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

Abstract

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

Description

[Technical Field]

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

[0002] Glutaminyl peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like proteins (QPCTL) catalyze the intramolecular cyclization of N-terminal glutamine (Q) residues to pyroglutamic acid (qE), liberating ammonia [Stephan Schilling et al., “Identification of Human Glutaminyl Cyclase as a Metalloenzyme: Potent Inhibition by Imidazole Derivatives and Heterocytic Chelators,” Journal of Biological Chemistry 278, no. 50 (2003): 49773-79, https: / / doi.org / 10.1074 / jbc.m309077200; Holger Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Anett Stephan et al., “Mammalian Glutaminyl Cyclases and Their Isoenzymes Have Identical Enzymatic Characteristics,” FEBS Journal 276, no. 22 (2009): 6522-36, https: / / doi.org / 10.1111 / j.1742-4646.2009.07337.x.]. QPCT is a secreted protein, while QPCTL resides within the Golgi complex. Both enzymes share high homology in the active site and similar catalytic specificity. Due to the high homology in the active site, inhibition of the active site inhibits the enzymatic activity of both enzymes: QPCT and QPCTL. Therefore, the term "QPCT / L" simultaneously represents both enzymes. Due to the different cellular localization of QPCT and QPCTL, differences in their relevance for the modification of biological substrates have been reported. Known substrates of intracellular QPCTL and / or extracellular QPCT include CD47 [Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612-19, https: / / doi.org / 10.1038 / s41591-019-0035-z.], various chemokines (e.g., CCL2 and 7, or CX3CL1) [Rosa Barreira da Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology 23, no. 4 (2022): 568-80, https: / / doi.org / 10.1038 / s41590-022-01153-x; Astrid Kehlen et al., “N-Terminal Pyroglutamate Formation in CX3CL1 Is Essential for Its Full Biological Activity,” Bioscience Reports 37, no. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.], amyloid-b peptide [Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery.”] or hormones such as TRH [Andreas Becker et al., “IsoQC (QPCTL) Knock-out Mice Suggest Differential Substrate Conversion by Glutaminyl Cyclase Isoenzymes,” Biological Chemistry 397, no. 1 (2016): 45–55, https: / / doi.org / 10.1515 / hsz-2015-0192.]. The modification of the N-terminal glutamine to pyroglutamic acid on the substrate has functional consequences for the protein and may affect various pathological mechanisms in several diseases. CD47 is expressed on the cell surface of almost all cells in the body, including apoptotic, senescent, and cancerous 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.2020.04.001]. The primary ligand for CD47 is signal-regulatory protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells (e.g., macrophages, monocytes, neutrophils, dendritic cells, etc.). QPCTL-mediated N-terminal pyroglutamic acid modification on CD47 is required for SIRPα binding [Deborah Hatherley et al., “Paired Receptor Specificity Explained by Structures of Signal Regulatory Proteins Alone and Complexed with CD47,” Molecular Cell 31, no. 2 (2008): 266–77, https: / / doi.org / 10.1016 / j.molcel.2008.05.026; Meike EW Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612–19, https: / / doi.org / 10.1038 / s41591-019-0356-z.] This signaling axis triggers a “don’t eat me” signal, preventing macrophages from phagocytosis of 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 / 11.1016 / 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.] and pulmonary fibrosis [Gerlinde Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases,” Proceedings of the National Academy of Sciences 114, no. 18 (2017): 4757-62, https: / / doi.org / 10.1073 / pnas.1621375114; Lu Cui et al., “Activation of JUN in Fibroblasts Promotes Pro-Fibrotic Programme and Modulates Protective Immunity,” Nature Communications 11, no. 1 (2020): 2795, https: / / doi.org / 10.1038 / s41467-020-16466-4.], systemic sclerosis [Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases”; Tristan Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma,” JCI Insight 5, no. 16 (2020): e140458, https: / / doi.org / 10.1172 / jci.insight.140458.], and liver fibrosis [Taesik Gwag et al., “Anti‐CD47 Antibody Treatment Attenuates Liver Inflammation and Fibrosis in Experimental Non‐alcoholic Steatohepatitis Models,” Liver International 42, no. 4 (2022): 829-41, https: / / doi.org / 10.1111 / liv.15182.Increased CD47 expression inhibits the clearance of apoptotic cells, leading to an increase in apoptotic lung epithelial cells, which stimulates fibrosis and promotes lung inflammation and scarring [Alexandra L. McCubbrey and Jeffrey L. Curtis, “Efferocytosis and Lung Disease,” Chest 143, no. 6 (2013): 1750-57, https: / / doi.org / 10.1378 / chest.12-2413; Brennan D. Gerlach et al., “Efferocytosis Induces Macrophage Proliferation to Help Resolve Tissue Injury,” Cell Metabolism, 2021, https: / / doi.org / 10.1010 / j.cmet.2021.10.015.]. Because CD47 half-life and function are highly dependent on QPCTL enzyme activity, QPCT and QPCTL inhibition, either alone or in combination with current standard treatments for pulmonary fibrosis, such as nintenanib [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 future treatments, such as PDE4 inhibitors [Luca Richeldi et al., “Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis,” New England Journal of Medicine 386, no. 23 (2022): 2178-87, https: / / doi.org / 10.1056 / nejmoa2201737], may be a suitable mechanism for the treatment of pulmonary fibrosis, such as IPF or SSC-ILD [Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma.”].

[0003] Expression of CD47 allows cancer cells to avoid destruction by the immune system or to evade immune surveillance, for example, by avoiding phagocytosis by immune cells [Stephen B. Willingham et al., “The CD47-Signal Regulatory Protein Alpha (SIRPa) Interaction Is a Therapeutic Target for Human Solid Tumors,” Proceedings of the National Academy of Sciences 109, no. 17 (2012): 6662-67, https: / / doi.org / 10.1073 / pnas.1121623109].

[0004] In addition to CD47, chemokines such as CCL2 and CX3CL1 have been identified as QPCTL and / or QPCT substrates [Holger Cynis et al., “The Isoenzyme of Glutaminyl Cyclase Is an Important Regulator of Monocyte Infiltration under Inflammatory Conditions,” EMBO Molecular Medicine 3, no. 9 (2011): 545–58, https: / / doi.org / 10.1002 / emmm.201100158]. Formation of N-terminal pGlu has been shown to increase in vivo activity by both conferring resistance to aminopeptidases and increasing their ability to trigger chemokine receptor signaling. Two major monocyte chemoattractants, CCL2 and CCL7, are insensitive to DPP4 in vivo inactivation due to an intracellular mechanism of N-terminal cyclization mediated by the Golgi-associated enzyme QPCTL. QPCTL has been shown to be a key regulator 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 long been pursued as a potential strategy for modulating intracellular trafficking in the treatment of various diseases.

[0005] Therefore, it would be desirable to provide potent QPCT / L inhibitors.

[0006] Jimenez-Sanchez, et al., Nature Chemical Biology, 2015, 11, 347-357 (hereinafter referred to as “JS, NCB2015”) discloses human glutaminyl cyclase (hQC) inhibitors SEN177 and SEN180: [ka]

[0007] SEN177 has been reported in the same literature to have an IC of 53 nM for isolated hQC and 13 nM for isolated QPCTL. 50 SEN180 is disclosed in the same publication as having an IC of 170 nM for hQC and 58 nM for QPCTL (Supplementary Information). 50 (supplementary information).

[0008] Pozzi, C, et al., Journal of Biological Inorganic Chemistry, 2018, 23, (8), 1219-1226 (hereinafter referred to as "P, JBIC2018") further discloses SEN177 and its binding mode within the hQC cleft. SEN177 has a K of 20 nM for isolated hQC. i The document discloses that the compound has the following structure:

[0009] WO 2018 / 178384 discloses QPCTL inhibitors of the general formula ABDE, including examples 1094 and 1095 (formula (XIIa) on page 123 and table on page 125): [ka] are listed.

[0010] WO 2018 / 178384 does not disclose any biological data for Examples 1094 or 1095.

[0011] WO 2022 / 086920 describes the general formula [ka] The QPCTL inhibitors are described, and the QPCTL inhibitors include compounds 3 and 6: [ka] are listed.

[0012] The chemical name of compound 3 is disclosed in WO 2022 / 086920 as "1-(1-(6'-chloro-[3,3'-bipyridin]-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-amine", and does not correspond to the chemical structure disclosed in the document, but an alternative structure in which the fluorine atom is replaced with a chlorine atom:

[0013] [ka] Corresponds to.

[0014] Compounds 3 (including alternatives to compound 3) and 6 in WO 2022 / 086920 were IC 50 It is disclosed to have an inhibitory activity of <1 μM.

[0015] Chinese Patent Publication No. 114874186 discloses a compound of the general formula [ka] The glutamine acyl cyclase isoenzyme inhibitors listed in Examples 21 and 23 (Table on page 17): [ka] are listed.

[0016] In Chinese Patent Publication No. 114874186, for Examples 21 and 23, IC values ​​of 29.22 nM and 11.26 nM were obtained. 50 were given respectively.

[0017] Detailed Description of the Invention The present invention discloses novel phenylpiperidine derivatives of formula (I), which are inhibitors of glutaminyl peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like proteins (QPCTL), wherein said inhibitors have suitable pharmacological and pharmacokinetic properties that enable their use as pharmaceuticals for the treatment of conditions and / or diseases treatable by inhibition of QPCT / L. [ka] (I)

[0018] The compounds of the present invention may offer several advantages, such as enhanced potency, cellular efficacy, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein binding, enhanced bioavailability, suitable pharmacokinetic profiles, and the possibility of forming stable salts.

[0019] Compounds of the Invention The present invention provides novel phenylpiperidine derivatives, which are surprisingly potent inhibitors of QPCT and QPCTL (Assay A) and QPCT / L in cells associated with, but not limited to, lung disease or lung cancer (Assay B). Furthermore, the novel phenylpiperidine derivatives of the present invention have suitable membrane permeability and low in vitro efflux (Assay C).

[0020] As a result, the compounds of the present invention are more suitable for human use.

[0021] The compounds of the present invention are structurally different from SEN177 and SEN180 in JS and NCB2015, in that a phenyl ring is bonded to the piperidinyl ring instead of a pyridyl ring. Furthermore, a carbonitrile substituent is bonded to the phenyl ring at the ortho position relative to the piperidinyl ring bonding position. Furthermore, R 1 is not limited to hydrogen, and A represents pyridinyl as well as substituted heterocyclic ring systems.

[0022] The compounds of the present invention are structurally different from Examples 1094 and 1095 in WO 2018 / 17834 in that a phenyl ring is bonded to the piperidinyl ring instead of a pyridyl ring. Furthermore, a carbonitrile substituent is bonded to the phenyl ring at the ortho position relative to the piperidinyl ring bonding position. Furthermore, R 1 is not limited to hydrogen, and A represents not only pyridinyl but also heterocyclic ring systems. Furthermore, the 5-membered heterocyclic ring attached to the 4-position relative to the piperidinyl nitrogen of the piperidinyl ring is an aminothiazolyl ring in Example 1094 and an aminothiadiazolyl ring in Example 1095, but in the compounds of the present invention it is a 3-substituted 4-methyl-4H-1,2,4-thiazolyl ring.

[0023] The compounds of the present invention are structurally different from compounds 3 (including alternatives to compound 3) and 6 in WO 2022 / 086920 in that a phenyl ring is bonded to the piperidinyl ring instead of a pyridinyl ring. Furthermore, a carbonitrile substituent is bonded to the phenyl group in the ortho position relative to the piperidinyl group bond position. Furthermore, R 1is not limited to hydrogen, and A represents not only pyridinyl but also a heterocyclic ring system. Furthermore, the 5-membered heterocyclic ring "M" in the general formula of WO 2022 / 086920 is a positional isomer of the 3-substituted 4-methyl-4H-1,2,4-triazolyl ring in the compounds of the present invention in compound 3, and the 5-membered heterocyclic ring "M" in the general formula of WO 2022 / 086920 is a 3-substituted 4-methyl-4H-1,2,4-triazolyl ring in compound 4, as in the compounds of the present invention, but it has an amino group.

[0024] The compounds of the present invention are structurally different from compounds 21 and 23 in Chinese Patent Publication No. 114874186, in that the central sulfonamide moiety connecting the piperidinyl ring to the phenyl ring is replaced with a direct bond. Furthermore, a carbonitrile substituent is bonded to the phenyl group at the ortho position relative to the piperidinyl group bonding position. Furthermore, the compounds of the present invention do not contain an amino linker between the phenyl ring and the additional cyclic ring.

[0025] These structural differences between the compounds of the present invention and prior art compounds unexpectedly lead to an advantageous combination of (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells associated with, but not limited to, lung disease or lung cancer, and (iii) suitable membrane permeability and low in vitro efflux.

[0026] The compounds of the present invention are therefore superior to those disclosed in the prior art in terms of the combination of the following parameters: Potent inhibition of QPCT and QPCTL (Assay A) Potent inhibition of QPCT / L in cells associated with, but not limited to, lung disease or lung cancer Adequate membrane permeability and low in vitro efflux (Assay C).

[0027] The present invention provides novel compounds of formula (I) or salts thereof, particularly pharmaceutically acceptable salts thereof. [ka] (I) (In the formula, A is a 5- or 6-membered mono-heteroaryl ring, A1a, containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein at least one heteroatom is nitrogen; or Or, A is [ka] selected from Group A1c consisting of: R 1 is H, C 1-4 - selected from the group R consisting of alkyl and halogen; R 2 is H, halogen, hydroxy, C 1-6 -Alkyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, HO-C 1-6 -Alkyl, C 1-6 -Alkyloxy, C 1-4 -Alkyl-O-H2CH2C-O-, C 3-6 -cycloalkyloxy, C 3-6 -Cycloalkyl-H2C-O-, F 1-9 -Fluoro-C 1-4 -Alkyloxy, C 1-6 -Alkyl-OC(O)-, HN-C(O)-, and C 1-6 -alkyl-NH-C(O)-; or Or R 2 is selected from the group R consisting of phenyl, benzyl, phenoxy, and benzyloxy, wherein R is one or two R 4 is replaced by Or R 2is R2c, a 5- or 6-membered mono-heteroaryl ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2c is selected from one or two R 4 or R2c, which is substituted with Or R 2 teeth, [ka] R2d consisting of; R 3 is H, C 1-4 selected from the group R3a consisting of alkyl and halogen; R 4 is H, C 1-4 - selected from the group R consisting of alkyl and halogen.

[0028] Another embodiment of the present invention is a compound in which A is a 5- or 6-membered mono-heteroaryl ring A2 containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen; and 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0029] Another embodiment of the present invention is a compound wherein A is a 9- or 10-membered fused bicyclic heteroaryl ring A3 containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen and oxygen, wherein at least one heteroatom is nitrogen; 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0030] Another embodiment of the present invention is where A is selected from the group consisting of pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl-pyrimidonyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2-dihydropyrimidin-2-onyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 1H-[1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 1H-[1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-[1,2,3]triazolo[4,3-c]pyrid ... selected from group A4 consisting of rhodamine, [1,2,5]oxadiazolo[3,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 2H-[1,3]dioxolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[1,5-b]pyridazinyl, 2H,3H,4H-pyrano[2,3-b]pyridinyl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl, and 1,8-naphthyridinyl; and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0031] Another embodiment of the present invention is an alkyl group wherein A is selected from the group A5 consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrimidonyl, and isothiazolyl; and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0032] Another embodiment of the present invention is an alkyl group wherein A is selected from the group A6 consisting of pyridinyl, pyridazinyl, 2H-pyrazolo[3,4-b]pyridinyl, and pyrazolo[1,5-b]pyridazinyl; and the substituent R 1 , R 2 , R 3 , and R 4relates to a compound of formula (I) as defined in any of the above embodiments.

[0033] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0034] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0035] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0036] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4relates to a compound of formula (I) as defined in any of the above embodiments.

[0037] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0038] Another embodiment of the present invention is wherein A is [ka] and the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0039] Another embodiment of the present invention is R 1 is selected from the group R consisting of H, HC—, HCHC—, HCHCHC—, (HC)HC—, Cl, and F; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0040] Another embodiment of the present invention is R 1 is selected from the group R consisting of H, H3C-, Cl, and F; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0041] Another embodiment of the present invention is R 1is selected from the group R consisting of H, H3C-, and F; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0042] Another embodiment of the present invention is R 1 is selected from the group R consisting of H; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0043] Another embodiment of the present invention is R 1 is selected from the group R1f consisting of H3C-; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0044] Another embodiment of the present invention is R 1 is selected from the group R1g consisting of F; and the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0045] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2A, R2A is H, halogen, hydroxy, C 1-4 -Alkyl, C 2-4 -alkynyl, C 3-4 -cycloalkyl, F 1-3 -Fluoro-C 1-4 Alkyl, HO-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 1-4 -Alkyl-O-H2CH2C-O-, C 3-4 -cycloalkyloxy, C 3-4-Cycloalkyl-H2C-O-, F 1-3 -Fluoro-C 1-4 -Alkyloxy, C 1-4 -Alkyl-OC(O)-, HN-C(O)-, and C 1-4 -alkyl-NH-C(O)-; Or, R2A is selected from the group R2b consisting of phenyl, benzyl, phenoxy, and benzyloxy, where R2b is selected from one or two R 4 Is it replaced by; Or, R2A is R2c, which is a 5- or 6-membered mono-heteroaryl ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2c is selected from 1 or 2 R 4 Is R2c substituted with; Or, R2A is [ka] R2d consisting of; And the substituents A and R 1 , R 3 , and R 4 is defined in any of the above embodiments.

[0046] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2B, R2B is H, halogen, hydroxy, C 1-4 -Alkyl, C 2-4 -alkynyl, C 3-4 -cycloalkyl, F 1-3 -Fluoro-C 1-4 Alkyl, HO-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 1-4 -Alkyl-O-H2CH2C-O-, C 3-4 -cycloalkyloxy, C 3-4 -Cycloalkyl-H2C-O-, F 1-3 -Fluoro-C 1-4 -Alkyloxy, C 1-4-Alkyl-OC(O)-, HN-C(O)-, and C 1-4 -alkyl-NH-C(O)-; Or, R2B is selected from the group R2b consisting of phenyl, benzyl, phenoxy, and benzyloxy, wherein R2b is selected from one or two R 4 Is it replaced by; Or, R2B is R2f, which is a 5- or 6-membered mono-heteroaryl ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen, wherein R2f is selected from 1 or 2 R 4 Is substituted with, R2f; Or, R2B is [ka] R2d consisting of; And the substituents A and R 1 , R 3 , and R 4 is defined in any of the above embodiments.

[0047] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2C, R2C is H, halogen, hydroxy, C 1-4 -Alkyl, C 2-4 -alkynyl, C 3-4 -cycloalkyl, F 1-3 -Fluoro-C 1-4 Alkyl, HO-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 1-4 -Alkyl-O-H2CH2C-O-, C 3-4 -cycloalkyloxy, C 3-4 -Cycloalkyl-H2C-O-, F 1-3 -Fluoro-C 1-4 -Alkyloxy, C 1-4 -Alkyl-OC(O)-, HN-C(O)-, and C 1-4 -alkyl-NH-C(O)-; Or, R2C is selected from the group R2b consisting of phenyl, benzyl, phenoxy, and benzyloxy, where R2b is selected from one or two R 4 Is it replaced by; Or, R2C is [ka] wherein R2g is selected from the group consisting of one or two R 4 Is it replaced by; Or, R2C is [ka] R2d consisting of; And the substituents A and R 1 , R 3 , and R 4 is defined in any of the above embodiments.

[0048] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2D, R2D is H, F, Cl, hydroxy, C 1-4 -Alkyl, H3C-Alkynyl, C 3-4 -cycloalkyl, F 1-3 -Fluoro-C 1-4 Alkyl, HO-C 1-4 -Alkyl, C 1-4 -Alkyloxy, C 1-4 -Alkyl-O-H2CH2C-O-, C 3-4 -cycloalkyloxy, C 3-4 -Cycloalkyl-H2C-O-, F 1-3 -Fluoro-C 1-4 -Alkyloxy, C 1-4 -Alkyl-OC(O)-, HN-C(O)-, and C 1-4 -alkyl-NH-C(O)-; Or, R2D is selected from the group R2b consisting of phenyl, benzyl, phenoxy, and benzyloxy, wherein R2b is selected from one or two R 4Is it replaced by; Or R2D, [ka] wherein R2g is selected from the group consisting of one or two R 4 Is it replaced by; Or R2D, [ka] R2d consisting of; And the substituents A and R 1 , R 3 , and R 4 is defined in any of the above embodiments.

[0049] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2E, R2E is H, F, Cl, hydroxy, methyl, t-butyl, H3C-alkynyl, cyclopropyl, F3C-, F3CCH2-, F2CHCH2-, F3C-C(CH3)2-, HO-CH2-, H3C-O-, (H3C)2CH-O-, H3C-O-H2CH2C-O-, F2HC-O-, F3C-O-, H3C-OC(O)-, H2N-C(O)-, H3C-NH-C(O)-, [ka] is selected from the group R2i consisting of: or R2E is selected from the group R2j consisting of phenyl, m-chlorophenyl, benzyl, phenoxy, and benzyloxy; Or, R2E is [ka] wherein R2g is substituted with H or methyl; Or, R2E is [ka] R2d consisting of; And the substituents A and R 1 , and R 3 is defined in any of the above embodiments.

[0050] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2F, R2F is H, F, Cl, hydroxy, methyl, t-butyl, H3C-alkynyl, cyclopropyl, F3C-, F3CCH2-, F2CHCH2-, F3C-C(CH3)2-, HO-CH2-, H3C-O-, (H3C)2CH-O-, H3C-O-H2CH2C-O-, F2HC-O-, F3C-O-, H3C-OC(O)-, H2N-C(O)-, H3C-NH-C(O)-, [ka] is selected from the group R2i consisting of: or R2F is selected from the group R2j consisting of phenyl, m-chlorophenyl, benzyl, phenoxy, and benzyloxy; Or, R2F is [ka] wherein R2g is substituted with H or methyl; Or, R2F is [ka] R2d consisting of; And the substituents A and R 1 , and R 3 is defined in any of the above embodiments.

[0051] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2G, R2G is H, F, Cl, methyl, t-butyl, F3C-, F3C-C(CH3)2-, H3C-O-, F2HC-O-, and [ka] is selected from the group R2k consisting of; Or, R2G is selected from the group R2b consisting of phenyl, benzyl, phenoxy, and benzyloxy, wherein R2b is selected from one or two R 4 is replaced by; And the substituents A and R 1 , R 3 , and R 4 is defined in any of the above embodiments.

[0052] Another embodiment of the present invention relates to compounds of formula (I) wherein R 2 is R2H, R2H is H, F, Cl, methyl, t-butyl, F3C-, F3C-C(CH3)2-, H3C-O-, F2HC-O-, and [ka] is selected from the group R2k consisting of; Or R2H is selected from the group R2j consisting of phenyl, m-chlorophenyl, benzyl, phenoxy, and benzyloxy; And the substituents A and R 1 , and R 3 is defined in any of the above embodiments.

[0053] Another embodiment of the present invention is R 2 is R2J, where R2J is Cl, methyl, H3C—O—, F2HC—O—, and [ka] selected from the group R2m consisting of: And the substituents A and R 1 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0054] Another embodiment of the present invention is R2 is R2K, wherein R2K is selected from the group R2n consisting of t-butyl, F3C-, and F3C-C(CH3)2-; And the substituents A and R 1 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0055] Another embodiment of the present invention is R 2 is R2L, and R2L is selected from the group R2b consisting of H and phenyl, benzyl, phenoxy, and benzyloxy, where R2b is selected from one or two R 4 is replaced by; And the substituents A and R 1 , R 3 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0056] Another embodiment of the present invention is R 2 is R2M, and R2M is selected from the group R2p consisting of phenyl and m-chlorophenyl; And the substituents A and R 1 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0057] Another embodiment of the present invention is R 2 is R2N selected from H; And the substituents A and R 1 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0058] Another embodiment of the present invention is R 3 is selected from the group R3b consisting of H, methyl, and F; And the substituents A and R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0059] Another embodiment of the present invention is R 3 is selected from the group R3c consisting of H; And the substituents A and R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0060] Another embodiment of the present invention is R 3 is selected from the group R3d consisting of methyl; And the substituents A and R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0061] Another embodiment of the present invention is R 3 is selected from the group R3e consisting of F; And the substituents A and R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined in any of the above embodiments.

[0062] Another embodiment of the present invention is R 4 is selected from the group R4b consisting of H, methyl, Cl, and F; And the substituents A and R 1 , R 2 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0063] Another embodiment of the present invention is R 4 is selected from the group R4c consisting of H; And the substituents A and R 1 , R 2 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0064] Another embodiment of the present invention is R 4 is selected from the group R4d consisting of methyl; And the substituents A and R 1 , R 2 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0065] Another embodiment of the present invention is R 4 is selected from the group R4e consisting of F; And the substituents A and R 1 , R 2 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0066] Another embodiment of the present invention is R 4 is selected from the group R4f consisting of Cl-; And the substituents A and R 1 , R 2 , and R 3 relates to a compound of formula (I) as defined in any of the above embodiments.

[0067] Another embodiment of the present invention is a compound of formula (Ia) [ka] (Ia) wherein the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0068] Another embodiment of the present invention is a compound of formula (Ib) [ka] (Ib) wherein the substituents A, R 2 , R 3 , and R 4relates to a compound of formula (I) as defined above in any of the above embodiments.

[0069] Another embodiment of the present invention is a compound of formula (Ic) [ka] (I C) wherein the substituents A, R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0070] Another embodiment of the present invention is a compound of formula (Id) [ka] (Id) wherein the substituent R 1 , R 2 , R 3 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0071] Another embodiment of the present invention is a compound of formula (Ie) [ka] (Ie) wherein the substituent R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0072] Another embodiment of the present invention is a compound of formula (If) [ka] (If) wherein the substituent R 1 , R 2 , R 3 , and R 4relates to a compound of formula (I) as defined above in any of the above embodiments.

[0073] Another embodiment of the present invention is a compound of formula (Ig) [ka] (Ig) wherein the substituent R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0074] Another embodiment of the present invention is a compound of formula (Ih) [ka] (Ih) wherein the substituent R 1 , R 2 , and R 4 relates to a compound of formula (I) as defined above in any of the above embodiments.

[0075] Further preferred embodiments of compounds of formula (I) are included as embodiments (EMB-1) to (EMB-20) in Table 1 below, where the above substituent definitions are used.

[0076] [Table 1]

[0077] For example, the compound of embodiment EMB-1 may have R 1 and the other generic groups defined within the same row of the table for the other substituents in formula (I). The same applies analogously to the other variables incorporated in the general formula.

[0078] Particularly preferably, the compound of formula (I) is [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka]

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] [ka] is selected from the group consisting of:

[0087] Particularly preferably, the compound of formula (I) is selected from the group consisting of Example 1, Example 5, Example 20, Example 36, Example 37, Example 42, Example 44, Example 49, Example 52, Example 53, Example 56, Example 61, Example 62, Example 66, Example 70, Example 75, Example 79, and Example 81, as described in the Examples below.

[0088] Particularly preferably, the compound of formula (I) is selected from the group consisting of Example 1, Example 5, Example 36, Example 37, Example 42, Example 44, Example 49, Example 52, Example 53, Example 61, Example 62, Example 70, Example 75, Example 79, and Example 81, as described in the Examples below.

[0089] The present invention provides novel phenylpiperidine derivatives of formula (I), which are surprisingly potent QPCT / L inhibitors.

[0090] Another aspect of the present invention relates to compounds of formula (I) that surprisingly possess potent inhibition of QPCT / L in cells associated with, but not limited to, lung disease or lung cancer.

[0091] Another aspect of the present invention relates to compounds of formula (I) as potent QPCT / L inhibitors in cells, which surprisingly have suitable membrane permeability and low in vitro efflux.

[0092] Another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I) and, optionally, one or more inert carriers and / or diluents.

[0093] A further aspect of the invention relates to compounds of formula (I) for use in the prevention and / or treatment of disorders associated with QPCT / L inhibition.

[0094] Another aspect of the present invention relates to methods for preparing the compounds of the present invention.

[0095] Further aspects of the present invention will be apparent to those skilled in the art directly from the description and examples herein.

[0096] Terms and definitions used General definition Terms not expressly defined herein should be given the meaning that one of ordinary skill in the art would give them in light of the disclosure and context herein. However, as used herein, unless specified to the contrary, the following terms have the meanings indicated and the following conventions are observed.

[0097] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified before the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having from 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., one skilled in the art can recognize the point of attachment of the radical to the molecule from the free valence of the group itself. For combined groups containing two or more subgroups, the last named subgroup is the radical point of attachment, e.g., the substituent "aryl-C 1-3 -alkylene" means that the aryl group is C 1-3 -alkyl- group, C 1-3 It means that the -alkyl- group is attached to the group or nucleus to which the substituent is attached.

[0098] When a compound of the invention is described by chemical name and formula, in the event of a conflict, the formula shall prevail. An asterisk may be used in a subformula to indicate the bond that connects to the core molecule being defined.

[0099] The numbering of atoms in a substituent begins with the atom closest to the group or nucleus to which the substituent is attached. For example, the term "3-carboxypropyl-group" refers to the following substituent: [ka] where the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", and "cyclopropylmethyl-" refer to the following groups: [ka] An asterisk may be used in a subformula to indicate the bond that connects to the core molecule being defined.

[0100] As used herein, the term "substituted" means replacing one or more hydrogens on a specified atom with a group selected from the defined group of substituents, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Similarly, the term "substituted" can be used in connection with a chemical moiety in place of a single atom, such as, for example, "substituted alkyl," "substituted aryl," etc.

[0101] Unless expressly indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, as well as mixtures of separated enantiomers in different proportions, mixtures of diastereomers, or mixtures of such isomers and enantiomers in any of the above forms, where such forms exist, and solvates thereof, such as, for example, hydrates.

[0102] Unless expressly indicated, "pharmaceutically acceptable salts," as defined in more detail below, are also intended to encompass solvates thereof, such as, for example, hydrates.

[0103] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. Methods for preparing optically active forms, for example, by resolution of racemic forms or by synthesis beginning with optically active starting materials and / or using chiral reagents, are known in the art.

[0104] Enantiomerically pure compounds or intermediates of the invention may be prepared through asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates, which may be separated by known methods (e.g., by chromatographic separation or crystallization), and / or by using chiral reagents (e.g., chiral starting materials, chiral catalysts, or chiral auxiliaries).

[0105] Furthermore, methods for preparing enantiomerically pure compounds from the 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 forming diastereomeric salts of the racemate with an optically active acid or base, followed by salt resolution and liberation of the desired compound from the salt; or by derivatization of the corresponding racemate with an optically active chiral auxiliary, followed by diastereomeric separation and removal of the chiral auxiliary; or by kinetic resolution of the racemate (for example, by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomeric crystals under appropriate conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0106] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human tissues without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0107] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds that are modified by making acid or base salts of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0108] For example, such salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Additional pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0109] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0110] Other acid salts than those mentioned above, for example acid salts that are useful for purifying or isolating the compounds of the invention (eg trifluoroacetate salts), also form part of the present invention.

[0111] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0112] The term “C 1-n "-alkyl" means, alone or in combination with another radical, an acyclic, saturated, branched, or straight-chain hydrocarbon radical having 1 to n carbon atoms, where n is an integer selected from 2, 3, 4, 5, or 6, preferably 4, 5, or 6. For example, the term C 1-5-Alkyl encompasses the radicals HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)-, and HC-CH-CH(CHCH)-.

[0113] The term “C 2-m -alkynyl" refers to the group "C 2-m "-alkyl" is used for said groups when at least two carbon atoms of said group are joined to each other by a triple bond, where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6.

[0114] The term “C 3-k "-cycloalkyl" means, alone or in combination with another radical, a cyclic, saturated, unbranched hydrocarbon radical having from 3 to k carbon atoms, where k is an integer selected from 3, 4, 5, 7, or 8, preferably 4, 5, or 6. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0115] The term "halo" attached to an "alkyl," "alkylene," or "cycloalkyl" group (saturated or unsaturated) means an alkyl, alkylene, or cycloalkyl group in which one or more hydrogen atoms have been replaced by a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, and most preferably fluorine. Examples include: HFC-, HFC-, FC-.

[0116] The term "mono-heteroaryl ring" means a monocyclic aromatic ring system containing one or more heteroatoms selected from N, O, or S and consisting of 5 to 6 ring atoms.

[0117] The term "mono-heteroaryl ring" is intended to include all possible isomeric forms. Thus, the term "mono-heteroaryl ring" includes the following exemplary structures (not depicted as radicals, as each form may optionally be attached to any atom through a covalent bond, provided that appropriate valences are maintained): [ka]

[0118] The term "fused bicyclic heteroaryl ring" refers to a bicyclic aromatic ring system of 9 to 10 ring atoms containing one or more heteroatoms selected from N, O, or S. The term "fused bicyclic heteroaryl ring" is intended to include all possible isomeric forms. Thus, the term "bicyclic heteroaryl ring" includes the following exemplary structures (not depicted as radicals, as each form may optionally be attached to any atom through a covalent bond as long as appropriate valences are maintained): [ka]

[0119] The term pyridinyl refers to the following ring radical: [ka]

[0120] The term pyridazinyl refers to the following ring radical: [ka]

[0121] The term pyrimidyl refers to the following ring radical: [ka]

[0122] The term 1,2-dihydropyrimidin-2-onyl refers to the radical of the following ring: [ka]

[0123] The term pyrazolyl refers to a radical of the following ring: [ka]

[0124] The term thiazolyl refers to a radical of the following ring: [ka]

[0125] The term isothiazolyl refers to a radical of the following ring: [ka]

[0126] The term oxazolyl refers to a radical of the following ring: [ka]

[0127] The term isoxazolyl refers to a radical of the following ring: [ka]

[0128] The term 3H-imidazo[4,5-b]pyridinyl refers to the radical of the following ring: [ka]

[0129] The term imidazo[1,2-a]pyrimidinyl refers to the radical of the following ring: [ka]

[0130] The term 2H-pyrazolo[3,4-b]pyridinyl refers to the radical of the following ring: [ka]

[0131] The term 1H-[1,2,3]triazolo[4,5-b]pyridinyl refers to the radical of the following ring: [ka]

[0132] The term [1,2,4]triazolo[4,3-a]pyrimidinyl refers to the radical of the following ring: [ka]

[0133] The term 1H-pyrazolo[4,3-c]pyridinyl refers to the radical of the following ring: [ka]

[0134] The term [1,2,5]oxadiazolo[3,4-b]pyridinyl refers to the radical of the following ring: [ka]

[0135] The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to the radical of the following ring: [ka]

[0136] The term [1,2,5]thiadiazolo[3,4-b]pyridinyl refers to the radical of the following ring: [ka]

[0137] The term 2H-[1,3]dioxolo[4,5-b]pyridinyl refers to the radical of the following ring: [ka]

[0138] The term imidazo[1,2-a]pyrimidinyl refers to the radical of the following ring: [ka]

[0139] The term pyrazolo[1,5-b]pyridazinyl refers to the following ring radical: [ka]

[0140] The term 2H,3H,4H-pyrano[2,3-b]pyridinyl refers to the radical of the following ring: [ka]

[0141] The term 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl refers to the radical of the following ring: [ka]

[0142] The term 1,8-naphthyridinyl refers to the radical of the following ring: [ka]

[0143] Bioassay Evaluation of inhibitory activity against QPCT and QPCTL Assay A: Biochemical QPCT and QPCTL activity assays The activity of the compounds of the present invention may be verified using the following biochemical enzyme activity assays:

[0144] QPCT- or QPCTL-dependent conversion of the N-terminal glutamine of CD47 to pyroglutamine was monitored by MALDI-TOF MS. Test compounds were dissolved in 100% DMSO and serially diluted into a clean 1,536-well microtiter plate. Enzyme reactions were prepared 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 double-concentrated QPCTL (in-house) or QPCT (Origine #TP700028) enzyme in assay buffer (final concentration 0.5 nM, columns 1-23) or plain assay buffer (column 24) was added to each well. The plate was incubated at 24°C in a humidified incubator for 10 minutes. Subsequently, 2.5 μL of CD47 peptide substrate surrogate ( 19 QLLFNKTKSVEFTFC 33 ) was added to each well (final concentration: 10 μM for QPCTL / 20 μM for QPCT). The plate was mixed for 30 seconds at 1,000 rpm and then incubated for 40 minutes at 24°C in a humidified incubator. After incubation, the enzyme reaction was stopped by adding a stable isotope-labeled internal standard peptide. 19 [Pyr]LLFN(K)TKSVEFTFC 33 The reaction mixture was stopped by adding 1 μL of 10 μM SEN177 (final concentration 4.0 μM). The plate was sealed with adhesive foil, mixed at 1,000 rpm for 30 seconds, and stored at room temperature until preparation of the MALDI target plate. The MALDI target plate was prepared as previously described. Mass spectra were obtained for the product (19 [Pyr]LLFNKTKSVEFTFC 33 , m / z 1,787.9037) and the signal of the internal standard ( 19 [Pyr]LLFN(K)TKSVEFTFC 33 Data were acquired using a rapifleX MALDI-TOF / TOF instrument, tracking the signal of the peptide (m / z 1,795.9179). QPCT or QPCTL activity was monitored by calculating the ratio of the product signal to the internal standard signal, followed by normalization to a high control (100% activity) and a low control (0% activity). Compound potency was determined by fitting the dose-response data to a four-parameter logistic equation.

[0145] [Table 2] JPEG2026501078000081.jpg218146 JPEG2026501078000082.jpg192143

[0146] [Table 3]

[0147] Assay B: SIRPα signaling assay (using either Raji cells or A549 cells) The activity of the compounds of the present invention can be verified using the following SIRPα signaling assay, which measures SIRPα engagement triggered by CD47, which is presented through cell-cell interaction. Two types of cells are used independently: Raji cell line (a lymphoblastoid human cell line derived from B lymphocytes of a patient with Burkitt's lymphoma in 1963) and A549 cells (adenocarcinoma human alveolar basal epithelial cells).

[0148] Test compounds were dissolved in 100% DMSO and serially diluted into white 384-well microtiter cell culture plates (PerkinElmer #60076780 for the Raji assay; Greiner PDL-coated plates #781945 for the A549 assay). Five thousand Raji cells (ATCC #CC86) or 5,000 A549 cells (ATCC #CCL-185) in Assay Complete Cell Plate Reagent 30 (DiscoverX 93-0563R30B) were added per well. The assay plates were incubated for 48 hours at 37°C, 95% humidity, and 5% CO2. Fifteen thousand reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93-1135C19) were added to each well, and the plates were incubated for 5 hours at 37°C, 95% humidity, and 5% CO2. Bioassay Reagent 1 from the PathHunter Bioassay Detection Kit was added to each well of the plate using a multichannel pipette, followed by incubation at room temperature for 15 minutes. Bioassay Reagent 2 was then added, followed by incubation at room temperature for 60 minutes (incubation in the dark).

[0149] Data analysis was performed using the luminescent signal generated by beta-galactosidase in the PathHunter reporter cell line. Luminescence measurements were performed using a Pherastar multimode reader. Dose-response curves and IC 50 Data were calculated using a four-parameter sigmoidal dose-response equation.

[0150] [Table 4] JPEG2026501078000085.jpg218146 JPEG2026501078000086.jpg67114

[0151] [Table 5]

[0152] Permeability assessment Assay C: Permeability in CACO-2 cells Caco-2 cells (1-2 x 105 cells / cm2 area) were seeded onto filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.

[0153] Compounds are dissolved in an appropriate solvent (e.g., DMSO, 1-20 mM stock solution). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO x 7H2O, 0.41 mM NaHPO x H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare transport solution (0.1-300 μM compound, final DMSO <= 0.5%). Transport solution (TL) is applied to the apical or basolateral donor side to measure AB or BA permeability, respectively (repeated measurements on three filters). Samples are collected from the donor at the beginning and end of the experiment, and from the receiver at various time intervals up to 2 hours, for concentration measurement by HPLC-MS / MS or scintillation counter. The collected receiver volume is replaced with fresh receiver solution. Efflux ratio (ER) = Permeability BA / Permeability AB

[0154] [Table 6] JPEG2026501078000089.jpg239149 JPEG2026501078000090.jpg22112

[0155] [Table 7]

[0156] Assessment of microsomal clearance Microsomal clearance: Metabolic degradation of test compounds was analyzed at 37°C using pooled liver microsomes from various species. The final incubation volume per time point, 60 μl, contained TRIS buffer (0.1 M) at pH 7.6, magnesium chloride (5 mM), microsomal protein (1 mg / mL for humans and dogs, 0.5 mg / mL for other species), and a final concentration of 1 μM test compound at room temperature. After a short preincubation at 37°C, the reaction was initiated by the addition of beta-nicotinamide adenine dinucleotide phosphate-reduced form (NADPH, 1 mM) and terminated after various time points by transferring aliquots to solvent. After centrifugation (10,000 g, 5 min), aliquots of the supernatant were analyzed for the amount of parent compound by LC-MS / MS. Half-lives were determined by the slope of a semi-logarithmic plot of the concentration-time profile.

[0157] The intrinsic clearance (CL_INTRINSIC) is calculated by taking into account the amount of protein in the incubation: CL_INTRINSIC [μl / min / mg protein] = Ln2 / (half-life [min] * protein amount [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]) Hepatocyte density, human: 120 x 10e6 cells / g liver Liver factor, human: 25.7 g / kg body weight Blood flow rate, human: 21 ml / (min x kg)

[0158] Assessment of hepatocyte clearance Hepatocyte clearance Metabolic degradation of test compounds is analyzed in human hepatocyte suspensions. After recovery from cryopreservation, human hepatocytes are diluted in Dulbecco's modified Eagle's medium (3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, supplemented with 5% human serum) and diluted to 1.0 × 10 6 Obtain a final cell density of 0.05 cells / mL.

[0159] After 30 minutes of pre-incubation in a cell culture incubator (37° C., 10% CO 2 ), the test compound solution is added to the hepatocyte suspension to give a final compound concentration of 1 μM and a final DMSO concentration of 0.05%.

[0160] The cell suspension is incubated at 37°C (cell culture incubator, vertical shaker) and samples are removed from incubation after 0, 0.5, 1, 2, 4, and 6 hours. Samples are quenched with acetonitrile (containing an internal standard) and precipitated by centrifugation. The supernatant is transferred to a 96-deep-well plate and prepared for analysis of parent compound depletion by HPLC-MS / MS.

[0161] The percentage of test compound remaining is calculated using the peak area ratio (test compound / internal standard) at each incubation time point relative to the peak area ratio at time 0. The log-transformed data are plotted against incubation time, and the absolute value of the slope obtained by linear regression analysis is used to estimate the in vitro half-life (T1 / 2).

[0162] The in vitro intrinsic clearance (CLint) is calculated from the in vitro T1 / 2 and converted to whole liver using the following equation using a hepatocyte density of 120 x 106 cells / g liver, a human liver per body weight of 25.7 g liver / kg, and in vitro incubation parameters: CL_INTRINSIC_IN VIVO[mL / min / kg]=(CL_INTRINSIC[μL / min / 106 cells]×hepatocyte density[106 cells / g liver]×liver factor[g / kg body weight]) / 1000

[0163] Hepatic in vivo blood clearance (CL) is predicted according to a well-stirred liver model considering a mean hepatic blood flow (QH) of 20.7 mL / min / kg: CL[mL / min / kg]=CL_INTRINSIC_IN VIVO[mL / min / kg]×hepatic blood flow [mL / min / kg] / (CL_INTRINSIC_IN VIVO[mL / min / kg]+hepatic blood flow [mL / min / kg])

[0164] Results are expressed as % hepatic blood flow: QH[%]=CL[mL / min / kg] / hepatic blood flow [mL / min / kg])

[0165] Evaluation of plasma protein binding The equilibrium dialysis technique was applied to Dianorm Teflon dialysis cells (micro 0.2) to measure the approximate in vitro binding rate of test compounds to plasma proteins. Each dialysis cell consisted of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. A stock solution for each test compound was prepared at 1 mM in DMSO and serially diluted to obtain a final test concentration of 1 μM. The following dialysis solutions were prepared in plasma (supplemented with NaEDTA as an anticoagulant), and a 200 μl aliquot of the test compound dialysis solution in plasma was dispensed into the donor (plasma) chamber. A 200 μl aliquot of dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7% dextran) was dispensed into the buffer (acceptor) chamber. Incubation was performed for 2 hours at 37 °C under rotation to achieve equilibrium.

[0166] At the end of the dialysis, aliquots from the donor and acceptor chambers, respectively, are transferred to reaction tubes and processed for HPLC-MS / MS analysis.

[0167] Analyte concentrations are quantified in sample aliquots by HPLC-MS / MS against a calibration curve.

[0168] The binding rate is calculated using the formula: % Binding = (Plasma Concentration - Buffer Concentration / Plasma Concentration) x 100

[0169] Solubility evaluation Saturated solutions are prepared in well plates (configuration depends on the automation system) by adding an appropriate volume (typically in the range of 0.25-1.5 ml) of the selected aqueous medium to each well containing a known amount (typically in the range of 0.5-5 mg) of solid active pharmaceutical ingredient. The wells are shaken or stirred for a predetermined time (typically in the range of 2-24 hours) and then filtered using an appropriate filtration membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter adsorption is avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance is measured by ultraviolet spectroscopy. Furthermore, the pH of the saturated aqueous solution is measured using a glass electrode pH meter.

[0170] Assessment of in vitro metabolism in human hepatocytes The metabolic pathway of test compounds is investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes are incubated in Dulbecco's modified Eagle's medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg / 500 ml hydrocortisone.

[0171] After 30 minutes of pre-incubation in a cell culture incubator (37°C, 10% CO2), the test compound solution was added to the hepatocyte suspension, and the cells were incubated at 1.0*10 6 From 4.0*10 6 A final cell density of cells / ml (based on compound turnover rates observed in primary human hepatocytes), a final test compound concentration of 10 μM, and a final DMSO concentration of 0.05% are obtained.

[0172] Cells are incubated for 6 hours on a vertical shaker in a cell culture incubator, and samples are removed from incubation after 0, 0.5, 1, 2, 4, or 6 hours based on turnover rate. Samples are quenched with acetonitrile and pelleted by centrifugation. Supernatants are transferred to 96-deep-well plates, evaporated under nitrogen, and reprecipitated prior to bioanalysis by liquid chromatography-high-resolution mass spectrometry for identification of putative metabolites.

[0173] The structure was analyzed by Fourier transform MS n Tentative assignments are made based on the data. Metabolites are reported as a percentage of the parent compound in human hepatocyte incubations, with a threshold of ≧4%.

[0174] Pharmacokinetic characterization Test compounds are administered to each test species either intravenously or orally. After application of the test compound, blood samples are taken at multiple time points, anticoagulated and centrifuged.

[0175] Analyte (administered compound and / or metabolite) concentrations are quantified in plasma samples. PK parameters are calculated using non-compartmental methods. AUC and Cmax are normalized to a dose of 1 μmol / kg.

[0176] Treatment method The present invention is directed to compounds of general formula (I) that are useful for the prevention and / or treatment of diseases and / or conditions associated with or mediated by QPCT / L activity, wherein the prevention and / or treatment includes, but is not limited to, the treatment and / or prevention of cancer, fibrotic diseases, neurodegenerative diseases, arteriosclerosis, infectious diseases, chronic kidney disease.

[0177] The compounds of general formula (I) are useful for the prevention and / or treatment of (1)-(4): (1) Pulmonary fibrosis, e.g., pneumonia or interstitial pneumonia associated with connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis, and dermatomyositis); idiopathic interstitial pneumonia, e.g., idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis associated with interstitial lung disease, desquamative interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia, and lymphocytic interstitial pneumonia; lymphangioleiomyomatosis; pulmonary alveolar proteinosis; Langerhans cell histiocytosis; idiopathic pleuroparenchymal fibroelastosis; interstitial lung disease due to known causes, e.g., occupational exposure (e.g., asbestosis, silicosis, anthrax (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne triggers, e.g., Interstitial pneumonia as a result of exposure to pathogens such as metal dust or mycobacteria, or as a result of treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy drugs); or interstitial pneumonia caused by granulomatous diseases such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or bronchitis or pneumonia or interstitial pneumonia caused by various factors (aspiration, inhalation of toxic gases or vapors, heart failure, x-rays, radiation, chemotherapy, M. Boake's disease or sarcoidosis, granulomatosis, cystic fibrosis or mucous membrane fibrosis, or alpha-I-antitrypsin deficiency).

[0178] (2) Other fibrotic diseases, such as hepatic bridging fibrosis, liver cirrhosis, nonalcoholic fatty liver disease (NASH), atrial fibrillation, endomyocardial fibrosis, previous myocardial infarction, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; these are spontaneous acute exacerbations of pulmonary fibrosis and progressive pulmonary fibrosis, or spontaneous acute exacerbations caused by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, exacerbations, and drug treatment.

[0179] (3) Leukemia, Acute Myeloid Leukemia (AML), Acute Myeloid Glomerulonephritis (APL), Chronic Myeloid Leukemia (CML), Acute Rinpoche Leukemia (ALL), T-cell Acute Rinpocheomyelitis (T-ALL), Rinpoche, B-cell Rinpoche, T-cell Rinpoche, Hodgkin's Disease, Non-Hodgkin's Rinpoche (NHL), Hairy Cell Rinpoche, Batch Rinpoche, Multiple Osteoma (MM), Osteomatosis Syndrome, Solid Carcinoma, Lung Cancer, Adenocarcinoma, Small Cell Lung Cancer (SCLC), Non-Small Cell Lung Cancer (NSCLC), Septal Cancer, Peritoneal Cancer, Mesothelioma, Gastrointestinal Cancer, Gastric Cancer, Stomach Cancer Cancer, colorectal cancer, small bowel cancer, large bowel cancer, colon cancer, colonic adenocarcinoma, colonic adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, urogenital cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, seminal vesicle cancer, seminal epithelial carcinoma, bile duct cancer, scrotum cancer, exocrine scrotum cancer, esophageal cancer, hypopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, caopioid sarcoma, leukoma, malformed leukoma, xeroderma pigmentosum, ketoacanthoma, bone cancer, osteosarcoma. Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Fibrosarcoma, Thyroid Cancer, Thyroid Follicular Carcinoma, Adrenal Cancer, Neurogenic Cancer, Brain Cancer, Astrocytoma, Neuroblastoma, Neuroglioma, Schuwan Cell Carcinoma, Gluoma, Also known as Sarcoma, Digestive Tract Cancer, Gastric Cancer, Stomach Cancer Cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, bowel cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, visceral cancer, exocrine visceral cancer, leukemia, acute osteomyeloid leukemia (AML), osteomyelopathy syndrome, ringworm, B-cell ringworm, non-Hodgkin ringworm (NHL), urothelial carcinoma, and peritoneal cancer.

[0180] (4) Inflammatory, autoimmune, or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, airway hyperresponsiveness, allergic conjunctivitis, bronchiectasis, acute 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 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.

[0181] (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.

[0182] Accordingly, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0183] Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or conditions associated with or mediated by QPCT / L activity.

[0184] Furthermore, the present invention relates to use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment and / or prevention of cancer, a fibrotic disease, a neurodegenerative disease, arteriosclerosis, an infectious disease, or a chronic kidney disease.

[0185] Furthermore, the present invention relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment and / or prevention of (1)-(4): (1) pulmonary fibrosis, for example, pneumonia or interstitial pneumonia associated with collagen diseases (e.g., systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, etc.); idiopathic interstitial pneumonia, for example, idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis associated with interstitial lung disease, desquamative interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia, and lymphocytic interstitial pneumonia; lymphangioleiomyomatosis; pulmonary alveolar proteinosis; Langerhans cell histiocytosis; idiopathic pleuroparenchymal fibroelastosis; interstitial lung diseases due to known causes, for example, occupational exposure (e.g., asbestosis, silicosis, anthraxosis (coal dust)), Interstitial pneumonias such as farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne causes (e.g., metal dust or mycobacteria), or as a result of treatment (e.g., radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy drugs); or interstitial pneumonias caused by granulomatous diseases such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or various factors (e.g., aspiration, inhalation of toxic gases, vapors, bronchitis or pneumonia or interstitial pneumonia caused by heart failure, x-rays, radiation, chemotherapy, M. Boake's disease or sarcoidosis, granulomatosis, cystic fibrosis or mucous membrane fibrosis, or alpha-I-antitrypsin deficiency).

[0186] (2) Other fibrotic diseases, such as hepatic bridging fibrosis, liver cirrhosis, nonalcoholic fatty liver disease (NASH), atrial fibrillation, endomyocardial fibrosis, previous myocardial infarction, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; these are spontaneous acute exacerbations of pulmonary fibrosis and progressive pulmonary fibrosis, or spontaneous acute exacerbations caused by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, exacerbations, and drug treatment.

[0187] (3) Leukemia, Acute Myeloid Leukemia (AML), Acute Myeloid Glomerulonephritis (APL), Chronic Myeloid Leukemia (CML), Acute Rinpoche Leukemia (ALL), T-cell Acute Rinpocheomyelitis (T-ALL), Rinpoche, B-cell Rinpoche, T-cell Rinpoche, Hodgkin's Disease, Non-Hodgkin's Rinpoche (NHL), Hairy Cell Rinpoche, Batch Rinpoche, Multiple Osteoma (MM), Osteomatosis Syndrome, Solid Carcinoma, Lung Cancer, Adenocarcinoma, Small Cell Lung Cancer (SCLC), Non-Small Cell Lung Cancer (NSCLC), Septal Cancer, Peritoneal Cancer, Mesothelioma, Gastrointestinal Cancer, Gastric Cancer, Stomach Cancer Cancer, colorectal cancer, small bowel cancer, large bowel cancer, colon cancer, colonic adenocarcinoma, colonic adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, urogenital cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, seminal vesicle cancer, seminal epithelial carcinoma, bile duct cancer, scrotum cancer, exocrine scrotum cancer, esophageal cancer, hypopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous cell carcinoma, squamous cell carcinoma, caopioid sarcoma, leukoma, malformed leukoma, xeroderma pigmentosum, ketoacanthoma, bone cancer, osteosarcoma. Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Fibrosarcoma, Thyroid Cancer, Thyroid Follicular Carcinoma, Adrenal Cancer, Neurogenic Cancer, Brain Cancer, Astrocytoma, Neuroblastoma, Neuroglioma, Schuwan Cell Carcinoma, Gluoma, Also known as Sarcoma, Digestive Tract Cancer, Gastric Cancer, Stomach Cancer Cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, bowel cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, visceral cancer, exocrine visceral cancer, leukemia, acute osteomyeloid leukemia (AML), osteomyelopathy syndrome, ringworm, B-cell ringworm, non-Hodgkin ringworm (NHL), urothelial carcinoma, and peritoneal cancer.

[0188] (4) Inflammatory, autoimmune, or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, airway hyperresponsiveness, allergic conjunctivitis, bronchiectasis, acute 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 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.

[0189] (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.

[0190] In a further aspect, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of the above-mentioned diseases and conditions.

[0191] 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 the treatment and / or prevention of the above-mentioned diseases and conditions.

[0192] In a further aspect, the present invention relates to a method for the treatment or prevention of the above-mentioned diseases and conditions, wherein said method comprises administering to a human an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0193] Combination therapy The compounds of the present invention may further be used in combination with one or more, preferably one, additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of the diseases or conditions described above, in particular diseases or conditions associated with cancer, fibrotic diseases, Alzheimer's disease, arteriosclerosis, infectious diseases, chronic kidney disease, and autoimmune diseases.

[0194] Suitable additional therapeutic agents for such combinations include, in particular, therapeutic agents that can enhance the therapeutic effect of one or more active substances and / or reduce the dosage of one or more active substances for one of the mentioned indications.

[0195] Thus, the compounds of the present invention may be used in combination with one or more therapeutic agents selected from the group consisting of chemotherapy, targeted cancer therapy, cancer immunotherapy, radiation, antifibrotic agents, antitussive expectorants, anti-inflammatory agents, anti-atopic dermatitis agents, and bronchodilators.

[0196] Chemotherapy is a type of cancer treatment that uses one or more chemical anti-cancer agents, such as cytostatic or cytotoxic agents, cell growth inhibitors, anti-angiogenic agents, etc. Examples include folinic acid (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, azacitidine, gemcitabine, alkylating agents, antimitotic agents, taxanes, as well as front-line or standard-of-care compounds.

[0197] Targeted therapy is a type of cancer treatment that uses drugs to target specific genes and proteins that help cancer cells survive and grow. Targeted therapies include drugs such as inhibitors of growth factors (e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER2, HER3, HER4), and hepatocyte growth factor), tyrosine kinases, KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinase, or MDM2.

[0198] 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 PDGFR antibodies; and anti-GD2 (ganglioside G2) antibodies. Examples include dinutuximab, olaratumab, trastuzumab, pertuzumab, ertumaxomab, cetuximab, necitumumab, nimotuzumab, panitumumab, and 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, durvalumab, ipilimumab, nivolumab, and pembrolizumab. Cancer immunotherapies also include agents that target (inhibit) the CD47-SIRPα signaling axis, such as agents that bind to CD47 or SIRPα. Non-limiting examples include antibodies, such as anti-CD47 antibodies and anti-SIRPα antibodies, and recombinant Fc fusion proteins, such as CD47-Fc and SIRPα-Fc. Cancer immunotherapies also include STING-targeting agents or T cell signal engagers, such as blinatumomab.

[0199] Antifibrotic agents include, for example, nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors (e.g., certain PDE4b inhibitors such as roflumilast or BI1015550), autotaxin inhibitors (e.g., GLPG-1690 or BBT-877); connective tissue growth factor (CTGF) blocking antibodies (e.g., pamrevlumab); B-cell activating factor receptor (BAFF-R) blocking antibodies (e.g., ranalumab), alpha V / beta 6 blocking inhibitors (e.g., BG-00011 / STX-100), recombinant pentalaxin-2 (PTX-2) (e.g., 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-associated 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., tipelukast); recombinant immunomodulatory domain of histidyl-tRNA synthetase (HARS) (e.g., ATYR-1923), prostaglandin synthase inhibitors (e.g., ZL-2102 / SAR-191801); 15- Hydroxy-eicosapentaenoic acid (15-HEPE, e.g., DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors (e.g., PAT-1251, PXS-5382 / PXS-5338); hoshinositide 3-kinase (PI3K) / mammalian target of rapamycin (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); transforming growth factor beta I (TGF-beta I) small interfering RNA (e.g., TRKZSO / BNC-1021);or a lysophosphatidic acid receptor antagonist (e.g., BMS986278);

[0200] The dose for the combination partners listed above is usually 1 / 5 of the lowest dose, which is usually recommended to be at most 1 / 1 of the normally recommended dose. Thus, in another aspect, the present invention relates to the use of a compound of the present invention in combination with one or more additional therapeutic agents as described herein for the treatment of a disease or condition affected or mediated by QPCT / L, particularly a disease or condition as described herein.

[0201] In a further aspect, the present invention relates to a method for treating a disease or condition in a patient that can be affected by the inhibition of QPCT / L, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0202] In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, in a patient in need thereof, for the treatment of a disease or condition that can be affected by the inhibition of QPCT / L.

[0203] In yet another aspect, the present invention relates to a method for treating a disease or condition in a patient that is mediated by QPCT / L activity, said method comprising administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described herein.

[0204] The use of the compounds of the present invention in combination with an additional therapeutic agent may be done simultaneously or at staggered times. The compound of the invention and the one or more additional therapeutic agents may both be present together in one formulation, e.g., a tablet or capsule, or may be present separately in two formulations, which may be the same or different, e.g., a so-called kit of parts.

[0205] Consequently, in another aspect, the present invention relates to pharmaceutical compositions comprising a compound of the present invention and one or more additional therapeutic agents described herein, optionally together with one or more inert carriers and / or diluents.

[0206] Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

[0207] preparation The compounds of the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis. Preferably, the compounds can be obtained by methods similar to the preparation methods described more fully below, in particular those described in the experimental section. In some cases, the order in which the reaction steps are carried out can be changed. Modifications of the reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0208] General methods for preparing compounds of this invention will be apparent to those skilled in the art upon examination of the following schemes. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at an appropriate stage in the reaction sequence using methods well known to those skilled in the art.

[0209] The compounds of the present invention are prepared by the synthetic methods described below, in which the substituents of the general formula have the meanings given above. These methods are intended to be illustrative of the present invention, and the scope of the subject matter of the present invention and the compounds claimed are not limited to these examples. If the preparation of starting compounds is not described, they are commercially available or can be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to published synthetic methods. Abbreviations are as defined in the Examples section.

[0210] Compounds of formula (I) can be prepared as shown in Scheme I below. Scheme I: [ka] In Scheme I, N-methyltriazolylpiperidine (Intermediate B; R = H, F, Me) undergoes a nucleophilic aromatic substitution reaction with an aryl fluoride (Intermediate C). The reaction is typically carried out at elevated temperatures (100-130 °C). The intermediate (Intermediate D) is then subjected to a Suzuki cross-coupling reaction with a heteroarylboronic acid derivative in the presence of a suitable catalyst (e.g., Pd(dppf)Cl) and a suitable base (e.g., aqueous KCO) at elevated temperatures (e.g., 100 °C) to give a compound of general formula (I).

[0211] Scheme II: [ka] An alternative route to compounds of formula (I) is depicted in Scheme II. Heteroarylboronic acid derivatives can be prepared from the corresponding halides (RRA-X, where X is Cl, Br, or I) using a suitable borylation reagent (e.g., bis(pinacolato)diboron) in the presence of a suitable catalyst (e.g., Pd(dppf)Cl*CHCl) and a suitable base (e.g., KOAc) at elevated temperatures (e.g., 100°C). The heteroarylboronic acid derivatives (RRA-B(OR)) can be isolated either as boronic acid pinacol esters or boronic acids (R=H) based on the stability of the boronic acid pinacol esters (R=CMe, and both R's, together with O, B, and O, form a five-membered ring), or the heteroarylboronic acid derivatives can be used in subsequent Suzuki couplings by adding intermediate D, a suitable catalyst (e.g., Pd(dppf)Cl*CHCl), and a suitable base (e.g., aqueous NaCO). Once isolated, the boronic acid derivatives can be converted to examples of general formula (I) as depicted in Scheme I.

[0212] Scheme III: [ka] Intermediate Int.B (R1 = Me, F) can be prepared from the corresponding piperidinyl ester (Intermediate E) equipped with a suitable protecting group (PG, e.g., BOC) by treatment with a suitable hydrazine source (e.g., N2H4 * HO) at elevated temperatures (e.g., 50 °C). The resulting hydrazine (Intermediate F) is then activated with DMF / DMA at elevated temperatures (e.g., 50 °C), followed by treatment with methylamine at elevated temperatures (e.g., 90 °C) to give the triazole derivative (Intermediate G). Intermediate Int.B (R1 = Me, F) can be obtained by cleavage of the protecting group under appropriate conditions (e.g., 4N HCl in dioxane for PG = BOC; Pd / C under H2 atmosphere for PG = Bn). Intermediate Int.B (R1 = H) was obtained commercially (CAS No: 297172-18-0). [Example]

[0213] preparation The compounds of the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature, for example, 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 can be obtained analogously to the preparation methods described more fully below, particularly those described in the experimental section. In some cases, the order employed in carrying out the reaction schemes can be modified. Modifications of these reactions known to those skilled in the art but not described in detail herein can also be used. General methods for preparing the compounds of the present invention will be apparent to those skilled in the art upon examination of the following schemes. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared by similar or analogous methods. Prior to carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups may be cleaved again at an appropriate stage in the reaction sequence using methods well known to those skilled in the art and described in the literature, for example, in "Protecting Groups", 3rd Edition, Philip J. Kocienski, Thieme, 2005, and "Protective Groups in Organic Synthesis", 4th Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006. The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20° C., for example, between 19 and 24° C.

[0214] Abbreviation: [Table 8] JPEG2026501078000096.jpg161148

[0215] Preparation of intermediates Intermediate I [ka]

[0216] tert-Butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (160 g, 0.58 mol) is suspended in ethanol (640 mL) in a round-bottom flask. Hydrazine hydrate (70.6 mL, 1.16 mol) is added to the mixture at ambient temperature. The reaction mixture is heated to 50° C. and stirred for 12 hours. After cooling to ambient temperature, the mixture is concentrated under reduced pressure to give tert-butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate in 80% purity. C 11 H 20 FN3O3 (M = 261.3 g / mol) ESI-MS: 284.2 [M+Na]+ Rt(HPLC): 0.615min(Method A)

[0217] tert-Butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate tert-Butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate (135 g, 0.413 mol, 80% purity) is mixed with dioxane (945 mL) in a round-bottom flask. N,N-Dimethylformamide-dimethylacetal (137 mL, 1.03 mol) is added to the mixture at ambient temperature. The reaction mixture is heated to 50° C. and stirred for 1 hour. A solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) is added to the mixture. The resulting reaction mixture is heated to 90° C. and stirred for 11 hours. The mixture is concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, PE / ethyl acetate gradient from 20:1 to 0:1) to give tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate. C 13 H 21 FN4O2 (M = 284.3 g / mol) ESI-MS: 285.1 [M+H]+ Rt(HPLC): 0.766min(Method A)

[0218] Intermediate I: 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine tert-Butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (90 g, 0.316 mol) is mixed with MeOH (90 mL) in a round-bottom flask. A solution of HCl (4 M in MeOH, 450 mL, 1.79 mol) is added slowly at ambient temperature. The resulting reaction mixture is stirred at ambient temperature for 12 h. The desired product is collected by filtration, washed with MeOH, and dried to give 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride.

[0219] The hydrochloride salt (13.5 g) is taken up in a solution of ammonia in MeOH (7N, 150 mL) and purified by chromatography (Biotage SNAP Cartridge KP-NH, gradient DCM / MeOH 4:1 to 7:3). C8H 13 FN4 (M = 184.2 g / mol) ESI-MS: 185 [M+H]+ Rt(HPLC): 0.20min(Method B)

[0220] 4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine (MFCD09055373, CAS: 297172-18-0), 4-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine dihydrochloride (MFCD32875324) were obtained from commercial suppliers. The hydrochlorides were converted to the free piperidine or piperazine according to the procedure described for intermediate I.

[0221] Intermediate II.1 [ka]

[0222] A solution of 3-bromo-2-fluorobenzonitrile (1.5 g, 7.5 mmol) and 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (3.6 g, 22 mmol) in DMSO (18 mL) is stirred for 18 h at 130° C. The reaction mixture is diluted with ACN and directly purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give intermediate II.1. C 15 H 16 BrN5 (M = 346.2 g / mol) ESI-MS: 346 / 348[M+H]+ Rt(HPLC): 0.40min(Method C)

[0223] [Table 9]

[0224] Intermediate III.1 [ka]

[0225] To a stirred solution of 3-bromo-5-(1-methyl-1-H-imidazol-2-yl)pyridine (50 mg, 0.20 mmol), bis(pinacolato)diboron (63 mg, 0.25 mmol), and potassium acetate (39 mg, 0.40 mmol) in 1,4-dioxane (1 mL) was added [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (7.2 mg, 0.01 mmol). After stirring at 100 °C for 1.5 h and then at ambient temperature for 18 h, the mixture was diluted with DCM and HO. The organic layer was separated and concentrated to give crude intermediate III.1, which was used in the subsequent step without further purification. C 15 H 20 BN3O2 (M = 203.0 g / mol) ESI-MS: 204[M+H]+ Rt(HPLC): 0.20min(Method C)

[0226] Intermediate III.2 [ka] To a stirred solution of 5-bromo-2-fluoro-3-(trifluoromethoxy)pyridine (CAS: 1361822-98-1) (50 mg, 0.16 mmol), bis(pinacolato)diboron (50 mg, 0.20 mmol), and potassium acetate (39 mg, 0.40 mmol) in 1,4-dioxane (1 mL) was added [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (7.2 mg, 0.01 mmol). After stirring at 100 °C for 45 min, the mixture was diluted with DCM and HO. The organic layer was separated and concentrated to give crude intermediate III.2, which was used in the subsequent step without further purification. C6H4BF4NO3 (M = 224.9 g / mol) ESI-MS: 225 / 226[M+H]+ Rt(HPLC): 0.45min(Method C)

[0227] Synthesis of intermediates III.3a and III.3b [ka]

[0228] 6-Bromo-1-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine and 6-Bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine To a stirred solution of 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (CAS: 92276-38-5) (0.550 g, 2.71 mmol) in DMSO (5 mL) was added DIPEA (0.92 mL, 5.4 mmol) and iodomethane (0.17 mL, 2.7 mmol). After stirring at 90 °C for 18 h, the reaction mixture was cooled to ambient temperature and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% NH3) to give the corresponding methylated regioisomer.

[0229] 6-Bromo-1-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine: C6H5BrN4 (M = 213.0 g / mol) ESI-MS: 213 / 215[M+H]+ Rt(HPLC): 0.36min(Method B)

[0230] 6-Bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine (coeluted with regioisomer 6-bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine): C6H5BrN4 (M = 213.0 g / mol) ESI-MS: 213 / 215[M+H]+ Rt(HPLC): 0.44min(Method B)

[0231] Intermediate III.3a To a stirred solution of 6-bromo-1-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine (171 mg, 0.80 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (305 mg, 1.20 mmol) and potassium acetate (236 mg, 2.41 mmol). The resulting mixture was purged with Ar for 10 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (56 mg, 0.08 mmol). After stirring at 90 °C for 5 h, the mixture was cooled to ambient temperature, concentrated, redissolved in MeCN and HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.3a. C6H7BN4O2 (M = 178.0 g / mol) ESI-MS: 179[M+H]+ Rt(HPLC): 0.21min(Method C)

[0232] Intermediate III.3b To a stirred solution of a 1:1 mixture of 6-bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine and 6-bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine (310 mg, 0.73 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (276 mg, 1.09 mmol) and potassium acetate (214 mg, 2.18 mmol). The resulting mixture was purged with Ar for 10 minutes, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (51 mg, 0.07 mmol). After stirring at 100 °C for 3 hours, the mixture was cooled to ambient temperature, diluted with EtOAc, and filtered through a silica plug. The filtrate was concentrated, redissolved in MeCN and HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give a 1:1 mixture of intermediate III.3b and the corresponding regioisomeric boronic acid, which was used without further purification. C6H7BN4O2 (M = 178.0 g / mol) ESI-MS: 179[M+H]+ Rt(HPLC): 0.21min(Method C)

[0233] Synthesis of intermediate III.4 [ka]

[0234] 3-Bromo-4-methyl-5-(1H-pyrazol-1-yl)pyridine A solution of 3-bromo-5-fluoro-4-methylpyridine (0.25 mL, 1.2 mmol), pyrazole (87 mg, 1.2 mmol), and CsCO (1.22 g, 3.75 mmol) in DMSO (2 mL) is stirred for 18 h at 90 °C. After cooling to ambient temperature, the mixture is diluted with MeCN / HO and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% NH) to give 3-bromo-4-methyl-5-(1H-pyrazol-1-yl)pyridine. C9H8BrN3 (M = 238.1 g / mol) ESI-MS: 238 / 240[M+H]+ Rt(HPLC): 0.52min(Method C)

[0235] Intermediate III.4 To a stirred solution of 3-bromo-4-methyl-5-(1H-pyrazol-1-yl)pyridine (130 mg, 0.55 mmol) in 1,4-dioxane (1 mL) was added bis(pinacolato)diboron (207 mg, 0.82 mmol) and potassium acetate (160 mg, 1.64 mmol). The resulting mixture was purged with Ar for 10 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (38 mg, 0.05 mmol). After stirring at 100 °C for 3 h, the mixture was cooled to ambient temperature, diluted with EtOAc, and filtered through a silica plug. The filtrate was concentrated, redissolved in MeCN and HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.4. C9H 10 BN3O2 (M = 203.0 g / mol) ESI-MS: 204[M+H]+ Rt(HPLC): 0.22min(Method C)

[0236] Synthesis of intermediate III.5 [ka]

[0237] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine To a stirred solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.00 g, 19.8 mmol) in toluene (23 mL) was added tert-butyl acetate (26.6 mL, 198 mmol) and methanesulfonic acid (1.3 mL, 19.8 mmol). After stirring at 80 °C for 1 h, the reaction was treated with additional methanesulfonic acid (1.3 mL, 19.8 mmol). The reaction mixture was cooled to ambient temperature, concentrated, redissolved in MeCN / HO, and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine. C 10 H 12 BrN3 (M = 254.1 g / mol) ESI-MS: 254 / 256[M+H]+ Rt(HPLC): 0.50min(Method C)

[0238] Intermediate III.5 A solution of 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.50 g, 3.87 mmol), bis(pinacolato)diboron (1.20 g, 4.78 mmol), and potassium acetate (763 mg, 7.77 mmol) in 1,4-dioxane (15 mL) was purged with Ar for 10 min, followed by the addition of [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (190 mg, 0.23 mmol). After stirring at 110° C. for 4 h, the mixture is cooled to ambient temperature, concentrated, redissolved in MeCN / H 2 O, and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give intermediate III.5. C 10 H 14 BN3O2 (M = 219.0 g / mol) ESI-MS: 220[M+H]+ Rt(HPLC): 0.27min(Method C)

[0239] Synthesis of intermediate III.6 [ka]

[0240] 3-(3,5-dimethyl-1H-pyrazol-1-yl)-5-iodopyridine A solution of 3-bromo-5-iodopyridine (591 mg, 2.08 mmol), 3,5-dimethyl-1H-pyrazole (100 mg, 1.04 mmol), DL-proline (12 mg, 0.10 mmol), CuI (20 mg, 0.10 mmol), and CsCO (339 mg, 1.04 mmol) in DMF (1 mL) was purged with Ar for 10 min. After stirring at 120 °C for 18 h, the mixture was cooled to ambient temperature, diluted with MeOH, and directly purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give 3-(3,5-dimethyl-1H-pyrazol-1-yl)-5-iodopyridine. C 10 H 10 IN3 (M = 299.1 g / mol) ESI-MS: 300[M+H]+ Rt(HPLC): 0.53min(Method C)

[0241] Intermediate III.6 To a stirred solution of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-5-iodopyridine (50 mg, 0.17 mmol), bis(pinacolato)diboron (52 mg, 0.21 mmol), and potassium acetate (33 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was added [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (8.0 mg, 0.01 mmol). After stirring at 100 °C for 18 h, the mixture was diluted with DCM and HO. The organic layer was concentrated to give crude intermediate III.6, which was used in the subsequent step without further purification. C 10 H 12 BN3O2 (M = 217.0 g / mol) ESI-MS: 218[M+H]+ Rt(HPLC): 0.28min(Method C)

[0242] Synthesis of intermediate III.7 [ka]

[0243] 2-Azido-5-bromopyridine-3-carbaldehyde To a stirred solution of 5-bromo-2-fluoropyridine-3-carbaldehyde (1.0 g, 4.7 mmol) and tetrabutylammonium iodide (172 mg, 0.47 mmol) in DMSO (6 mL) is added sodium azide (367 mg, 5.6 mmol). After stirring for 45 min, the reaction is diluted with HO and the precipitate is collected by filtration and dried to give 2-azido-5-bromopyridine-3-carbaldehyde, which is used in the subsequent step without further purification. C6H3BrN4O (M=227.0g / mol) ESI-MS: 227 / 229[M+H]+ Rt(HPLC): 0.25min(Method C)

[0244] 5-Bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine To a stirred solution of 2-azido-5-bromopyridine-3-carbaldehyde (310 mg, 1.37 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride (335 mg, 2.05 mmol) in ethanol (6 mL) was added 3 Å molecular sieves. After stirring for 18 h, the mixture was concentrated, redissolved in toluene (6 mL), and stirred for an additional 18 h. The resulting mixture was concentrated, redissolved in MeCN / HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% NH3) to give 5-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine. C 10H9BrF3N3 (M = 308.1 g / mol) ESI-MS: 308 / 310[M+H]+ Rt(HPLC): 0.62min(Method B)

[0245] Intermediate III.7 A solution of 5-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine (643 mg, 1.67 mmol), bis(pinacolato)diboron (678 mg, 2.67 mmol), and potassium acetate (678 mg, 2.67 mmol) in 1,4-dioxane (6 mL) was purged with Ar for 15 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (141 mg, 0.20 mmol). After stirring at 60 °C for 10 h, the mixture was cooled to ambient temperature, concentrated, redissolved in MeCN / HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.7. C 10 H 11 BF3N3O2 (M = 273.0 g / mol) ESI-MS: 274[M+H]+ Rt(HPLC): 0.32min(Method C)

[0246] Synthesis of intermediates III.8a and III.8b [ka]

[0247] 1-benzyl-6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine and 2-benzyl-6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine To a stirred solution of 6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (0.600 g, 2.95 mmol) in DMSO (5 mL) was added DIPEA (1.0 mL, 5.9 mmol) and benzyl bromide (0.36 mL, 2.9 mmol). After stirring at 90 °C for 18 h, the reaction mixture was cooled to ambient temperature and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% NH3) to give the corresponding benzylated regioisomer.

[0248] 1-benzyl-6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine: C 12 H9BrN4 (M = 289.1 g / mol) ESI-MS: 289 / 291[M+H]+ Rt(HPLC): 0.52min(Method C)

[0249] 2-benzyl-6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine (coeluted with regioisomer 3-benzyl-6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine): C 12 H9BrN4 (M = 289.1 g / mol) ESI-MS: 289 / 291[M+H]+ Rt(HPLC): 0.59min(Method C)

[0250] Intermediate III.8a To a stirred solution of 1-benzyl-6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (386 mg, 1.34 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (507 mg, 2.00 mmol) and potassium acetate (392 mg, 4.01 mmol). The resulting mixture was purged with Ar for 10 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (94 mg, 0.13 mmol). After stirring at 90 °C for 5 h, the mixture was cooled to ambient temperature, concentrated, redissolved in MeCN and HO, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.8a. C 12 H 11 BN4O2 (M = 254.1 g / mol) ESI-MS: 255[M+H]+ Rt(HPLC): 0.38min(Method C)

[0251] Intermediate III.8b To a stirred solution of a 1:1 mixture of 2-benzyl-6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine and 3-benzyl-6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine (310 mg, 1.07 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (407 mg, 1.61 mmol) and potassium acetate (315 mg, 3.22 mmol). The resulting mixture was purged with Ar for 10 minutes, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (75 mg, 0.11 mmol). After stirring at 100 °C for 3 hours, the mixture was cooled to ambient temperature, diluted with EtOAc, and filtered through a silica plug. The filtrate is concentrated, redissolved in MeCN and H2O, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.8b. C 12 H 11 BN4O2 (M = 254.1 g / mol) ESI-MS: 255[M+H]+ Rt(HPLC): 0.41min(Method C)

[0252] Intermediate III.9 [ka]

[0253] A mixture of 2,3-diamino-5-bromopyridine (200 mg, 1.01 mmol) and pivalic acid (2.09 g, 20.2 mmol) is heated neat with vigorous stirring to 120°C for 10 h, 140°C for 10 h, and 150°C for 20 h. After cooling to ambient temperature, the mixture is diluted with EtOAc, and the resulting solution is washed three times with aqueous KCO (2 M). The organic layer is dried over NaSO and concentrated. The residue is purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% NH) to give the desired product. C 10 H 12 BrN3 (M = 254.1 g / mol) ESI-MS: 254 / 256[M+H]+ Rt(HPLC): 0.62min(Method D)

[0254] Synthesis of intermediate III.10 [ka]

[0255] 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine Ethanol (2 mL) is added to a mixture of 2-amino-5-bromopyrimidine (1.00 g, 5.63 mmol) and 1-chloropinacolone (1.14 mL, 8.5 mmol). The resulting mixture is stirred at 90° C. for 5 days. After cooling to ambient temperature, the mixture is loaded onto EXtrelut® and purified by column chromatography (SiO, DCM / MeOH gradient) to give the desired product. C 10H 12 BrN3 (M = 254.1 g / mol) ESI-MS: 254 / 256[M+H]+ Rt(HPLC): 0.28min(Method C)

[0256] Intermediate III.10 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine (144 mg, 0.567 mmol) was added to 1,4-dioxane (1.0 mL). Bis(pinacolato)diborane (215.0 mg, 850 mmol) and potassium acetate (167 mg, 1.70 mmol) were added, and the resulting mixture was degassed by passing a stream of argon through it. Pd(PPh3)2Cl2 (39.8 mg, 0.057 mmol) was added, and the reaction mixture was heated to 90 °C and stirred for 5 h. After cooling to ambient temperature, the mixture was concentrated, resuspended in a mixture of water and ACN, and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give the desired product. C 10 H 14 BN3O2 (M = 219.1 g / mol) ESI-MS: 220[M+H]+ Rt(HPLC): 0.25min(Method C)

[0257] Synthesis of intermediate III.11 [ka]

[0258] 6-Bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine Ethanol (2 mL) is added to a mixture of 2-amino-5-bromopyrimidine (1.00 g, 5.63 mmol) and 1-chloro-3,3,3-trifluoroacetone (889 μL, 8.45 mmol). The resulting mixture is stirred at 90° C. for 5 days. After cooling to ambient temperature, the mixture is loaded onto EXtrelut® and purified by column chromatography (SiO, DCM / MeOH gradient) to give the desired product. C7H3BrF3N3 (M = 266.1 g / mol) ESI-MS: 266 / 268[M+H]+ Rt(HPLC): 0.38min(Method C)

[0259] Intermediate III.11 6-Bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine (82 mg, 0.308 mmol) was added to 1,4-dioxane (1.0 mL). Bis(pinacolato)diborane (117 mg, 462 mmol) and potassium acetate (90.6 mg, 0.925 mmol) were added, and the resulting mixture was degassed by passing a stream of argon through it. Pd(PPh3)2Cl2 (21.6 mg, 0.031 mmol) was added, and the reaction mixture was heated to 90 °C and stirred for 5 h. After cooling to ambient temperature, the mixture was concentrated, resuspended in a mixture of water and ACN, and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to give the desired product. C7H5BF3N3O2 (M = 230.9 g / mol) ESI-MS: 232[M+H]+ Rt(HPLC): 0.29min(Method C)

[0260] Synthesis of intermediate III.12 [ka]

[0261] 5-Bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine 5-Bromo-2-fluoro-pyridin-3-ol (4.00 g, 20.4 mmol) and diisopropylethylamine (5.28 g, 40.8 mmol) are added to DCM (100 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (3.94 g, 22.5 mmol) is added dropwise via syringe under stirring. The resulting reaction mixture is stirred at ambient temperature for 90 minutes. The mixture is concentrated and diluted with EtOAc and water. The organic layer is separated, dried over Na2SO4, and concentrated. The residue is purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the desired product. C 11 H 17 BrFNO2Si (M=322.2g / mol) ESI-MS: 322 / 324[M+H]+ Rt(HPLC): 0.90min(Method C)

[0262] Intermediate III.12 5-Bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine (3.0 g, 9.31 mmol), bis(pinacolato)diboron (4.68 g, 18.4 mmol), and potassium acetate (2.74 g, 27.9 mmol) were suspended in 1,4-dioxane (30 mL), and the resulting mixture was purged with argon for 15 minutes. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl; CAS: 72287-26-4) (476 mg, 0.652 mmol) was added, and the mixture was purged with argon for an additional 3 minutes. The reaction mixture was heated at 80 °C for up to 6 hours. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The organic layer was separated and dried over Na SO . Charcoal was added and the mixture was filtered through celite and concentrated to give the desired product which was used in the next step without further purification. C 17 H 29 BFNO4Si (M=369.3g / mol) ESI-MS: 370[M+H]+ Rt(HPLC): 0.90min(Method C)

[0263] Synthesis of intermediate III.13 [ka]

[0264] 5-Bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine To a stirred solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (6.00 g, 28.8 mmol) in DMF (200 mL) was added sodium hydride (1.50 g, 34.5 mmol; 55% in mineral oil) at 0 °C. After stirring for 30 min, the reaction mixture was treated with dibromodifluoromethane (8.3 mL, 86.3 mmol) and warmed to ambient temperature. The resulting mixture was stirred for 18 h, diluted with MeCN / HO, and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give 5-bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine. C7H3Br2F2N3 (M = 326.9 g / mol) ESI-MS: 326 / 328 / 330[M+H]+ Rt(HPLC): 0.56min(Method C)

[0265] 5-Bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine A solution of 5-bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (2.1 g, 6.4 mmol) and silver tetrafluoroborate (2.5 g, 12 mmol) in DCM (40 mL) is stirred at 50° C. for 18 h. The reaction mixture is concentrated, redissolved in DCE (40 mL), and stirred at 80° C. for 18 h. The resulting mixture is concentrated, loaded onto EXtrelut®, and purified by column chromatography (SiO, DCM / MeOH gradient 100 / 0 to 1 / 1) to give the title compound. C7H3BrF3N3 (M = 266.0 g / mol) ESI-MS: 266 / 268[M+H]+ Rt(HPLC): 0.47min(Method C)

[0266] Intermediate III.13 To a stirred solution of 5-bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine (741 mg, 1.39 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (529 mg, 2.09 mmol) and potassium acetate (409 mg, 4.18 mmol). The resulting mixture was purged with Ar for 10 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl; CAS: 72287-26-4) (102 mg, 0.14 mmol). After stirring at 90° C. for 5 h, the mixture is cooled to ambient temperature, concentrated, redissolved in H 2 O / MeCN, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to give intermediate III.13. C7H5BF3N3O2 (M = 230.9 g / mol) ESI-MS: 232[M+H]+ Rt(HPLC): 0.30min(Method C)

[0267] Synthesis of intermediate III.14 [ka]

[0268] 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine 5-tert-Butyl-4H-1,2,4-triazol-3-amine (400 mg, 2.71 mmol) and 2-bromopropanedial (646 mg, 4.07 mmol) are added to acetic acid (5 mL). After stirring at 60 °C for 3 h, the reaction mixture is concentrated, neutralized with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic layers are dried (Na2SO4), concentrated, and purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the title compound. C9H11 BrN4 (M = 255.1 g / mol) ESI-MS: 255 / 257[M+H]+ Rt(HPLC): 0.84min(Method D)

[0269] Intermediate III.14 A solution of 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg, 0.63 mmol), bis(pinacolato)diboron (260 mg, 1.02 mmol), and potassium acetate (240 mg, 2.45 mmol) in 1,4-dioxane (4 mL) was purged with Ar for 15 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (55 mg, 0.08 mmol). After stirring at 60 °C for 24 h, the mixture was cooled to ambient temperature, diluted with EtOAc, and filtered through a silica plug. The filtrate was concentrated, redissolved in MeCN / HO / TFA, and purified by preparative HPLC (SunFire C18, MeCN / HO gradient with 0.1% TFA) to give intermediate III.14. C9H 13 BN4O2 (M = 220.0 g / mol) ESI-MS: 221[M+H]+ Rt(HPLC): 0.34min(Method C)

[0270] Synthesis of intermediate III.15 [ka]

[0271] 6-Bromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine 5-(Trifluoromethyl)-4H-1,2,4-triazol-3-amine (500 mg, 3.12 mmol) and 2-bromopropanedial (744 mg, 4.69 mmol) are added to acetic acid (5 mL). After stirring at 60 °C for 3 h, the reaction mixture is concentrated, neutralized with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic layers are dried (Na2SO4), concentrated, and purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the title compound. C6H2BrF3N4 (M = 267.0 g / mol) ESI-MS: 267 / 269[M+H]+ Rt(HPLC): 0.78min(Method D)

[0272] Intermediate III.15 A solution of 6-bromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (155 mg, 0.58 mmol), bis(pinacolato)diboron (200 mg, 0.79 mmol), and potassium acetate (175 mg, 1.78 mmol) in 1,4-dioxane (3 mL) was purged with Ar for 15 min, followed by the addition of bis(triphenylphosphine)palladium chloride (CAS: 13965-03-2) (40 mg, 0.06 mmol). After stirring at 60 °C for 3 h, the mixture was cooled to ambient temperature, diluted with EtOAc, and filtered through a silica plug. The filtrate was concentrated, redissolved in MeCN / HO, and purified by preparative HPLC (Xbridge C18, MeCN / HO gradient with 0.1% TFA) to give intermediate III.15. C6H4BF3N4O2 (M=231.9g / mol) ESI-MS: 233[M+H]+ Rt(HPLC): 0.32min(Method C)

[0273] Synthesis of intermediates III.16 and III.17 [ka]

[0274] 7-Bromo-1H-pyrazolo[4,3-c]pyridine (500 mg, 2.42 mmol) and potassium carbonate (838 mg, 6.06 mmol) are added to THF (10 mL). After 10 min, benzyl bromide (353 μL, 2.91 mmol) is added, and the resulting reaction mixture is stirred at ambient temperature for 18 h. The reaction mixture is filtered, concentrated, and purified by preparative HPLC (Xbridge C18, water / MeCN gradient with 0.1% NH3) to give the desired isolated product.

[0275] Intermediate III.16: C 13 H 10 BrN3 (M = 288.1 g / mol) ESI-MS: 288 / 290[M+H]+ Rt(HPLC): 1.06min(Method E) 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1 H), 8.53 (s, 1 H), 8.51 (s, 1 H), 7.23 - 7.35 (m, 3 H), 7.08 - 7.13 (m, 2 H), 5.98 (s, 2 H).

[0276] Intermediate III.17: C 13 H 10 BrN3 (M = 288.1 g / mol) ESI-MS: 288 / 290[M+H]+ Rt (HPLC): 0.91 min (Method E) 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 1 H), 8.97 (s, 1 H), 8.36 (s, 1 H), 7.31 - 7.42 (m, 5 H), 5.76 (s, 2 H).

[0277] Synthesis of intermediate III.18 [ka] 5-Bromo-2-methyl-2h-pyrazolo[3,4-b]pyridine (1.00 g, 4.72 mmol) and zinc(II) trifluoromethanesulfinate (2.35 g, 7.04 mmol) were suspended in a mixture of DCM (50 mL) and water (10 mL). TFA (351 μL, 4.72 mmol) and tert-butyl hydroperoxide (70% in water, 3.26 mL, 23.6 mmol) were added, and the resulting reaction mixture was stirred at ambient temperature for 18 hours. Zinc(II) trifluoromethanesulfinate (0.50 g, 1.51 mmol) and tert-butyl hydroperoxide (70% in water, 1.00 mL, 7.22 mmol) were added, and the reaction mixture was stirred at 45° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with DCM. The combined organic extracts are dried over MgSO, DMF (10 mL) is added, and the mixture is concentrated. The remaining DMF solution is purified by preparative HPLC (Sunfire C18, water / ACN gradient with 0.1% NH) to give the desired product, along with other regioisomers from the trifluoromethylation reaction. C8H5BrF3N3(M=280.0g / mol) ESI-MS: 280 / 282[M+H]+ Rt(HPLC): 1.01min(Method D) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (d, J=2.3 Hz, 1 H), 8.53 (dq, J=2.2, 1.1 Hz, 1 H), 4.35 (q, J=0.9 Hz, 3 H)

[0278] Synthesis of intermediate III.19 [ka]

[0279] 3-(3-chlorophenyl)pyridazine Under a nitrogen atmosphere, (3-chlorophenyl)boronic acid (0.50 g, 3.19 mmol), KOAc (0.72 g, 7.36 mmol), and Pd(dppf)Cl*DCM (0.10 g, 0.123 mmol) were added to a mixture of 3-bromopyridazine (0.50 g, 2.45 mmol) in 1,4-dioxane (5 mL) and water (1 mL). The resulting reaction mixture was stirred at 100 °C for 12 h. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc gradient) to give 3-(3-chlorophenyl)pyridazine. C 10 H7ClN2 (M = 190.6 g / mol) ESI-MS: 191[M+H]+ Rt(HPLC): 0.54min(Method F)

[0280] Methyl 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate To a mixture of NH2OHSO3 (3.63 g, 32.1 mmol) in HO (20 mL) is added saturated aqueous NaHCO3 (40 mL), the pH is adjusted to 6, and heated to 70 °C. 3-(3-chlorophenyl)pyridazine (4.00 g, 21.0 mmol) is added to the mixture. The resulting reaction mixture is stirred at 70 °C for 2 h. After cooling to ambient temperature, the pH value is adjusted to pH 7, and methyl prop-2-ynoate (0.45 g, 5.35 mmol) in DCM (20 mL) is added to the mixture. The resulting mixture is stirred at ambient temperature for 12 h. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO2, petroleum ether / EtOAc gradient) to give methyl 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate. C 14 H 10ClN3O2 (M = 287.7 g / mol) ESI-MS: 288[M+H]+ Rt(HPLC): 0.74min(Method F)

[0281] 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylic acid To a mixture of methyl 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate (5.00 g, 10.4 mmol) in THF (50 mL) was added LiOH (2.00 equiv., 0.88 g, 20.9 mmol) and water (30 mL). The resulting reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH 1 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired compound, which was used in the next step without further purification. C 13 H8ClN3O2 (M=273.7g / mol) ESI-MS: 274[M+H]+ Rt(HPLC): 0.64min(Method F)

[0282] 3-Bromo-6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine To a mixture of 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylic acid (1.60 g, 5.44 mmol) in DMF (15 mL) is added NBS (1.94 g, 10.9 mmol). The resulting reaction mixture is stirred at ambient temperature for 12 h. The reaction mixture is diluted with water and extracted with EtOAc (2 × 100 mL). The combined organic extracts are washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (SiO, petroleum ether / EtOAc gradient) to give the desired product. C 12 H7BrClN3 (M = 308.6 g / mol) ESI-MS: 308 / 310[M+H]+ Rt(HPLC): 0.81min(Method F)

[0283] Intermediate III.19 Under a nitrogen atmosphere, 3-bromo-6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine (0.40 g, 1.04 mmol) was added to 1,4-dioxane (5 mL), and bis(pinacolato)diboron (1.58 g, 6.22 mmol), Pd(PPh3)4 (0.24 g, 0.21 mmol), and KOAc (0.37 g, 3.73 mmol) were added. The resulting reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc gradient). C 18 H 19 BClN3O2 (M = 355.6 g / mol) ESI-MS: 356[M+H]+ Rt(HPLC): 0.90min(Method F)

[0284] Synthesis of intermediate III.20 [ka]

[0285] 5-Bromo-2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.00 g, 3.93 mmol) is added to acetonitrile (15 mL) and N-chlorosuccinimide (0.58 g, 4.33 mmol) is added at ambient temperature. The resulting reaction mixture is stirred at 85° C. for 12 hours. After cooling to ambient temperature, the mixture is concentrated and resuspended in water. It is extracted with EtOAc (3×). The combined organic extracts are dried over NaSO, filtered, and concentrated. The residue is purified by column chromatography (SiO, PE / EtOAc gradient) to give the desired product. C 10 H 11 BrClN3 (M = 288.6 g / mol) ESI-MS: 288 / 290[M+H]+ Rt(HPLC): 0.80min(Method R)

[0286] Intermediate III.20 A solution of 5-bromo-2-tert-butyl-3-chloro-pyrazolo[3,4-b]pyridine (0.80 g, 2.77 mmol), bis(pinacolato)diboron (0.92 g, 3.61 mmol), and potassium acetate (815 mg, 8.32 mmol) in 1,4-dioxane (16 mL) was purged with N for 10 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (202 mg, 0.23 mmol). After stirring at 100 °C for 12 hours, the mixture was cooled to ambient temperature, concentrated, and resuspended in water. It was extracted with EtOAc (3x), dried over NaSO, and concentrated. The residue is purified by preparative HPLC (Welch Xtimate C18, acetonitrile / water gradient containing 10 mM NH4HCO3) to give intermediate III.4. C 10 H 13 BClN3O2 (M = 253.5 g / mol) ESI-MS: 254[M+H]+ Rt(HPLC): 0.71min(Method S)

[0287] Intermediate IV.1 [ka]

[0288] To a mixture of 3-bromo-2-fluorobenzonitrile (500 mg, 2.50 mmol) and pyridine-3-boronic acid (307 mg, 2.50 mmol) in 1,4-dioxane (5 mL) was added sodium carbonate (2 M in water, 2 mL, 4.0 mmol). The resulting mixture was purged with argon for 15 minutes, followed by the addition of [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (0.091 g, 125 μmol), and the mixture was further purged with argon for 3 minutes. The reaction mixture was heated to 90 °C and stirred for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were treated with charcoal, filtered through Celite, and concentrated. The residue is used in the next step without further purification. C 12 H7FN2 (M = 198.2 g / mol) EI-MS: 199[M+H]+ Rt(HPLC): 0.28min(Method C)

[0289] Intermediate V.1 [ka]

[0290] 3-(6-fluoro-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile To a mixture of intermediate II.1 (2.50 g, 7.22 mmol) and intermediate III.12 (~65% purity, 5.07 g, 8.9 mmol) in 1,4-dioxane (30 mL) is added cesium carbonate (2 M in water, 11.8 mL, 21.7 mmol). The resulting mixture is purged with argon for 15 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.834 g, 0.722 mmol), and the mixture is further purged with argon for 3 minutes. The reaction mixture is heated to 80 °C and stirred for 2 hours. After cooling to ambient temperature, the reaction mixture is diluted with diethyl ether, washed with half-concentrated NaCl solution, dried over Na2SO4, and concentrated. The crude material is carried on to the next step without further purification. C 26 H 33 FN6O2Si (M=508.7g / mol) EI-MS: 509[M+H]+ Rt(HPLC): 0.68min(Method C)

[0291] Intermediate V.1 3-(6-Fluoro-5-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (~65% purity, 6.77 g, 8.65 mmol) is added to 1,4-dioxane (60 mL) and a solution of HCl in 1,4-dioxane (4 M, 16.6 mL, 66.5 mmol) is added. The resulting reaction mixture is stirred at ambient temperature for 66 h. The mixture is concentrated and the residue is purified by preparative HPLC (XBridge C18, ACN / water gradient, 0.1% NH3) to give the desired product. C 20 H 19 FNO (M = 378.4 g / mol) EI-MS: 379[M+H]+ Rt(HPLC): 0.42min(Method C)

[0292] Intermediate V.2 [ka]

[0293] To a mixture of intermediate II.2 (110 mg, 302 μmol) and (1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (62.2 mg, 362 μmol) in 1,4-dioxane (5 mL) was added potassium carbonate (2 M in water, 302 μL, 604 μmol). The resulting mixture was purged with argon for 15 minutes, followed by the addition of [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (22.1 mg, 30.2 μmol), and the mixture was purged with argon for another 3 minutes. The reaction mixture was heated to 100° C. and stirred for 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, filtered through Celite, and concentrated. The residue is purified by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% TFA) to give the desired compound. C 21 H 19 FN8 (M = 402.4 g / mol) ESI-MS: 403[M+H]+ Rt(HPLC): 0.75min(Method E)

[0294] Preparation of final compounds Example 1 [ka] To a mixture of intermediate II.1 (750 mg, 2.2 mmol) and 2-fluoropyridine-5-boronic acid pinacol ester (CAS: 329214-79-1) (580 mg, 2.6 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (2 M in water, 3.2 mL, 6.5 mmol). The resulting mixture was purged with argon for 15 minutes, and [1,1'-bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) (Pd(dppf)Cl, CAS: 72287-26-4) (158 mg, 0.22 mmol) was added, and the mixture was purged with argon for another 3 minutes. The reaction mixture was heated to 100 °C and stirred for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with H O and saturated aqueous NaHCO, dried over Na SO, and concentrated. The crude product is purified by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% NH3) to give the desired compound. C 20 H 19 FN6 (M = 362.4 g / mol) ESI-MS: 363[M+H]+ Rt(HPLC): 0.42min(Method C) 1 H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.08 (dt, J = 2.3, 8.2 Hz, 1H), 7.80 (dd, J = 1.6, 7.7 Hz, 1H), 7.57 (dd, J = 1.5, 7.6 Hz, 1H), 7.37 - 7.27 (m, 2H), 3.79 (s, 3H), 3.28 - 3.09 (m, 3H), 2.99 (br s, 2H), 1.86 (br d, J = 10.8 Hz, 2H), 1.73 - 1.58 (m, 2H)

[0295] The following examples were prepared using the procedure of Example 1 with slight modifications: [Table 10-1]

[0296] Table 10-2

[0297] Table 10-3

[0298] Table 10-4

[0299] Table 10-5

[0300] Table 10-6

[0301] Table 10-7

[0302] Table 10-8

[0303] Table 10-9

[0304] Table 10-10

[0305] Table 10-11

[0306] [Table 10-12]

[0307] [Table 10-13]

[0308] [Table 10-14]

[0309] [Table 10-15]

[0310] Example 34 [ka] Intermediate V.1 (60.0 mg, 159 mmol) is added to DMF (1.0 mL), and cesium carbonate (155 mg, 476 mmol) and bromocyclobutane (98.2 mg, 634 mmol) are added. The resulting reaction mixture is heated to 100 °C and stirred at this temperature for 3 h. After cooling to ambient temperature, the reaction mixture is diluted with water and MeOH and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% NH3) to give the desired product. C 24 H 25 FNO (M = 432.5 g / mol) ESI-MS: 433[M+H]+ Rt(HPLC): 0.53min(Method C) 1H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1 H), 7.77 (dd, J=7.7, 1.6 Hz, 1 H), 7.72 (t, J=1.8 Hz, 1 H), 7.49 - 7.56 (m, 2 H), 7.27 (t, J=7.7 Hz, 1 H), 4.90 (quin, J=7.1 Hz, 1 H), 3.58 (s, 3 H), 3.20 - 3.28 (m, 2 H), 2.91 - 3.02 (m, 2 H), 2.85 (tt, J=11.2, 3.8 Hz, 1 H), 2.43 - 2.51 (m, 2 H), 2.08 - 2.20 (m, 2 H), 1.55 - 1.86 (m, 6 H)

[0311] The following examples were prepared using the procedure of Example 34 with slight modifications: [Table 11]

[0312] Example 37 [ka]

[0313] In a microwave vial, intermediate V.1 (50.0 mg, 132 μmol) and potassium carbonate (45.7 mg, 330 μmol) are added to a mixture of DMF and water (9:1, 1.5 mL), and sodium chlorodifluoroacetate (42.0 mg, 264 μmol) is added. The vial is sealed, and the resulting reaction mixture is stirred at 120° C. for 3 hours. After cooling to ambient temperature, a second portion of sodium chlorodifluoroacetate (42.0 mg, 264 μmol) is added. The vial is sealed, and the resulting reaction mixture is stirred at 120° C. for 2 hours. After cooling to ambient temperature, the mixture is diluted with water and MeOH, filtered, and purified by preparative HPLC (Sunfire C18, ACN / water gradient with 0.1% TFA). C 21 H 19 F3N6O (M=428.4g / mol) ESI-MS: 429[M+H]+ Rt(HPLC): 0.64min(Method H) 1 H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1 H), 8.16 (t, J=1.6 Hz, 1 H), 8.04 (dd, J=9.4, 1.5 Hz, 1 H), 7.82 (dd, J=7.7, 1.6 Hz, 1 H), 7.60 (dd, J=7.6, 1.6 Hz, 1 H), 7.33 (t, J=7.7 Hz, 1 H), 7.38 (t, J=72.5 Hz, 1 H), 3.72 (s, 3 H), 3.18 - 3.28 (m, 2 H), 2.94 - 3.11 (m, 3 H), 1.79 - 1.90 (m, 2H), 1.55 - 1.70 (m, 2 H).

[0314] Example 38 [ka] Intermediate V.1 (50.0 mg, 132 μmol) is added to DMSO (0.5 mL) in a microwave vial, and iodobenzene (33 mg, 159 μmol), copper(I) iodide (6.3 mg, 33 μmol), potassium phosphate monohydrate (96 mg, 396 μmol), and picolinic acid (3.3 mg, 26 μmol) are added under an argon atmosphere. The vial is sealed, and the resulting reaction mixture is stirred at 100° C. for 45 minutes and at 130° C. for 3 hours. After cooling to ambient temperature, the mixture is diluted with DCM and washed with half-concentrated aqueous ammonia. The organic layer is dried, concentrated, and purified by preparative HPLC (X-Bridge C18, ACN / water gradient with 0.1% NH) to give the desired product. C 26 H 23 FNO (M = 454.5 g / mol) ESI-MS: 455[M+H]+ Rt(HPLC): 0.86min(Method I) 1H NMR (400 MHz, DMSO-d6) δ = 8.33 (s, 1 H), 8.03 (t, J=1.8 Hz, 1 H), 7.76 (dd, J=7.7, 1.6 Hz, 1 H), 7.59 (dd, J=9.8, 2.0 Hz, 1 H), 7.55 (dd, J=7.7, 1.7 Hz, 1 H), 7.39 - 7.46 (m, 2 H), 7.27 (t, J=7.7 Hz, 1 H), 7.17 - 7.23 (m, 3 H), 3.61 (s, 3 H), 3.13 - 3.21 (m, 2 H), 2.88 - 2.99 (m, 2 H), 2.84 (tt, J=11.4, 3.6 Hz, 1 H), 1.72 - 1.82 (m, 2 H), 1.55 - 1.68 (m, 2 H).

[0315] Example 41

change

[0316] Intermediate III.18 (72.8 mg, 0.260 mmol), potassium acetate (51.0 mg, 0.52 mmol), and bis(pinacolato)diboron (66.0 mg, 0.260 mmol) were suspended in 1,4-dioxane (1.5 mL), and the resulting mixture was purged with argon for 15 minutes. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) dichloride DCM complex (Pd(dppf)Cl*CHCl, CAS: 95464-05-4) (14.1 mg, 0.017 mmol) was added, and the mixture was purged with argon for another 3 minutes. The reaction mixture was heated to 100 °C and stirred for 4 hours. After cooling to ambient temperature, intermediate II.1 (60.0 mg, 0.173 mmol), Na2CO3 solution (2 M in water, 260 μL, 0.520 mmol), and (Pd(dppf)Cl2*CHCl2, CAS: 95464-05-4) (14.1 mg, 0.017 mmol) are added. The mixture is again purged with argon for 3 minutes, heated to 100 °C, and stirred at 100 °C for 4 hours. After cooling to ambient temperature, the reaction is diluted with a mixture of water / ACN, acidified with TFA, filtered, and purified by preparative HPLC (Sunfire C18, ACN / water gradient with 0.1% TFA) to give the desired compound. C 23 H 21 F3N8 (M = 466.5 g / mol) ESI-MS: 467[M+H]+ Rt(HPLC): 0.78min(Method D) 1 H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.21 - 8.27 (m, 1 H), 7.82 (dd, J=7.7, 1.5 Hz, 1 H), 7.68 (dd, J=7.6, 1.5 Hz, 1 H), 7.35 (t, J=7.7 Hz, 1 H), 4.38 (s, 3 H), 3.69 (s, 3H), 3.23 - 3.34 (m, 2 H), 2.94 - 3.13 (m, 3 H), 1.73 - 1.84 (m, 2 H), 1.47 - 1.63 (m, 2H)

[0317] The following examples were prepared using the procedure of Example 41 with slight modifications: [Table 12-1]

[0318] [Table 12-2]

[0319] [Table 12-3]

[0320] [Table 12-4]

[0321] Example 55 [ka] Intermediate V.2 (20.0 mg, 49.7 μmol) is added to THF (2.0 mL) and a solution of NaHMDS in THF (1.0 m, 49.7 μL, 49.7 μmol) is added. The mixture is stirred at ambient temperature for 5 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (7.4 μL, 49.7 μmol) is added, and the resulting reaction mixture is stirred at ambient temperature for 1 hour. A second portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.4 μL, 49.7 μmol) is added, and the reaction mixture is stirred for 2 hours. The mixture is filtered and purified by preparative HPLC (XBridge C18, water / ACN gradient with 0.1% NH3) to give the desired product. C 23 H 20 F4N8 (M = 484.5 g / mol) ESI-MS: 485[M+H]+ Rt(HPLC): 0.65min(Method J) 1H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J=2.3 Hz, 1 H), 8.65 (s, 1 H), 8.44 (s, 1 H), 8.27 (d, J=2.3 Hz, 1 H), 7.82 (dd, J=7.7, 1.6 Hz, 1 H), 7.63 (dd, J=7.7, 1.6 Hz, 1 H), 7.35 (t, J=7.7 Hz, 1 H), 5.57 (q, J=9.0 Hz, 2 H), 3.68 (d, J=1.5 Hz, 3 H), 3.12 - 3.23 (m, 4 H), 2.02 - 2.20 (m, 4 H).

[0322] The following examples were prepared using the procedure of Example 55 with slight modifications: [Table 13]

[0323] Example 58 [ka]

[0324] Example 54 (30.0 mg, 60.8 μmol) and potassium carbonate (25.2 mg, 182 μmol) are added to DMF (2.0 mL), and iodomethane (13.0 mg, 91.2 μmol) is added. The resulting reaction mixture is stirred at ambient temperature for 4 hours. It is diluted with ACN and water and directly purified by preparative HPLC (XBridge C18, ACN / water containing 0.1% TFA) to give the desired product. C 20 H 20 FNO (M=393.4g / mol) ESI-MS: 394[M+H]+ Rt(HPLC): 0.36min(Method C) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, J=3.0 Hz, 1 H), 8.56 (s, 1 H), 8.43 (d, J=3.2 Hz, 1 H), 7.78 (dd, J=7.7, 1.6 Hz, 1 H), 7.63 (dd, J=7.7, 1.6 Hz, 1 H), 7.36 (t, J=7.7 Hz, 1 H), 3.76 (d, J=1.5 Hz, 3 H), 3.51 (s, 3 H), 3.33 - 3.45 (m, 2 H), 3.13 - 3.22 (m, 2 H), 2.08 - 2.29 (m, 4H)

[0325] The following examples were prepared according to the procedure of Example 58: [Table 14]

[0326] Example 65 [ka] Intermediate IV.1 (100 mg, 0.505 mmol) is suspended in NMP (1.0 mL), and potassium carbonate (209 mg, 1.51 mmol) and 4-methyl-4-(4-methyl-1,2,4-triazol-3-yl)piperidine dihydrochloride (128 mg, 0.505 mmol) are added. The resulting reaction mixture is stirred at 160 °C for 18 h. After cooling to ambient temperature, the mixture is diluted with water and purified by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% NH3) and further purified by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% TFA) to give the desired product. C 21 H 22 N6 (M = 358.4 g / mol) ESI-MS: 359[M+H]+ Rt(HPLC): 0.38min(Method K) 1H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 1 H), 8.71 (d, J=1.8 Hz, 1 H), 8.68 (dd, J=4.9, 1.5 Hz, 1 H), 8.01 (dt, J=7.9, 1.8 Hz, 1 H), 7.80 (dd, J=7.7, 1.6 Hz, 1 H), 7.63 (dd, J=7.8, 5.0 Hz, 1 H), 7.59 (dd, J=7.6, 1.6 Hz, 1 H), 7.33 (t, J=7.7 Hz, 1 H), 3.79 (s, 3 H), 2.92 - 3.13 (m, 4 H), 2.04 - 2.16 (m, 2 H), 1.60 - 1.72 (m, 2 H), 1.30 (s, 3 H).

[0327] Synthesis of Example 80 [ka]

[0328] 5-{3-cyano-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl}pyridine-3-carboxylic acid To a stirred solution of Example 27 (150 mg, 0.37 mmol) in MeOH (1.5 mL) is added 2 M aqueous lithium hydroxide (0.56 mL, 1.1 mmol). After stirring for 2 h, the reaction is neutralized with 4 M aqueous hydrogen chloride and concentrated. The resulting residue is suspended in HO and filtered to give the title compound. C 21 H 20 N6O2 (M = 388.4 g / mol) ESI-MS: 389[M+H]+ Rt(HPLC): 0.44min(Method H)

[0329] Example 80 To a stirred solution of 5-{3-cyano-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl}pyridine-3-carboxylic acid (35 mg, 0.09 mmol) and HATU (38 mg, 0.10 mmol) in DMF (1 mL) was added DIPEA (53 μL, 0.29 mmol). After stirring for 2 minutes, the reaction was treated with 2 M methylamine in MeOH (0.14 mL, 0.27 mmol) and further stirred for 18 hours. Purification directly by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% NH3) gave Example 80. C 22 H 23 NO (M=401.5g / mol) ESI-MS: 402[M+H]+ Rt(HPLC): 0.47min(Method L) 1 H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J=2.2 Hz, 1 H), 8.74 (d, J=2.2 Hz, 1 H), 8.67 (q, J=4.1 Hz, 1 H), 8.28 (s, 1 H), 8.20 (t, J=2.2 Hz, 1 H), 7.80 (dd, J=7.7, 1.6 Hz, 1 H), 7.59 (dd, J=7.7, 1.6 Hz, 1 H), 7.32 (t, J=7.7 Hz, 1 H), 3.56 (s, 3 H), 3.16 - 3.23 (m, 2 H), 2.91 - 3.02 (m, 2H), 2.77 - 2.88 (m, 4 H), 1.70 - 1.78 (m, 2 H), 1.55 - 1.69 (m, 2 H)

[0330] Analytical data for synthesized examples [Table 15-1]

[0331] [Table 15-2]

[0332] Table 15-3

[0333] Table 15-4

[0334] Table 15-5

[0335] Table 15-6

[0336] Table 15-7

[0337] Table 15-8

[0338] Table 15-9

[0339] Table 15-10

[0340] Table 15-11

[0341] Table 15-12

[0342] Table 15-13

[0343] Table 15-14

[0344] Table 15-15

[0345] Table 15-16

[0346] Table 15-17

[0347] Table 15-18

[0348] Table 15-19

[0349] Table 15-20

[0350] Table 15-21

[0351] Table 15-22

[0352] [Table 15-23]

[0353] [Table 15-24]

[0354] [Table 15-25]

[0355] [Table 15-26]

[0356] Analytical HPLC method Method A [Table 16] Analytical column: Kinetex EVO C18 2.1 x 30 mm 5 μm; column temperature: 40 °C

[0357] Method B [Table 17] Instrument description: Waters Acquity; analytical column: Xbridge (Waters) BEH C18 2.1 × 30 mm 2.5 μm; column temperature: 60 °C

[0358] Method C [Table 18] Instrument description: Waters Acquity; analytical column: Xbridge (Waters) BEH C18 2.1 × 30 mm 1.7 μm; column temperature: 60 °C

[0359] Method D [Table 19] Instrument: Agilent 1200; analytical column: Sunfire C18 3.0 × 30 mm 2.5 μm (Waters); column temperature: 60 °C

[0360] Method E [Table 20] Instrument: Agilent 1200; analytical column: Xbridge (Waters) C18 3.0 × 30 mm 2.5 μm; column temperature: 60 °C

[0361] Method F [Table 21] Instrument: Shimadzu LC-20 ADXR; analytical column: Halo C18 3.0 × 30 mm 5 μm; column temperature: 40 °C

[0362] Method G [Table 22] Instrument: Agilent 1200; Analytical column: Zorbax (Agilent) StableBond C18 3.0 × 30 mm 1.8 μm; Column temperature: 60 °C

[0363] Method H [Table 23] Instrument: Waters Acquity; analytical column: Sunfire (Waters) C18 3.0 × 30 mm 2.5 μm (Waters); column temperature: 60 °C

[0364] Method I [Table 24] Instrument: Waters Acquity; analytical column: Xbridge BEH (Waters) C18 2.1 × 30 mm 1.7 μm; column temperature: 60 °C

[0365] Method J [Table 25] Instrument: Waters Acquity; Analytical column: Xbridge (Waters) C18 3.0 × 30 mm 2.5 μm; Column temperature: 60 °C

[0366] Method K [Table 26] Instrument: Waters Acquity; analytical column: Sunfire C18 3.0 × 30 mm 2.5 μm (Waters); column temperature: 60 °C

[0367] Method L [Table 27] Instrument description: Waters Acquity; analytical column: Xbridge C18 3.0 × 30 mm 2.5 μm (Waters); column temperature: 60 °C

[0368] Method M [Table 28] Instrument: Waters Acquity; Analytical column: Sunfire (Waters) C18 3.0 x 30 mm 2.5 μm; Column temperature: 60°C

[0369] Method N [Table 29] Instrument description: Agilent 1260 SFC; Column: Chiral ART® Amylose SA, 4.6 x 250 mm, 2.5 μm (YMC); Column temperature: 40°C

[0370] Method O [Table 30] Instrument: Waters Acquity; Analytical column: Xbridge (Waters) C18 3.0 × 30 mm 2.5 μm; Column temperature: 60 °C

[0371] Method P [Table 31] Instrument: Waters Acquity; analytical column: Sunfire C18 3.0 × 30 mm 2.5 μm (Waters); column temperature: 60 °C

[0372] Method Q [Table 32] Instrument: Waters Acquity; Analytical column: Sunfire (Waters) C18 3.0 x 30 mm 2.5 μm; Column temperature: 60°C

[0373] Method R [Table 33] Instrument: Shimadzu LC-20ADXR; analytical column: Halo C18 3.0 × 30 mm 5 μm; column temperature: 40 °C

[0374] Method S [Table 34] Instrument: Agilent 1200 HPLC; analytical column: Halo C18 3.0 × 30 mm 5 μm; column temperature: 40 °C

Claims

1. A compound of formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (I) (In the formula, A is a 5- or 6-membered mono-heteroaryl ring, A1a, containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein at least one heteroatom is nitrogen; or Or, A is 【Chemistry 2】 Selected from Group A1c consisting of: R 1 is H, C 1-4 selected from the group R1a consisting of alkyl and halogen; R 2 is H, halogen, hydroxy, C 1-6 -Alkyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, F 1-9 -Fluoro-C 1-4 -Alkyl, HO-C 1-6 -Alkyl, C 1-6 -Alkyloxy, C 1-4 -Alkyl-O-H 2 CH 2 C-O-, C 3-6 -cycloalkyloxy, C 3-6 -cycloalkyl-H 2 C-O-, F 1-9 -Fluoro-C 1-4 -Alkyloxy, C 1-6 -Alkyl-O-C(O)-, H 2 N—C(O)— and C 1-6 -alkyl-NH-C(O)-; or Or, R 2 is selected from the group R consisting of phenyl, benzyl, phenoxy, and benzyloxy, wherein R is one or two R 4 is replaced by Or, R 2 is R2c, a 5- or 6-membered mono-heteroaryl ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R2c is selected from one or two R 4 or R2c substituted with Or, R 2 teeth, 【Transformation 3】 R2d consisting of: R 3 is H, C 1-4 selected from the group R3a consisting of alkyl and halogen; R 4 is H, C 1-4 - selected from the group R4a consisting of alkyl and halogen.

2. A is pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl-pyrimidonyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2-dihydropyrimidin-2-onyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-c]pyridinyl, [1,2,5]oxo The compound of formula (I) according to claim 1 or a salt thereof, selected from group A4 consisting of thiadiazolo[3,4-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,5]thiadiazolo[3,4-b]pyridinyl, 2H-[1,3]dioxolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[1,5-b]pyridazinyl, 2H,3H,4H-pyrano[2,3-b]pyridinyl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl, and 1,8-naphthyridinyl.

3. A is, 【Chemistry 4】 2. The compound of formula (I) according to claim 1, or a salt thereof, selected from group A7 consisting of:

4. R 1 But, H, H 3 The compound of formula (I) according to any one of claims 1 to 3, wherein R1d is selected from the group R1d consisting of C-, and F, or a salt thereof.

5. R 2 is R2E, R2E is H, F, Cl, hydroxy, methyl, t-butyl, H 3 C-alkynyl, cyclopropyl, F 3 C-, F 3 CCH 2 -, F 2 CHCH 2 -, F 3 C-C (CH 3 ) 2 -, HO-CH 2 -, H 3 C—O—, (H 3 C) 2 C-H-O-, H 3 C-O-H 2 CH 2 C-O-, F 2 HC-O-, F 3 C-O-, H 3 C-O-C(O)-, H 2 N—C(O)—, H 3 C-NH-C(O)-, 【Transformation 5】 or selected from the group R2i consisting of: Or R2E is selected from the group R2j consisting of phenyl, m-chlorophenyl, benzyl, phenoxy, and benzyloxy; Or, R2E is 【Transformation 6】 R2g is selected from the group consisting of: wherein R2g is substituted with H or methyl; Or, R2E is 【Transformation 7】 The compound of formula (I) or a salt thereof according to any one of claims 1 to 4, wherein R2d consists of:

6. R 3 A compound of formula (I) or a salt thereof according to any one of claims 1 to 5, wherein R3e is selected from the group R3e consisting of F.

7. Formula (1-e) 【Transformation 8】 (Ie) 6. A compound of formula (I) or a salt thereof according to any one of claims 1, 4 or 5, having the formula:

8. Formula (1-a) 【Chemistry 9】 (Ia) 7. The compound of formula (I) or a salt thereof according to any one of claims 1, 2, 3, 5, or 6, wherein: 【Request Item 9】 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] [Transformation 10-5] 【Chemistry 10-6】 【Chemistry 10-7】 [Transformation 10-8] 2. The compound of formula (I) according to claim 1, or a salt thereof, selected from the group consisting of:

10. 10. A pharmaceutically acceptable salt of a compound according to at least one of claims 1 to 9.

11. 10. A pharmaceutical composition comprising at least one compound according to at least one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and optionally at least one inert carrier and / or diluent.

12. 10. A pharmaceutical composition comprising at least one compound according to at least one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, and optionally at least one inert carrier and / or diluent.

13. 13. The pharmaceutical composition of claim 12, wherein the at least one additional therapeutic agent is selected from the group consisting of an anti-cancer agent and an anti-fibrotic agent.

14. 10. A compound according to at least one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use as a medicament.

15. 10. A method for the treatment of diseases such as cancer or fibrotic diseases and symptoms associated with these diseases in a patient in need of such treatment, characterized in that at least one compound according to at least one of claims 1 to 9 or a pharmaceutically acceptable salt thereof is administered to the patient.

16. 10. A compound according to at least one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in a method for the treatment of cancer, a fibrotic disease, a neurodegenerative disease, arteriosclerosis, an infectious disease, or chronic kidney disease.

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