 234 / 236[M+H] + Rt(HPLC): 0.44 min (Method B)

[0118] 6-Bromo-2-chloro-3-fluoropyridine-4-carboxamide Mix ammonium acetate (12.0 g, 15.5 mmol) and 6-bromo-2-chloro-3-fluoropyridine-4-carbaldehyde (3.70 g, 15.5 mmol), and add acetonitrile (50 mL). Gradually add phenyltrimethylammonium tribromide (12.0 g, 31.0 mmol), and stir the resulting reaction mixture at ambient temperature for 16 hours. Filter the mixture, wash the residue with acetonitrile, and purify by column chromatography (dry packing, SiO2, CyH / Â gradient 1:0 to 1:1) to obtain the desired product. C6H3BrClFN2O (M=253.5g / mol) ESI-MS: 251 / 253 [MH] - Rt(HPLC): 0.41 min (Method B)

[0119] Intermediate II.3: 6-bromo-2-chloro-3-fluoropyridine-4-carbonitrile 6-Bromo-2-chloro-3-fluoropyridine-4-carboxamide (510 mg, 2.01 mmol) is dissolved in dichloromethane (10 mL), and Burgess reagent (CAS: 29684-56-8, 742 mg, 3.02 mmol) is added at ambient temperature. The resulting reaction mixture is stirred for 16 hours, and then directly purified by column chromatography (SiO2, CyH / siRNA gradient 1:0-9:1) to obtain the title compound. C6HBrClFN2 (M=235.4g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.61 min (Method B) 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 3.8 Hz, 1H)

[0120] Intermediate II.4: 2-chloro-6-(1-ethoxyethenyl)-3-fluoropyridine-4-carbonitrile [ka] Under an argon atmosphere, Int II.3 (50.0 mg, 0.21 mmol) and tributyl(1-ethoxyethenyl) stannane (87.9 μL, 0.23 mmol) were dissolved in 1,4-dioxane (0.5 mL). Then, [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (15.5 mg, 0.02 mmol) were added, and the mixture was degassed for a further 5 minutes. The reaction mixture was heated at 70°C for 10 hours. The mixture was concentrated, and the residue was purified by column chromatography (dry packing, SiO2, CyH / Â gradient 1:0~9:1) to obtain the title compound. C 10 H8ClFN2O (M=226.6g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.80 min (Method B) 1 H NMR (400 MHz, DMSO-d6) δ = 8.08 (d, J = 4.1 Hz, 1H), 5.31 (d, J = 2.3 Hz, 1H), 4.62 (d, J = 2.4 Hz, 1H), 3.97 (d, J = 7.0 Hz, 2H), 1.38 (s, 3H)

[0121] Synthesis of Intermediate II.5 [ka] 2-Bromo-6-(difluoromethyl)-3-fluoropyridine-4-carbaldehyde Under an argon atmosphere, 2-bromo-6-(difluoromethyl)-3-fluoropyridine (1.00 g, 4.12 mmol) is dissolved in THF (25 mL), and the resulting mixture is cooled to -70°C. A solution of lithium diisopropylamide (1 M in THF, 4.33 mL, 4.33 mmol) is added dropwise, and the mixture is stirred at -70°C for 1 hour. DMF (381 μL, 4.95 mmol) dissolved in THF (2 mL) is added dropwise. The mixture is stirred at -70°C for a further 1 hour. The reaction is quenched by adding a saturated solution of NH4Cl, and diluted with Me-THF. After extraction, the organic phase is separated, washed with water, dried, and concentrated. The residue is purified by column chromatography (SiO2, CyH / siRNA gradient 1:0~7:3) to obtain 2-bromo-6-(difluoromethyl)-3-fluoropyridine-4-carbaldehyde. C7H3BrF3NO (M=254.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.47 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ = 10.19 (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.10 (t, J = 54.3 Hz, 1H)

[0122] 2-Bromo-6-(difluoromethyl)-3-fluoropyridine-4-carboxamide Ammonium acetate (2.05 g, 26.6 mmol) and 2-bromo-6-(difluoromethyl)-3-fluoropyridine-4-carbaldehyde (675 mg, 2.66 mmol) are mixed, and acetonitrile (15 mL) is added. Phenylentrimethylammonium tribromide (2.06 g, 5.32 mmol) is added little by little, and the resulting reaction mixture is stirred at ambient temperature for 18 hours. The mixture is filtered, the residue is washed with acetonitrile, and the mixture is purified by column chromatography (dry packing, SiO2, CyH / Ã gradient 1:0~7:3) to obtain the desired product. C7H4BrF3N2O (M=269.0g / mol) ESI-MS: 270 / 272[M+H] + Rt(HPLC): 0.57 min (Method C)

[0123] Intermediate II.5: 2-bromo-6-(difluoromethyl)-3-fluoropyridine-4-carbonitrile 2-Bromo-6-(difluoromethyl)-3-fluoropyridine-4-carboxamide (290 mg, 1.08 mmol) is dissolved in dichloromethane (4 mL), and Burgess reagent (CAS: 29684-56-8, 318 mg, 1.29 mmol) is added at ambient temperature. The resulting reaction mixture is stirred for 48 hours, and then directly purified by column chromatography (SiO2, CyH / siRNA gradient 1:0 to 85:15) to obtain the title compound. C7H2BrF3N2 (M=251.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.40 min (Method C)

[0124] Synthesis of Intermediate II.6 [ka] 2,6-Dichloro-3-fluoropyridine-4-carbaldehyde Under an argon atmosphere, 2,6-dichloro-3-fluoropyridine (5.00 g, 28.6 mmol) is added to THF (80 mL), and the resulting mixture is cooled to -70°C. A solution of lithium diisopropylamide (1 M in THF, 31.5 mL, 31.5 mmol) is added dropwise, and the mixture is stirred at -70°C for 1.5 hours. DMF (2.64 mL, 34.3 mmol) is added dropwise. The mixture is stirred at -70°C for a further 0.5 hours. The reaction is quenched by the addition of acetic acid (0.5 mL), warmed to rt, and diluted with water and ethyl acetate. The organic phase is separated, dried, and concentrated. The residue is purified by column chromatography (SiO2, CyH / ethyl acetate gradient 95:5~60:40) to obtain the desired product. C6H2Cl2FNO (M=194.0g / mol) ESI-MS: 212 / 214[M+H2O] + Rt(HPLC): 0.70 min (Method F)

[0125] 2,6-Dichloro-3-fluoropyridine-4-carboxamide Mix ammonium acetate (7.82 g, 101 mmol) and 2,6-dichloro-3-fluoropyridine-4-carbaldehyde (2.46 g, 10.1 mmol, 80% purity), and add acetonitrile (30 mL). Gradually add phenyltrimethylammonium tribromide (7.86 g, 20.3 mmol), and stir the resulting reaction mixture at ambient temperature over the weekend. Filter the mixture, wash the residue with acetonitrile, and purify by column chromatography (SiO2, CyH / siRNA gradient 92:8~34:66) to obtain the desired product. C6H3Cl2FN2O (M=209.0g / mol) ESI-MS: 207[MH] - Rt(HPLC): 0.71 min (Method F)

[0126] Intermediate II.6: 2,6-Dichloro-3-fluoropyridine-4-carbonitrile 2,6-Dichloro-3-fluoropyridine-4-carboxamide (460 mg, 2.20 mmol) is dissolved in dichloromethane (20 mL), and Burgess reagent (CAS: 29684-56-8, 1.08 g, 4.40 mmol) is added at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 18 hours. The mixture is diluted with DCM and washed with water (2 ×). The organic layer is dried, filtered, and concentrated. The residue is purified by column chromatography (SiO2, CyH / siRNA gradient 95:5~70:30) to obtain the title compound. C6HCl2FN2 (M=191.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.91 min (Method F) 1H NMR (400 MHz, DMSO-d6) δ = 8.36 (d, J = 3.7 Hz, 1H)

[0127] Synthesis of Intermediate II.7 [ka] 2,5-Dichloro-3-fluoropyridine-4-carboxylic acid To a solution of 2,5-dichloro-3-fluoropyridine (10.00 g, 60.2 mmol) and DIPA (7.5 mL, 66.3 mmol) in THF (100 mL), n-BuLi (5.7 mL, 60.2 mmol) is added under N2 conditions at -70°C. The mixture is stirred at -70°C for 2 hours. Then, freshly crushed solid CO2 (13.3 g, 301 mmol) is added gradually at -70°C. The resulting mixture is stirred at 25°C for 12 hours. The reaction mixture is quenched by adding NH4Cl (500 mL), diluted with H2O (500 mL), and extracted with siRNA (2 × 500 mL). The combined organic layers are washed with brine (200 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain 2,5-dichloro-3-fluoropyridine-4-carboxylic acid. C6H2Cl2FNO2 (M=210.0g / mol) ESI-MS: 210m / z Rt(HPLC): 0.26 min (Method G)

[0128] 2,5-Dichloro-3-fluoropyridine-4-carboxamide To a solution of 2,5-dichloro-3-fluoropyridine-4-carboxylic acid (6.00 g, 28.6 mmol) in DCM (60 mL), oxalyl chloride (21.8 g, 171 mmol) was added under N2 conditions at 0°C. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (60 mL). The reaction mixture was then slowly poured into NH3 / H2O (50 mL) and stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain 2,5-dichloro-3-fluoropyridine-4-carboxamide. C6H3Cl2FN2O (M=209.0g / mol) ESI-MS: No mass was detected. Rt(HPLC): 0.40 min (Method G)

[0129] Intermediate II.7: 2,5-Dichloro-3-fluoropyridine-4-carbonitrile To a solution of 2,5-dichloro-3-fluoropyridine-4-carboxamide (3.00 g, 14.4 mmol) in DCM (30 mL), TEA (3.19 g, 31.6 mmol) and TFAA (3.32 g, 15.8 mmol) were added under N2 conditions at 0°C. The mixture was stirred at 10°C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with HCl (2 × 100 mL). The combined organic layer was washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / HCl gradient 1:0 to 3:1) to obtain the title compound. C6HCl2FN2 (M=191.0g / mol) ESI-MS: 190 m / z Rt(GCMS): 6.40 minutes (Method H 200.qgm, Equipment: GCMS-005)

[0130] Synthesis of Intermediate II.8 [ka]

[0131] Methyl 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine-4-carboxylate Under an argon atmosphere, 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine (500 mg, 2.43 mmol) is dissolved in THF (10 mL), and the resulting mixture is cooled to -70°C. A solution of lithium diisopropylamide (1 M in THF, 2.67 mL, 2.67 mmol) is added dropwise, and the mixture is stirred at -70°C for 80 minutes. Methyl chloroformate (225 μL, 2.92 mmol) is added dropwise. The mixture is stirred for a further 15 minutes at -70°C. The reaction is quenched by adding semi-concentrated acetic acid (1 mL), warmed to rt, and diluted with water and siRNA. The organic phase is separated, dried, and concentrated. The residue is purified by column chromatography (SiO2, CyH / siRNA gradient 1:0 to 95:5) to obtain the desired product. C8H4ClF4NO2 (M=257.6g / mol) ESI-MS: 258 / 260[M+H] + Rt(HPLC): 0.60 min (Method C)

[0132] Methyl 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylate Under an argon atmosphere, methyl 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine-4-carboxylate (130 mg, 0.51 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (133 mg, 0.61 mmol), and K2CO3 (2 M in water, 505 μL, 1.01 mmol) were dissolved in 1,4-dioxane (2 mL). The resulting mixture was degassed by passing it through an argon stream. [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2*CH2Cl2, CAS:95464-05-4) (36.9 mg, 0.05 mmol) was added, and the mixture was degassed. The mixture was then heated to 90°C and stirred at this temperature for 3 hours. After cooling to ambient temperature, the mixture is concentrated, the residue is dissolved in ACN, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to obtain methyl 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylate. C 13 H9F4N3O2 (M=315.2g / mol) ESI-MS: 316[M+H] + Rt(HPLC): 0.41 min (Method C)

[0133] 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylic acid Methyl 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylate (115 mg, 0.37 mmol) was dissolved in 1,4-dioxane (3 mL), and LiOH (26.2 mg, 1.09 mmol) dissolved in water (1 mL) was added. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was acidified to pH 5 with an acidic acid and diluted with water (3 mL). The formed precipitate was filtered, washed with water, and dried to obtain the desired compound. C 12 H7F4N3O2 (M=301.2g / mol) ESI-MS: 302[M+H] + Rt(HPLC): 0.24 min (Method C)

[0134] 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxylic acid (70.0 mg, 0.23 mmol) and HATU (155 mg, 0.41 mmol) are dissolved in DMF (1 mL), and ammonia (0.5 M in THF, 2.50 mL, 1.25 mmol) is added. The reaction mixture is stirred at ambient temperature for 20 hours, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to obtain the desired compound. C 12 H8F4N4O (M=300.2g / mol) ESI-MS: 301[M+H] + Rt(HPLC): 0.35 min (Method B)

[0135] Intermediate II.8: 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carbonitrile 6'-amino-3-fluoro-5-(trifluoromethyl)-[2,3'-bipyridine]-4-carboxamide*trifluoroacetic acid (50.0 mg, 0.12 mmol) is dissolved in DCM (4 mL). TEA (234 μL, 1.69 mmol) and anhydrous trifluoroacetic acid (101 μL, 0.72 mmol) are added, and the reaction mixture is stirred at ambient temperature for 30 hours. The reaction mixture is concentrated, the residue is dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 12 H6F4N4 (M=282.2g / mol) ESI-MS: 283[M+H] + Rt(HPLC): 0.39 min (Method C)

[0136] Synthesis of Intermediate II.9 [ka]

[0137] 2-Chloro-3-fluoro-5-methylpyridine-4-carboxylic acid To a solution of 2-chloro-3-fluoro-5-methylpyridine (5.00 g, 34.4 mmol) and DIPA (3.82 g, 37.8 mmol) in THF (50 mL), n-BuLi (2.20 g, 34.4 mmol) is added under N2 at -78°C. The mixture is stirred at -78°C for 2 hours. Then, fresh dry ice CO2 (7.56 g, 172 mmol) is added at -78°C. The resulting mixture is stirred at 25°C for 10 hours. The reaction mixture is diluted with H2O (100 mL) and extracted with siRNA (2 × 100 mL). The aqueous phase is acidified to pH 1, the mixture is filtered, and concentrated under reduced pressure to obtain 2-chloro-3-fluoro-5-methylpyridine-4-carboxylic acid. C7H5ClFNO2 (M=189.6g / mol) ESI-MS: 190m / z Rt(HPLC): 0.34 min (Method G)

[0138] 2-Chloro-3-fluoro-5-methylpyridine-4-carboxamide To a solution of 2-chloro-3-fluoro-5-methylpyridine-4-carboxylic acid (2.50 g, 13.1 mmol) in DCM (30 mL), oxalyl chloride (8.29 g, 65.3 mmol) and DMF (9.5 mg, 0.13 mmol) are added. The mixture is stirred at 25°C for 2 hours. The reaction mixture is concentrated and poured into NH3 / H2O (30 mL). The resulting mixture is stirred at 25°C for 12 hours. The reaction mixture is filtered and concentrated under reduced pressure to obtain crude 2-chloro-3-fluoro-5-methylpyridine-4-carboxamide, which can be used without further purification.

[0139] Intermediate II.9: 2-chloro-3-fluoro-5-methylpyridine-4-carbonitrile To a solution of 2-chloro-3-fluoro-5-methylpyridine-4-carboxamide (1.50 g, 7.95 mmol) in DCM (20 mL), TFAA (1.67 g, 7.95 mmol) and TEA (0.80 g, 7.95 mmol) were added at 0°C. The mixture was stirred at 10°C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (2 × 200 mL). The combined organic layer was washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 3:1) to obtain the title compound. C7H4ClFN2 (M=170.6g / mol) 1 H NMR (400 MHz, CDCl3) δ = 8.27 (s, 1H), 2.56 (s, 3H)

[0140] Intermediate III.1: 2-bromo-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]-6-(trifluoromethyl)pyridine-4-carbonilicate [ka]

[0141] Int. II.1 (30 mg, 0.11 mmol) was dissolved in DMSO (0.5 mL) and DIPEA (38.6 μL, 0.22 mmol) at 10°C, and Int. I.1 (24.7 mg, 0.13 mmol) was added. The resulting mixture was stirred at 10°C for 1.5 hours. The mixture was purified by preparative HPLC (Xbridge C18, acetonitrile / water gradient containing 0.1% NH3) to obtain the title compound. C 15 H 13 BrF4N6 (M=433.2g / mol) ESI-MS: 433 / 435[M+H] + Rt(HPLC): 0.54 min (Method C)

[0142] [Table 8-1] [Table 8-2] [Table 8-3]

[0143] Intermediate III.7: 2-Chloro-6-cyclopropyl-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]pyridine-4-carbonilicate [ka]

[0144] Int. III.6 (150 mg, 0.36 mmol), cyclopropylboronic acid (153 mg, 1.78 mmol), and potassium carbonate (aq. 2 M, 357 μL, 0.71 mmol) were added to 1,4-dioxane (3 mL), and the resulting mixture was degassed for 10 minutes by passing it through an argon stream. [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2) (26.1 mg, 0.04 mmol) was added, and the mixture was degassed for a further 5 minutes. The mixture was then heated in a microwave at 70°C for 15 hours. After cooling to ambient temperature, the mixture was purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 17 H 18 ClFN6 (M=360.8g / mol) ESI-MS: 361[M+H] + Rt(HPLC): 0.80 min (Method J)

[0145] Intermediate III.9: 2-Chloro-6-(1,1-difluoroethyl)-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]pyridine-4-carbonilicate [ka] Int. III.8 (300 mg, 0.83 mmol) is suspended in DCM (2 mL). DAST (400 μL, 3.03 mmol) is added, and the resulting reaction mixture is stirred in rt for 2 days. The reaction is basicized with aqueous ammonia, the organic layer is separated, dried, and concentrated. The residue is purified by preparative HPLC (Xbridge C18, ACN / water gradient containing 0.1% NH3) to obtain the title compound. C 16 H 16 ClF3N6 (M=384.8g / mol) ESI-MS: 385[M+H] + Rt(HPLC): 0.65 min (Method B)

[0146] Intermediate III.12: 2,5-Dichloro-3-[4-Fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]pyridine-4-carbonitrile [ka]

[0147] Int. II.7 (0.17 g, 0.89 mmol) in DMF (5 mL) is mixed with Int. I.1 (0.96 g, 5.21 mmol) and K2CO3 (2.40 g, 22.7 mmol). The mixture is stirred at 100 °C for 10 hours. The reaction mixture is diluted with H2O (100 mL) and extracted with siRNA (2 × 200 mL). The combined organic layer is washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) and by preparative HPLC (Agela DuraShell C18, ACN / water gradient containing 10 mM NH4HCO3) to obtain the title compound. C 14 H 13 Cl2FN6 (M=355.2g / mol) ESI-MS: 355 / 357[M+H] + Rt(HPLC): 2.27 minutes (Method K)

[0148] [Table 9]

[0149] Intermediate IV.1: 6'-amino-5-chloro-3-[4-fluoro-4-(4-methyl-4H-1,2,4-triazole-3-yl)piperidine-1-yl]-[2,3'-bipyridine]-4-carbonitrile [ka]

[0150] Under an argon atmosphere, Int. III.12 (50.0 mg, 0.14 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (34.3 mg, 0.15 mmol) are dissolved in 1,4-dioxane (3 mL). K2CO3 (aq. 2 M, 275 μL, 0.55 mmol) is added, and the resulting mixture is degassed by passing it through an argon stream. [1,1'-bis-(diphenylphosphino)ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2) (10.1 mg, 0.01 mmol) is added, and the mixture is degassed again. The mixture is then heated to 70°C for 1 hour. After cooling to ambient temperature, the mixture is diluted with H2O, filtered, washed with DMF, and purified by preparative HPLC (StableBond C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 19 H 18 ClFN8 (M=412.9g / mol) ESI-MS: 413[M+H] + Rt(HPLC): 0.57 min (Method L)

[0151] Synthesis of intermediate V.1 [ka]

[0152] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine 5-Bromo-2H-pyrazolo[3,4-b]pyridine (8.00 g, 39.6 mmol) is suspended in toluene (50 mL) and tert-butyl acetate (53.1 mL, 396 mmol). Methanesulfonic acid (2.60 mL, 39.6 mmol) is added. The resulting reaction mixture is heated to 80°C and stirred for 1 hour. After cooling to ambient temperature, methanesulfonic acid (2.60 mL, 39.6 mmol) is added, and the reaction mixture is heated to 80°C and stirred for 1 hour. After cooling to ambient temperature, the reaction mixture is concentrated, and the residue is diluted with DCM. The mixture is basicized by adding 1 M NaOH. The layers are separated, and the aqueous layer is extracted with DCM. The combined organic layers are washed with H2O, dehydrated with Na2SO4, filtered, and concentrated. The residue is purified by column chromatography (SiO2, CyH / Â gradient 9:1~0:10) to obtain the desired compound. C 10 H 12 BrN3 (M=254.1g / mol) ESI-MS: 254 / 256[M+H] + Rt(HPLC): 0.85 min (Method F)

[0153] Intermediate V.1: {2-tert-butyl-2H-pyrazolo[3,4-b]pyridine-5-yl}boronic acid 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.50 g, 3.87 mmol), bis(pinacolato)diborone (1.21 g, 4.78 mmol), and potassium acetate (763 mg, 7.77 mmol) were added to 1,4-dioxane (15 mL), and the resulting mixture was degassed for 10 minutes by passing it through an argon stream. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2*CH2Cl2, CAS:95464-05-4) (190 mg, 0.232 mmol) was added, and the mixture was degassed for a further 3 minutes. The mixture was then heated to 110°C and stirred at this temperature for 4 hours. After cooling to ambient temperature, the mixture is concentrated, the residue is dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 10 H 14 BN3O2 (M=219.1g / mol) ESI-MS: 220[M+H] + Rt(HPLC): 0.27 min (Method C)

[0154] Synthesis of intermediate V.2 [ka]

[0155] 5-Bromo-2-tert-butyl-3-fluoro-2H-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (4.70 g, 18.5 mmol) in ACN (47 mL), Selectfluor (13.1 g, 37.0 mmol) was added under N2 conditions at 20 °C. The mixture was stirred at 40 °C for 12 hours. The reaction mixture was quenched by adding H2O (50 mL) and extracted with siRNA (3 × 50 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain the desired compound. C 10 H 11 BrFN3 (M=272.1g / mol) ESI-MS: 272 / 274[M+H] + Rt(HPLC): 0.53 min (Method M)

[0156] Intermediate V.2: 2-tert-butyl-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-2-tert-butyl-3-fluoro-2H-pyrazolo[3,4-b]pyridine (2.30 g, 8.45 mmol) in 1,4-dioxane (23 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.36 g, 9.30 mmol), KOAc (2.48 g, 25.4 mmol), and Pd(dppf)Cl2 (0.62 g, 0.85 mmol) were added under N2 at 20°C. The mixture was stirred at 100°C for 12 hours. The residue was diluted with H2O (30 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / Â gradient 1:0~0:1) to obtain the title compound. C 16 H 23 BFN3O2 (M=319.2g / mol) ESI-MS: 320[M+H]+ Rt(HPLC): 2.94 minutes (Method N) R f (TLC) 0.4 (PE / SiO 2:1)

[0157] Synthesis of intermediate V.3 [ka]

[0158] 5-Bromo-2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (4.00 g, 14.2 mmol) in ACN (40 mL), NCS (2.08 g, 15.6 mmol) was added at 20 °C under N2. The mixture was stirred at 85 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain the desired compound. C 10 H 11 BrClN3 (M=288.6g / mol) ESI-MS: 288 / 290[M+H] + Rt(HPLC): 0.55 min (Method M)

[0159] Intermediate V.3: {2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine-5-yl}boronic acid To a solution of 5-bromo-2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine (3.00 g, 9.36 mmol) in 1,4-dioxane (60 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.09 g, 12.2 mmol), KOAc (2.75 g, 28.1 mmol), and Pd(dppf)Cl2 (0.68 g, 0.94 mmol) were added under N2. The mixture was stirred under N2 at 100°C for 12 hours. The reaction mixture was diluted with H2O (40 mL) and extracted with ELISA (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / Â gradient 1:0 to 1:1) to obtain the title compound. C 10 H 13 BClN3O3 (M=253.5g / mol) ESI-MS: 254 / 256[M+H] + Rt(HPLC): 0.33 min (Method M)

[0160] Synthesis of intermediate V.4 [ka]

[0161] 5-Bromo-2-tert-butyl-3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine 1-(trifluoromethyl)-3H-1λ is added to a solution of 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.51 g, 5.94 mmol) in MeOH (30 mL). 32-Benziodaoxal-3-one (2.44 g, 7.72 mmol) and Cu(OAc)2 (1.62 g, 8.91 mmol) were added under N2 conditions at 20°C. The mixture was stirred at 20°C for 12 hours. Then the mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain the desired compound. C 11 H 11 BrF3N3 (M=322.1g / mol) ESI-MS: 322 / 324[M+H] + Rt(HPLC): 0.89 min (Method G)

[0162] Intermediate V.4: [2-tert-butyl-3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5-yl]boronic acid 1. To a solution of 5-bromo-2-tert-butyl-3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (0.28 g, 0.87 mmol) in 1,4-dioxane (6 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.26 g, 1.04 mmol), KOAc (0.26 g, 2.61 mmol), and Pd(dppf)Cl2 (0.06 g, 0.09 mmol) were added under N2 at 20°C. The mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was diluted with H2O (15 mL) and extracted with ELISA (3 × 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge C18, ACN / water gradient containing 10 mM NH4HCO3) to obtain the title compound. C 11 H 13 BF3N3O2 (M=287.0g / mol) ESI-MS: 288[M+H]+ Rt(HPLC): 0.68 min (Method O)

[0163] Intermediate V.4a: 2-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine A procedure similar to that for intermediate V.4 is used, in which 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.3g, 16.8mmol), KOAc (4.1g, 41.9mmol), and Pd(dppf)Cl2 (0.06g, 0.09mmol) are added to 1,4-dioxane (100mL) containing 5-bromo-2-tert-butyl-3-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (4.5g, 14.0mmol). The crude product is purified by column chromatography (SiO2, PE / SiO gradient 1:0~1:1) to obtain the desired compound. C 17 H 23 BF3N3O2 (M=369.2g / mol) ESI-MS: 370[M+H] + Rt(HPLC): 3.54 minutes (Method N)

[0164] Synthesis of intermediate V.5 [ka]

[0165] 5-Bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine Dissolve 5-bromo-2H-pyrazolo[3,4-b]pyridine (6.00 g, 28.8 mmol) in DMF (200 mL). Add NaH (55%, 1.51 g, 34.5 mmol) at 0°C and stir the reaction mixture at 0°C for 30 minutes. Then add dibromodifluoromethane (8.30 mL, 86.4 mmol) and stir the reaction mixture overnight in rt. Dilute the reaction mixture with ACN / H2O and purify by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C7H3Br2F2N3 (M=326.9g / mol) ESI-MS: 326 / 328 / 330[M+H] + Rt(HPLC): 0.56 min (Method C)

[0166] 5-Bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine 5-Bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (2.10 g, 6.42 mmol) and silver tetrafluoroborate (2.53 g, 12.8 mmol) are dissolved in DCE (40 mL) and stirred overnight at 80°C. After cooling to ambient temperature, the reaction mixture is concentrated and purified by column chromatography (SiO2, DCM / MeOH gradient 1:0 to 1:1) to obtain the desired compound. C7H3BrF3N3 (M=266.0g / mol) ESI-MS: 266 / 268[M+H] + Rt(HPLC): 0.47 min (Method C)

[0167] Intermediate V.5: [2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine-5-yl]boronic acid 5-Bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (324 mg, 0.61 mmol, 50% purity), bis(pinacolato)diborone (231 mg, 0.91 mmol), and potassium acetate (179 mg, 1.83 mmol) were added to 1,4-dioxane (3 mL). The resulting mixture was degassed for 10 minutes by passing it through an argon stream. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2*CH2Cl2, CAS:95464-05-4) (49.7 mg, 0.06 mmol) was added, and the mixture was then heated to 90°C and stirred at this temperature for 5 hours. After cooling to ambient temperature, the mixture is concentrated, the residue is dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C7H5BF3N3O2 (M=230.9g / mol) ESI-MS: 232[M+H] + Rt(HPLC): 0.30 min (Method C)

[0168] Synthesis of intermediate V.6 [ka]

[0169] 2-azido-5-bromopyridine-3-carbaldehyde 5-Bromo-2-fluoropyridine-3-carbaldehyde (1.00 g, 4.66 mmol) and tetrabutylammonium iodide (172 mg, 0.47 mmol) are dissolved in DMSO (6 mL). Sodium azide (367 mg, 5.59 mmol) is added, and the reaction mixture is stirred in rt for 45 minutes. The reaction is quenched by adding water, the formed precipitate is filtered, washed with water, and dried to obtain the desired compound. C6H3BrN4O (M=227.0g / mol) ESI-MS: 227 / 229[M+H] + Rt(HPLC): 0.25 min (Method C)

[0170] 5-Bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine Dissolve 2-azido-5-bromopyridine-3-carbaldehyde (400 mg, 1.76 mmol) and 1,1,1-trifluoro-2-methylpropane-2-amine hydrochloride (432 mg, 2.64 mmol) in EtOH (20 mL) and stir at 100°C for 4 hours. Concentrate the reaction mixture. Dissolve the residue in toluene (20 mL) and stir overnight at rt. Concentrate the reaction mixture, dissolve it in ACN / water, filter, and purify by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to obtain the desired compound. C 10 H9BrF3N3 (M=308.1g / mol) ESI-MS: 308 / 310[M+H] + Rt(HPLC): 0.62 min (Method B)

[0171] Intermediate V.6: [2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]boronic acid 5-Bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine (643 mg, 1.67 mmol, 80% purity), bis(pinacolato)diborone (678 mg, 2.67 mmol), and potassium acetate (639 mg, 6.51 mmol) were added to 1,4-dioxane (6 mL). The resulting mixture was degassed for 15 minutes by passing it through an argon stream. PdCl2(PPh3)2 (141 mg, 0.20 mmol) was added, and the mixture was then heated to 60°C and stirred at this temperature for 10 hours. After cooling to ambient temperature, the mixture was concentrated, the residue was dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 10 H11 BF3N3O2 (M=273.0g / mol) ESI-MS: 274[M+H] + Rt(HPLC): 0.32 min (Method C)

[0172] Synthesis of intermediate V.7 [ka]

[0173] 5-Bromo-2-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-2H-pyrazolo[3,4-b]pyridine (5.00 g, 25.2 mmol) in DMF (50 mL), add K2CO3 (8.54 g, 30.3 mmol) under N2 at 0°C. Stir the mixture at 0°C for 1 hour. Then add 2-bromopropane (3.73 g, 30.3 mmol) to the above solution under N2 at 20°C. Stir the mixture at 70°C for 12 hours. Dilute the reaction with H2O (50 mL) and extract with siRNA (3 × 50 mL). Dehydrate the combined organic layer with Na2SO4, filter, and concentrate under reduced pressure to obtain the desired compound, which can be used directly without further purification. C9H 10 BrN3 (M=240.1g / mol) ESI-MS: 240 / 242[M+H] + Rt(HPLC): 0.39 min (Method M)

[0174] 5-Bromo-3-fluoro-2-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-2-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine (0.95 g, 3.96 mmol) in ACN (10 mL), Selectfluor (2.80 g, 7.91 mmol) was added under N2 conditions at 20°C. The mixture was stirred at 20°C for 12 hours and then at 40°C for 12 hours. After cooling to ambient temperature, the reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain the desired compound. C9H9BrFN3 (M=258.1g / mol) ESI-MS: 258 / 260[M+H] + Rt(HPLC): 0.46 min (Method M)

[0175] Intermediate V.7: [3-Fluoro-2-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]boronic acid To a solution of 5-bromo-3-fluoro-2-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine (0.50 g, 1.94 mmol) in 1,4-dioxane (5 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.54 g, 2.13 mmol), KOAc (0.57 g, 5.81 mmol), and Pd(dppf)Cl2 (0.14 g, 0.194 mmol) were added under N2 conditions at 20°C. The mixture was stirred at 100°C for 12 hours. After cooling to ambient temperature, the reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers are dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / siRNA gradient 1:0 to 0:1) to obtain the title compound. C9H 11 BFN3O2 (M=223.0g / mol) ESI-MS: 224[M+H] + Rt(HPLC): 0.28 min (Method M)

[0176] Synthesis of intermediate V.8 [ka] 6-Bromo-2-tert-butyl-2H-[1,2,3]triazolo[4,5-b]pyridine 6-Bromo-2H-[1,2,3]triazolo[4,5-b]pyridine (500 mg, 2.46 mmol) is suspended in toluene (1 mL) and tert-butyl acetate (3.30 mL, 24.6 mmol). Methanesulfonic acid (161 μL, 2.46 mmol) is added. The resulting reaction mixture is heated to 80°C and stirred for 2 hours. After cooling to ambient temperature, the reaction mixture is concentrated, the residue is dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C9H 11 BrN4 (M=255.1g / mol) ESI-MS: 255 / 257[M+H] + Rt(HPLC): 0.96 min (Method J)

[0177] Intermediate V.8: {2-tert-butyl-2H-[1,2,3]triazolo[4,5-b]pyridine-6-yl}boronic acid 6-Bromo-2-tert-butyl-2H-[1,2,3]triazolo[4,5-b]pyridine (369 mg, 0.72 mmol, 50% purity), bis(pinacolato)diborone (274 mg, 1.09 mmol), and potassium acetate (213 mg, 2.17 mmol) were added to 1,4-dioxane (5 mL). The resulting mixture was degassed for 5 minutes by passing it through an argon stream. PdCl2(PPh3)2 (50.8 mg, 0.07 mmol) was added, and the mixture was then heated to 100°C and stirred at this temperature for 3 hours. After cooling to ambient temperature, the mixture was diluted with siRNA and filtered through Celite. The filtrate was concentrated, the residue dissolved in an ACN / water mixture, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C9H 13 BN4O2 (M=220.0g / mol) ESI-MS: 221[M+H] + Rt(HPLC): 0.36 min (Method C)

[0178] Synthesis of intermediate V.9 [ka]

[0179] 6-Bromo-2-(bromodifluoromethyl)-2H-[1,2,3]triazolo[4,5-b]pyridine At 0°C, NaH (0.48 g, 20.1 mmol) is added to 6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine (2.00 g, 10.0 mmol) in DMF (20 mL) under N2 conditions, and the mixture is stirred for 30 minutes. Dibromodifluoromethane (5.85 g, 30.1 mmol) is added, and the mixture is stirred at 25°C for 12 hours. The reaction mixture is quenched by adding NH4Cl (50 mL), then diluted with H2O (50 mL), and extracted with siRNA (100 mL). The organic layer is washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / siRNA gradient 1:0~3:1) to obtain the desired compound. C6H2Br2F2N4 (M=327.9g / mol) ESI-MS: 329[M+H] + Rt(HPLC): 2.64 minutes (Method K)

[0180] 6-Bromo-2-(trifluoromethyl)-2H-[1,2,3]triazolo[4,5-b]pyridine 6-Bromo-2-(bromodifluoromethyl)-2H-[1,2,3]triazolo[4,5-b]pyridine (500 mg, 1.53 mmol) and silver tetrafluoroborate (1.00 g, 5.09 mmol) are dissolved in DCE (40 mL) and stirred at 80°C for 48 hours. The reaction mixture is concentrated, diluted with an ACN / water mixture, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C6H2BrF3N4 (M=267.0g / mol) ESI-MS: 267 / 269[M+H] + Rt(HPLC): 0.57 min (Method C)

[0181] Intermediate V.9: [2-(trifluoromethyl)-2H-[1,2,3]triazolo[4,5-b]pyridine-6-yl]boronic acid 6-Bromo-2-(trifluoromethyl)-2H-[1,2,3]triazolo[4,5-b]pyridine (319 mg, 0.60 mmol, 50% purity), bis(pinacolato)diborane (227 mg, 0.90 mmol), and potassium acetate (176 mg, 1.79 mmol) were added to 1,4-dioxane (3 mL). The resulting mixture was degassed for 10 minutes by passing it through an argon stream. Pd(dppf)Cl2 (43.7 mg, 0.06 mmol) was added, and the mixture was then heated to 90°C and stirred at this temperature for 5 hours. After cooling to ambient temperature, the mixture was concentrated, the residue was dissolved in an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C6H4BF3N4O2 (M=231.9g / mol) ESI-MS: 233[M+H] + Rt(HPLC): 0.38 min (Method C)

[0182] Synthesis of intermediate V.10 [ka]

[0183] 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine 5-bromo-2-hydrazinylpyrimidine (500 mg, 2.51 mmol) and pivaloyl chloride were mixed in a microwave vial and stirred at 120°C for 22 hours. After cooling to ambient temperature, the mixture was concentrated, the residue was dissolved in MeOH, and stirred for several minutes. This was then diluted with an ACN / water mixture, filtered, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to obtain the desired compound. C9H 11 BrN4 (M=255.1g / mol) ESI-MS: 255 / 257[M+H] + Rt(HPLC): 0.46 min (Method C)

[0184] Intermediate V.10: {2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}boronic acid 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg, 0.63 mmol, 80% purity), bis(pinacolato)diborane (260 mg, 1.02 mmol), and potassium acetate (240 mg, 2.45 mmol) were added to 1,4-dioxane (4 mL). The resulting mixture was degassed for 15 minutes by passing it through an argon stream. PdCl2(PPh3)2 (55.0 mg, 0.08 mmol) was added, and the mixture was then heated to 60°C and stirred at this temperature for 24 hours. After cooling to ambient temperature, the mixture was diluted with ELISA, filtered, and concentrated. The residue was dissolved in an ACN / water mixture and purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C9H 13 BN4O2 (M=220.0g / mol) ESI-MS: 221[M+H] + Rt(HPLC): 0.34 min (Method C)

[0185] Synthesis of intermediate V.11 [ka]

[0186] 6-Bromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine 5-(trifluoromethyl)-4H-1,2,4-triazole-3-amine (500 mg, 3.12 mmol) is dissolved in glacial acetic acid (5 mL). 2-bromopropanedial (744 mg, 4.69 mmol) is added, and the reaction mixture is stirred at 60°C for 3 hours. The reaction is concentrated, the residue is neutralized with a saturated solution of NaHCO3, and extracted by DCM (3×). The combined organic layer is dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, CyH / siRNA gradient 94:6~34:66) to obtain the desired compound. C6H2BrF3N4 (M=267.0g / mol) ESI-MS: 267 / 269[M+H] + Rt(HPLC): 0.78 min (Method F)

[0187] Intermediate V.11: [2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]boronic acid 6-Bromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (650 mg, 2.43 mmol), bis(pinacolato)diborane (0.93 g, 3.65 mmol), and potassium acetate (597 mg, 6.09 mmol) were added to 1,4-dioxane (10 mL). The resulting mixture was degassed by passing it through an argon stream. Pd(dppf)Cl2*DCM (199 mg, 0.24 mmol) was added, and the mixture was then heated to 100 °C and stirred at this temperature for 6 hours. After cooling to ambient temperature, the mixture was diluted with an ACN / water mixture, filtered, and purified by preparative HPLC (Sunfire C18, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C6H4BF3N4O2 (M=231.9g / mol) ESI-MS: 233[M+H] + Rt(HPLC): 0.65 min (Method F)

[0188] Preparation of the final compound (Example 1) [ka]

[0189] Potassium carbonate (2M in water, 0.17mL, 0.35 mmol) is added to a solution of Int. III.1 (50.0 mg, 0.12 mmol) and Int. V.1 (46.1 mg, 0.14 mmol) in 1,4-dioxane (2 mL). The resulting mixture is purged by passing the solution through an argon stream. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS:72287-26-4) (8.5 mg, 11.5 μmol) is added, and the mixture is further purged with argon. The reaction mixture is stirred at 95°C for 4.5 hours. After cooling to ambient temperature, the mixture is diluted with an ACN / water mixture and purified by preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% NH3) to obtain the title compound. C 25 H 25 F4N9 (M=527.5g / mol) ESI-MS: 528[M+H] + Rt(HPLC): 0.65 min (Method B) 1 H NMR (400 MHz, DMSO-d6) δ = 8.84 (d, J = 2.3 Hz, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.34 (s, 1H), 3.70 (d, J = 1.5 Hz, 3H), 3.43 - 3.35 (m, 2H), 3.29 - 3.23 (m, 2H), 2.36 - 2.18 (m, 4H), 1.72 (s, 9H). Examples synthesized according to the procedure described in Example 1

[0190] [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9]

[0191] (Example 24) [ka]

[0192] Int. III.4 (70.0 mg, 0.22 mmol), 5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (61.3 mg, 0.33 mmol), and Cs2CO3 (237 mg, 0.44 mmol) were suspended in DMSO (1 mL). The resulting mixture was heated to 100 °C and stirred for 24 hours. After cooling to ambient temperature, it was diluted with an ACN / water mixture and purified by preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% NH3). The mixture was then re-purified by column chromatography (SiO2, siRNA / MeOH gradient 10:0-8:2) to obtain the title compound. C 21 H 17 F4N9 (M=471.4g / mol) ESI-MS: 472[M+H] + Rt(HPLC): 0.79 min (Method F) 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (s, 1 H), 8.50 (d, J=4.9 Hz, 1 H), 8.45 (s, 1 H), 8.33 (d, J=8.2 Hz, 1 H), 8.04 (d, J=4.9 Hz, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 3.68 (d, J=1.7 Hz, 3 H), 3.15 - 3.26 (m, 4 H), 2.00 - 2.20 (m, 4 H)

[0193] (Example 39) [ka]

[0194] Int. IV.1 (22.0 mg, 0.05 mmol) is added at 0°C to a stirred solution of pyridine (166 μL, 1.85 mmol) in pyridine (166 μL). After stirring at 0°C for 45 minutes, the reaction is treated with sodium nitrite (4.78 mg, 0.07 mmol), warmed to ambient temperature, and stirred for 2 hours. The reaction mixture is quenched by adding a sat. solution of NaHCO3, diluted with ACN, filtered, and purified by preparative HPLC (C18 column, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 19 H 16 ClF2N7 (M=415.8g / mol) ESI-MS: 416[M+H] + Rt(HPLC): 0.70 min (Method P) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1 H), 8.55 (s, 1 H), 8.47 (d, J=2.4 Hz, 1 H), 8.21 (td, J= 8.2, 2.5 Hz, 1 H), 7.35 (dd, J=8.5, 2.7 Hz, 1 H), 3.74 (d, J=1.5 Hz, 3 H), 3.21 - 3.27 (m, 4 H), 2.11 - 2.27 (m, 4 H).

[0195] (Example 40) [ka]

[0196] Dissolve Int. III.13 (10.0 mg, 0.02 mmol) in pyridine (210 μL), and add pyridine hydrogen fluoride (70.6 μL, 0.78 mmol) at 0°C. After stirring at 0°C for 1 hour, treat the reaction with sodium nitrite (2.01 mg, 0.03 mmol), warm to ambient temperature, and stir overnight. Dilute the reaction mixture with ACN / water, filter, and purify by preparative HPLC (XBridge C18 column, ACN / water gradient containing 0.1% TFA) to obtain the title compound. C 20 H 16 F5N7 (M=449.4g / mol) ESI-MS: 450[M+H] + Rt(HPLC): 0.52 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (d, J=0.6 Hz, 1 H), 8.53 (s, 1 H), 8.51 (d, J=2.4 Hz, 1 H), 8.25 (td, J=8.2, 2.4 Hz, 1 H), 7.40 (dd, J=8.5, 2.5 Hz, 1 H), 3.74 (d, J=1.7 Hz, 3 H), 3.21 - 3.31 (m, 4 H), 2.14 - 2.30 (m, 4 H).

[0197] Analysis data of the synthesized examples [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] [Table 11-10] [Table 11-11]

[0198] Analytical HPLC method [Table 12]

[0199] [Table 13]

[0200] [Table 14]

[0201] Table 15

[0202] Table 16

[0203] Table 17

[0204] Table 18

[0205] Table 19

[0206] Table 20

[0207] Table 21

[0208] Table 22

[0209] Table 23

[0210] Table 24

[0211] Table 25

[0212] Table 26

[0213] Table 27

[0214] Table 28

[0215] Table 29

[0216] Table 30

[0217] Table 31

Claims

1. Compounds of formula (I) or salts thereof, especially pharmaceutically acceptable salts thereof. 【Chemistry 1】 (I) (In the formula, A is A1a, which is a 5 or 6-membered mono-heteroaryl ring containing one or two nitrogen atoms. Alternatively, A is A1b, which is a 9 or 10-membered condensed bicyclic heteroaryl ring containing 1 to 4 nitrogen atoms. A has one or two R 4 It may be replaced by, R 1 It is selected from R1a groups consisting of H and F, R 2 H, Halo, C 1-6 - Alkyl and F 1-9 -Fluoro-C 1-6 - Selected from R2a groups consisting of alkyl groups, R 3 is selected from R3a groups consisting of H, halo, C 1-4 -alkyl, F 1-9 -fluoro-C 1-4 -alkyl and C 3-6 -cycloalkyl, and R 4 Hello, C 1-6 - Alkyl, F 1-9 -Fluoro-C 1-6 - Alkyl and C 3-6 - Selected from R4a groups consisting of cycloalkyl groups)

2. A is selected from three A3 groups consisting of 1H-[1,2,3]triazolo[4,5-b]pyridinyl, pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and 1H-imidazo[4,5-b]pyridinyl. A2 independently has one or two R 4 A compound of formula (I) or a salt thereof according to claim 1, which is substituted with [the compound of formula (I)].

3. R 2 However, H, Haro, C 1-4 - Alkyl and F 1-3 -Fluoro-C 1-4 - A compound of formula (I) or a salt thereof according to any one of claims 1 to 2, wherein R2b is selected from alkyl groups.

4. R 3 However, H, chloro, fluoro, C 1-4 - Alkyl, F 1-9 -Fluoro-C 1-4 - A compound of formula (I) or a salt thereof according to any one of claims 1 to 3, wherein R3b is selected from alkyl and cyclopropyl.

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

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

7. Formula (1-c) 【Chemistry 4】 (I C) It has substituent R 5 is H or R 4 A compound of formula (I) or a salt thereof according to any one of claims 1 to 4.

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

9. A pharmaceutically acceptable salt of one or more of the compounds described in claims 1 to 8.

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

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

12. The pharmaceutical composition according to claim 11, wherein one or more additional therapeutic agents are selected from the group consisting of anticancer agents and antifibrotic agents.

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

14. 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 8.

15. Compounds or pharmaceutically acceptable salts thereof according to one or more of claims 1 to 8, for use in methods for treating cancer, fibrous diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, or chronic kidney diseases.

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