Phenylpiperidine derivatives as inhibitors of glutamyl peptide cyclotransferases and glutamyl peptide cyclotransferase-like proteins

Abstract

The present invention provides certain phenylpiperidine derivatives, and pharmaceutically acceptable salts thereof, which are inhibitors of glutamyl peptide cyclotransferase (QPCT) and glutamyl peptide cyclotransferase-like protein (QPCTL), and are thus useful in the treatment of diseases that can be treated by inhibition of QPCT / L. The invention also provides pharmaceutical compositions containing them and processes for preparing the compounds. # imgabs0 #

Description

TECHNICAL FIELD

[0001] The present invention 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 can thus be used for treating diseases that can be treated by inhibiting QPCT / L. The present invention also provides pharmaceutical compositions containing them and methods for preparing the compounds. BACKGROUND OF THE INVENTION

[0002] Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyze the intramolecular cyclization of the N-terminal glutamine (Q) residue to pyroglutamate (pE) and the release of ammonia [Stephan Schilling et al., “Identification of Human Glutaminyl Cyclase as a Metalloenzyme POTENTINHIBITION BY IMIDAZOLE DERIVATIVES AND HETEROCYCLIC CHELATORS,” Journal ofBiological Chemistry 278, no. 50 (2003): 49773-79, https: / / doi.org / 10.1074 / jbc.m309077200; Holger Cynis et al., “Isolation of an Isoenzyme of HumanGlutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in theProtein Maturation Machinery,” Journal of Molecular Biology 379, no. 5 (2008): 966-80, https: / / doi.org / 10.1016 / j.jmb.2008.03.078; Anett Stephan et al., “MammalianGlutaminyl Cyclases and Their Isoenzymes Have Identical EnzymaticCharacteristics,” FEBS Journal 276, no. 22 (2009): 6522-36, https: / / doi.org / 10.1111 / j.1742-4658.2009.07337.x.]. Although QPCT is a secreted protein, QPCTL remains in the Golgi complex. The two enzymes have a high degree of homology at the active site and similar catalytic specificities. Due to the high homology of the active site, inhibition of the active site blocks the enzymatic activities of both QPCT and QPCTL. Therefore, the term “QPCT / L” describes both enzymes simultaneously. Due to their different cellular localizations, differences in their relevance to the modification of biological substrates have been reported. A known substrate of intracellular QPCTL and / or extracellular QPCT is CD47 [Meike E.W.Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47 - SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612 - 19, https: / / doi.org / 10.1038 / s41591 - 019 - 0356 - z.]、different chemokines (such as CCL2 and 7 or CX3CL1) [Rosa Barreirada Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology 23, no. 4 (2022): 568 - 80, https: / / doi.org / 10.1038 / s41590 - 022 - 01153 - x; Astrid Kehlen et al., “N - Terminal Pyroglutamate Formation in CX3CL1 Is Essential for Its Full Biologic Activity,” Bioscience Reports 37, no. 4 (2017): BSR20170712, https: / / doi.org / 10.1042 / bsr20170712.]、amyloid - β peptide [Cynis et al., “Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery.”] or hormones such as TRH [Andreas Becker et al., “IsoQC (QPCTL) Knock - out Mice Suggest Differential Substrate Conversion by Glutaminyl Cyclase Isoenzymes,” Biological Chemistry 397, no. 1 (2016): 45 - 55, https: / / doi.org / 10.1515 / hsz-2015-0192.]。The modification of the N-terminal glutamine to pyroglutamate on the substrate has a functional impact on the protein and can affect the different pathomechanisms of several diseases. CD47 is expressed on the surface of almost all body cells, including apoptotic cells, senescent cells, or cancer cells. [Meike E.W. Logtenberg, Ferenc A. Scheeren, and Ton N. Schumacher, “The CD47-SIRPα Immune Checkpoint,” Immunity 52, no. 5 (2020): 742-52, https: / / doi.org / 10.1016 / j.immuni.2020.04.011]. The main ligand of CD47 is signal regulatory protein α (SIRPα), which is an inhibitory transmembrane receptor present on myeloid cells (such as macrophages, monocytes, neutrophils, dendritic cells, and other cells). The QPCTL-mediated N-terminal pyroglutamate modification on CD47 requires 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 E.W. Logtenberg et al., “Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy,” Nature Medicine 25, no. 4 (2019): 612-19, https: / / doi.org / 10.1038 / s41591-019-0356-z.This signaling axis induces the "Don't Eat Me Signal", thereby preventing macrophages from phagocytosing cells expressing CD47. Thus, high expression of CD47 is associated with the pathogenesis of the following diseases: cancer [Logtenberg et al., "Glutaminyl Cyclase Is an Enzymatic Modifier of the CD47-SIRPα Axis and a Target for Cancer Immunotherapy," 2019; Meike E. W. Logtenberg, Ferenc A. Scheeren and Ton N. Schumacher, "The CD47-SIRPα Immune Checkpoint," Immunity 52, no. 5 (2020): 742-52, https: / / doi.org / 10.1016 / j.immuni.2020.04.011.], COVID-19 [Katie-May McLaughlin et al., "A Potential Role of the CD47 / SIRPalpha Axis in COVID-19 Pathogenesis," Current Issues in Molecular Biology 43, no. 3 (2021): 1212-25, https: / / doi.org / 10.3390 / cimb43030086.], pulmonary fibrosis [Gerlinde Wernig et al., "Unifying Mechanism for Different Fibrotic Diseases," Proceedings of the National Academy of Sciences 114, no. 18 (2017): 4757-62, https: / / doi.org / 10.1073 / pnas.1621375114; Lu Cui et al., "Activation of JUN in Fibroblasts Promotes Pro-Fibrotic Programme and Modulates Protective Immunity," Nature Communications 11, no. 1 (2020): 2795, https: / / doi.org / 10.1038 / s41467-020-16466-4.1. Systemic sclerosis [Wernig et al., “Unifying Mechanism for Different Fibrotic Diseases”; Tristan Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma,” JCI Insight 5, no. 16 (2020): e140458, https: / / doi.org / 10.1172 / jci.insight.140458.] and liver fibrosis [Taesik Gwag et al., “Anti-CD47 Antibody Treatment Attenuates Liver Inflammation and Fibrosis in Experimental Non-alcoholic Steatohepatitis Models,” Liver International 42, no. 4 (2022): 829-41, https: / / doi.org / 10.1111 / liv.15182.]. Because enhanced CD47 expression blocks the clearance of apoptotic cells, there is an accumulation of apoptotic lung epithelial cells, leading to profibrotic stimuli and accelerating lung inflammation and scarring [Alexandra L. McCubbrey and Jeffrey L. Curtis, “Efferocytosis and Lung Disease,” Chest 143, no. 6 (2013): 1750-57, https: / / doi.org / 10.1378 / chest.12-2413; Brennan D. Gerlach et al., “Efferocytosis Induces Macrophage Proliferation to Help Resolve Tissue Injury,” Cell Metabolism, 2021, https: / / doi.org / 10.1016 / j.cmet.2021.10.015.]. Because the CD47 half-life and function mainly depend on QPCTL enzyme activity, inhibition of QPCT and QPCTL may be a suitable mechanism for the treatment of lung fibrosis such as IPF or SSC-ILD [Lerbs et al., “CD47 Prevents the Elimination of Diseased Fibroblasts in Scleroderma."], which can be used alone or in combination with current standard treatments for pulmonary fibrosis, such as nintedanib (Luca Richeldi et al., "Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis," The New England Journal of Medicine 370, no. 22 (2014): 2071 - 82, https: / / doi.org / 10.1056 / nejmoa1402584; Kevin R Flaherty et al., "Nintedanib in Progressive Fibrosing Interstitial Lung Diseases," New England Journal of Medicine 381, no. 18 (2019): 1718 - 27, https: / / doi.org / 10.1056 / nejmoa1908681.) or 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).

[0003] By expressing CD47, cancer cells can evade destruction by the immune system or 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]. The formation of N-terminal pGlu has been shown to increase in vivo activity by both conferring resistance to aminopeptidases and by increasing its ability to induce chemokine receptor signaling. Due to the intracellular mechanism of N-terminal cyclization mediated by the Golgi-associated enzyme QPCTL, the two major monocyte chemoattractants, CCL2 and CCL7, are insensitive to DPP4 inactivation in vivo. QPCTL has been demonstrated to be a key regulator of monocyte migration to solid tumors [Kaspar Bresser et al., “QPCTL Regulates Macrophage and Monocyte Abundance and Inflammatory Signatures in the Tumor Microenvironment,” Oncoimmunology 11, no. 1 (2022): 2049486, https: / / doi.org / 10.1080 / 2162402x.2022.2049486; Rosa Barreira da Silva et al., “Loss of the Intracellular Enzyme QPCTL Limits Chemokine Function and Reshapes Myeloid Infiltration to Augment Tumor Immunity,” Nature Immunology, 2022, 1-13, https: / / doi.org / 10.1038 / s41590-022-01153-x]. Targeting chemokines has long been pursued as a potential strategy for regulating cell trafficking in different disease scenarios.

[0005] Accordingly, there is a desire to provide potent QPCT / L inhibitors.

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

[0007]

[0008] Among them (Supplementary Information) discloses that the IC 50 of SEN177 for isolated hQC is 53 nM and the IC 50 for isolated QPCTL is 13 nM. Among them (Supplementary Information) discloses that the IC 50 of SEN180 for hQC is 170 nM and the IC 50 for QPCTL is 58 nM.

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

[0010] WO 2018 / 178384 discloses QPCTL inhibitors of the general formula A-B-D-E, which include Examples 1094 and 1095 (Formula (XIIa) on page 123 and Table on page 125):

[0011]

[0012] WO 2018 / 178384 does not disclose any biological data of Examples 1094 and 1095.

[0013] WO 2022 / 086920 discloses QPCTL inhibitors of the following general formula

[0014]

[0015] which include Compounds 3 and 6:

[0016]

[0017] The chemical name of compound 3 disclosed in WO 2022 / 086920 is "1-(1-(6'-chloro-[3,3'-bipyridin]-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-amine", which does not correspond to the chemical structure disclosed therein, but corresponds to an alternative structure in which a fluorine atom is replaced by a chlorine atom:

[0018]

[0019] WO 2022 / 086920 discloses the inhibitory activity IC of compound 3 (including alternative compound 3) and 6 pairs of isolated QPCTLs in

[00343] 50 <1 μM.

[0020] CN 114874186 discloses glutaminyl cyclase isoenzyme inhibitors of the following general formula

[0021]

[0022] which includes Examples 21 and 23 (table on page 17):

[0023]

[0024] The ICs given in CN 114874186 for Examples 21 and 23 50 are 29.22 nM and 11.26 nM, respectively. Detailed Description

[0025] The present invention discloses novel phenylpiperidine derivatives of formula (I)

[0026]

[0027] which are inhibitors of glutaminyl peptide cyclotransferase (QPCT) and glutaminyl peptide cyclotransferase-like protein (QPCTL), and have suitable pharmacological and pharmacokinetic properties to enable them to be used as drugs for treating conditions and / or diseases that can be treated by inhibiting QPCT / L.

[0028] The compounds of the present invention can offer several advantages, such as enhanced potency, cellular potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desired plasma protein binding, enhanced bioavailability, suitable pharmacokinetic profiles, and the possibility of forming stable salts.

[0029] The compounds of the present invention

[0030] The present invention provides novel phenylpiperidine derivatives which are surprisingly potent inhibitors of QPCT and QPCTL (assay A) and potent inhibitors of QPCT / L in cells associated with (but not limited to) lung diseases or cancer (assay B).

[0031] Furthermore, the novel phenylpiperidine derivatives of the present invention have suitable membrane permeability and low in vitro efflux (assay C).

[0032] Therefore, the compounds of the present invention are more suitable for human use.

[0033] The compounds of the present invention differ structurally from SEN177 and SEN180 of J-S, NCB2015 in that a benzene ring rather than a pyridyl ring is attached to the piperidyl ring. Furthermore, a nitrile substituent is attached ortho to the position where the piperidyl ring is attached to the benzene ring. Furthermore, R 1 is not limited to hydrogen, and A represents a substituted heterocyclic system other than a pyridyl group.

[0034] The compounds of the present invention differ structurally from Examples 1094 and 1095 of WO 2018 / 178384 in that a benzene ring rather than a pyridyl ring is attached to the piperidyl ring. Furthermore, a nitrile substituent is attached ortho to the position where the piperidyl ring is attached to the benzene ring. Furthermore, R 1 is not limited to hydrogen, and A represents a substituted heterocyclic system other than a pyridyl group. Furthermore, the 5-membered heterocyclic ring attached to the piperidyl ring at the 4-position relative to the piperidyl nitrogen is an aminothiazolyl ring in Example 1094 and an aminothiadiazolyl in Example 1095, whereas in the compounds of the present invention it is a 3-substituted-4-methyl-4H-1,2,4-triazolyl ring.

[0035] The compounds of the present invention differ structurally from Compound 3 (including alternative Compound 3) and Compound 6 of WO 2022 / 086920 in that a benzene ring rather than a pyridyl ring is attached to the piperidyl ring. Furthermore, a nitrile substituent is attached ortho to the position where the piperidyl ring is attached to the benzene ring. Furthermore, R 1 is not limited to hydrogen, and A represents a substituted heterocyclic system other than a pyridyl group. Furthermore, the 5-membered heterocyclic ring "M" in the general formula of WO 2022 / 086920 is a regioisomer of the 3-substituted 4-methyl-4H-1,2,4-triazolyl ring as 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 in Compound 4 is the 3-substituted 4-methyl-4H-1,2,4-triazolyl ring as in the compounds of the present invention, but it bears an amino group.

[0036] The compounds of the present invention differ structurally from Compounds 21 and 23 in CN114874186 in that the central sulfonamide moiety connecting the piperidyl ring to the benzene ring is replaced by a direct bond. In addition, the nitrile substituent is attached at the ortho position to the piperidyl ring attachment position on the benzene ring. Further, the compounds of the present invention do not contain an amino linker between the benzene ring and other rings.

[0037] These structural differences between the compounds of the present invention and the prior art unexpectedly result in a favorable combination of the following: (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT / L in cells relevant to (but not limited to) lung diseases or cancer, and (iii) appropriate membrane permeability and low in vitro efflux.

[0038] Thus, the compounds of the present invention are superior to those disclosed in the prior art in terms of the combination of the following parameters:

[0039] · Potent inhibition of QPCT and QPCTL (Assay A)

[0040] · Potent inhibition of QPCT / L in cells relevant to (but not limited to) lung diseases or cancer (Assay B)

[0041] · Appropriate membrane permeability and low in vitro efflux (Assay C)

[0042] The present invention provides novel compounds of formula (I)

[0043]

[0044] wherein

[0045] A is A1a, which is a 5- or 6-membered monocyclic heteroaryl ring containing one or two heteroatom members selected from nitrogen, oxygen, and sulfur;

[0046] or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing one to four heteroatom members selected from nitrogen, oxygen, and sulfur, wherein at least one of these heteroatom members is nitrogen;

[0047] or A is selected from the group A1c consisting of:

[0048]

[0049] R 1 is selected from the group R1a consisting of: H, C 1-4 -alkyl and halogen;

[0050] R 2 is selected from the group R2a consisting of: H, halogen, hydroxy, C 1-6 -alkyl, C 2-6 -alkynyl, C3-6 -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-O-C(O)-, H2N-C(O)- and C 1-6 -alkyl-NH-C(O)-;

[0051] or R 2 is a group R2b selected from phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0052] or R 2 is R2c, which is a 5- or 6-membered monocyclic heteroaryl ring containing one or two heteroatom members selected from nitrogen, oxygen and sulfur, wherein R2c is substituted with one or two R 4 substituents;

[0053] or R 2 is R2d, which consists of

[0054]

[0055] R 3 is a group R3a selected from H, C 1-4 -alkyl and halogen;

[0056] R 4 is a group R4a selected from H, C 1-4 -alkyl and halogen;

[0057] or a salt thereof, especially a pharmaceutically acceptable salt thereof.

[0058] Another embodiment of the present invention relates to a compound of formula (I) wherein A is a 5- or 6-membered monocyclic heteroaryl ring A2 containing one or two heteroatom members selected from nitrogen and oxygen; and the substituents R 1 , R 2 , R 3 and R 4 are as defined in any of the foregoing embodiments.

[0059] Another embodiment of the present invention relates to a compound of formula (I), wherein A is a 9- or 10-membered fused bicyclic heteroaryl ring A3 containing one to four heteroatom members selected from nitrogen and oxygen, wherein at least one of the heteroatom members is nitrogen; and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the preceding embodiments.

[0060] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A4 consisting of: pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl-pyrimidinone, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2-dihydropyrimidin-2-one, 3H-imidazo[4,5-b]pyridyl, imidazo[1,2-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyridyl, 1H-[1,2,3]triazolo[4,5-b]pyridyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-c]pyridyl, [1,2,5]oxadiazolo[3,4-b]pyridyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,5]thiadiazolo[3,4-b]pyridyl, 2H-[1,3]dioxoleno[4,5-b]pyridyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[1,5-b]pyridazinyl, 2H,3H,4H-pyrano[2,3-b]pyridyl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl and phthalazinyl; and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the preceding embodiments.

[0061] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A5 consisting of: pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrimidinone and isothiazolyl; and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the preceding embodiments.

[0062] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A6 consisting of: pyridyl, pyridazinyl, 2H-pyrazolo[3,4-b]pyridyl and pyrazolo[1,5-b]pyridazinyl; and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the preceding embodiments.

[0063] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A7 consisting of:

[0064]

[0065] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0066] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A8 consisting of:

[0067]

[0068] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0069] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A9 consisting of:

[0070] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0071] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A10 consisting of:

[0072] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0073] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A11 consisting of:

[0074] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0075] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group A12 consisting of:

[0076] and the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0077] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1b consisting of: H, H3C-, H3CH2C-, H3CH2CH2C-, (H3C)2HC-, Cl and F; and the substituents A, R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0078] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1c consisting of: H, H3C-, Cl and F; and the substituents A, R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0079] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1d consisting of: H, H3C- and F; and the substituents A, R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0080] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1e consisting of: H; and the substituents A, R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0081] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1 is selected from the group R1f consisting of: H3C-; and the substituents A, R 2 、R 3 and R 4 are as defined in any of the previous embodiments.

[0082] Another embodiment of the present invention relates to a compound of formula (I), wherein R 1Select the group R1g consisting of the following: F; and the substituents A, R 2 , R 3 and R 4 are as defined in any of the foregoing embodiments.

[0083] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2A, which is selected from the group R2e consisting of: 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-O-C(O)-, H2N-C(O)- and C 1-4 -alkyl-NH-C(O)-;

[0084] Or R2A is selected from the group R2b consisting of: phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0085] Or R2A is a 5- or 6-membered monocyclic heteroaryl ring R2c containing one or two heteroatom members selected from nitrogen, oxygen and sulfur, wherein R2c is substituted with one or two R 4 substituents;

[0086] Or R2A is R2d, which consists of:

[0087]

[0088] And the substituents A, R 1 , R 3 and R 4 are as defined in any of the foregoing embodiments.

[0089] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2B, which is selected from the group R2e consisting of: H, halogen, hydroxy, C 1-4 -alkyl, C 2-4 -alkynyl, C 3-4 -cycloalkyl, F 1-3 -fluoro-C1-4 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-O-C(O)-, H2N-C(O)- and C 1-4 -alkyl-NH-C(O)-;

[0090] or R2B is selected from the group consisting of R2b: phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0091] or R2B is a 5-membered monocyclic heteroaryl ring R2f containing one or two heteroatom members selected from nitrogen and oxygen, wherein R2f is substituted with one or two R 4 substituents;

[0092] or R2B is R2d, which consists of

[0093]

[0094] and the substituents A, R 1 , R 3 and R 4 are as defined in any of the foregoing embodiments.

[0095] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2C, which is selected from the group consisting of R2e: 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-O-C(O)-, H2N-C(O)- and C 1-4 -alkyl-NH-C(O)-;

[0096] or R2C is selected from the group R2b consisting of: phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0097] or R2C is R2g, which is selected from:

[0098]

[0099] wherein R2g is substituted with one or two R 4 substituents;

[0100] or R2C is R2d, which consists of:

[0101]

[0102] and the substituents A, R 1 , R 3 and R 4 are as defined in any of the foregoing embodiments.

[0103] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2D, which is selected from the group R2h consisting of: H, F, Cl, hydroxyl, 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-O-C(O)-, H2N-C(O)- and C 1-4 -alkyl-NH-C(O)-;

[0104] or R2D is selected from the group R2b consisting of phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0105] or R2D is R2g, which is selected from:

[0106]

[0107] wherein R2g is substituted with one or two R 4 substituents;

[0108] Or R2D is R2d, which consists of:

[0109]

[0110] And the substituents A, R 1 、R 3 and R 4 are as defined in any of the foregoing embodiments.

[0111] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2E, which is selected from the group R2i consisting of: H, F, Cl, hydroxy, methyl, tert-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-O-C(O)-, H2N-C(O)-, H3C-NH-C(O)-,

[0112] Or R2E is selected from the group R2j consisting of phenyl, m-chlorophenyl, benzyl, phenoxy and benzyloxy;

[0113] R2E is R2g, which is selected from:

[0114]

[0115] wherein R2g is substituted with H or methyl;

[0116] Or R2E is R2d, which consists of:

[0117]

[0118] And the substituents A, R 1 and R 3 are as defined in any of the foregoing embodiments.

[0119] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2F, which is selected from the group R2i consisting of: H, F, Cl, hydroxy, methyl, tert-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-O-C(O)-, H2N-C(O)-, H3C-NH-C(O)-,

[0120] or R2F is selected from the group R2j consisting of: phenyl, m-chlorophenyl, benzyl, phenoxy and benzyloxy;

[0121] or R2F is R2g, which is selected from the group consisting of:

[0122]

[0123] wherein R2g is substituted with H or methyl;

[0124] or R2F is R2d, which consists of:

[0125]

[0126] and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0127] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2G, which is selected from the group R2k consisting of: H, F, Cl, methyl, tert-butyl, F3C-, F3C-C(CH3)2-, H3C-O-, F2HC-O- and

[0128] or R2G is selected from the group R2b consisting of phenyl, benzyl, phenoxy and benzyloxy, wherein R2b is substituted with one or two R 4 substituents;

[0129] and the substituents A, R 1 , R 3 and R 4 are as defined in any of the preceding embodiments.

[0130] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2H, which is selected from the group R2k consisting of: H, F, Cl, methyl, tert-butyl, F3C-, F3C-C(CH3)2-, H3C-O-, F2HC-O- and

[0131] or R2H is selected from the group R2j consisting of: phenyl, m-chlorophenyl, benzyl, phenoxy and benzyloxy;

[0132] and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0133] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2is R2J, which is selected from the group R2m consisting of: Cl, methyl, H3C-O-, F2HC-O-, and and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0134] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2K, which is selected from the group R2n consisting of: tert-butyl, F3C-, and F3C-C(CH3)2-; and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0135] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2L selected from H and the group R2b, and the group R2b consists of phenyl, benzyl, phenoxy, and benzyloxy, wherein R2b is substituted with one or two R 4 ; and the substituents A, R 1 , R 3 and R 4 are as defined in any of the preceding embodiments.

[0136] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2M, which is selected from the group R2p consisting of phenyl and m-chlorophenyl; and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0137] Another embodiment of the present invention relates to a compound of formula (I), wherein R 2 is R2N selected from H; and the substituents A, R 1 and R 3 are as defined in any of the preceding embodiments.

[0138] Another embodiment of the present invention relates to a compound of formula (I), wherein R 3 is selected from the group R3b consisting of H, methyl, and F; and the substituents A, R 1 , R 2 and R 4 are as defined in any of the preceding embodiments.

[0139] Another embodiment of the present invention relates to a compound of formula (I), wherein R 3 is selected from the group R3c consisting of H; and the substituents A, R 1 , R 2 and R 4 are as defined in any of the preceding embodiments.

[0140] Another embodiment of the present invention relates to a compound of formula (I), wherein R 3 is a group R3d selected from the group consisting of methyl; and the substituents A, R 1 , R 2 and R 4 are as defined in any of the foregoing embodiments.

[0141] Another embodiment of the present invention relates to a compound of formula (I), wherein R 3 is a group R3e selected from the group consisting of F; and the substituents A, R 1 , R 2 and R 4 are as defined in any of the foregoing embodiments.

[0142] Another embodiment of the present invention relates to a compound of formula (I), wherein R 4 is a group R4b selected from the group consisting of H, methyl, Cl and F; and the substituents A, R 1 , R 2 and R 3 are as defined in any of the foregoing embodiments.

[0143] Another embodiment of the present invention relates to a compound of formula (I), wherein R 4 is a group R4c selected from the group consisting of H; and the substituents A, R 1 , R 2 and R 3 are as defined in any of the foregoing embodiments.

[0144] Another embodiment of the present invention relates to a compound of formula (I), wherein R 4 is a group R4d selected from the group consisting of methyl; and the substituents A, R 1 , R 2 and R 3 are as defined in any of the foregoing embodiments.

[0145] Another embodiment of the present invention relates to a compound of formula (I), wherein R 4 is a group R4e selected from the group consisting of F; and the substituents A, R 1 , R 2 and R 3 are as defined in any of the foregoing embodiments.

[0146] Another embodiment of the present invention relates to a compound of formula (I), wherein R 4 is a group R4f selected from the group consisting of Cl-; and the substituents A, R 1 , R 2 and R 3 are as defined in any of the foregoing embodiments.

[0147] Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-a)

[0148]

[0149] wherein the substituents A, R 2 、R 3 and R 4 are as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-b)

[0150]

[0151] wherein the substituents A, R 2 、R 3 and R 4 are as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-c)

[0152]

[0153] wherein the substituents A, R 2 、R 3 and R 4 are as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-d)

[0154]

[0155] wherein the substituents R 1 、R 2 、R 3 and R 4 are as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-e)

[0156]

[0157] wherein the substituents R 1 、R 2 and R 4 are as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has formula (I-f)

[0158]

[0159] wherein the substituents R 1 、R 2 、R 3 and R4 is as defined in any of the foregoing embodiments. Another embodiment of the present invention relates to a compound of formula (I) above, which has the formula (I-g)

[0160]

[0161] wherein the substituents R 1 、R 2 and R 4 are as defined in any of the foregoing embodiments.

[0162] Another embodiment of the present invention relates to a compound of formula (I) above, which has the formula (I-h)

[0163]

[0164] wherein the substituents R 1 、R 2 and R 4 are as defined in any of the foregoing embodiments.

[0165] Further preferred embodiments of the compound of formula (I) cover embodiments (EMB-1) to (EMB-20) of Table 1 below, wherein the substituents are as defined above.

[0166] Table 1: Further Preferred Embodiments

[0167]

[0168]

[0169] For example, the compound of embodiment EMB-1 has a combination of the general formula group R1d defined for R 1 above and other general formula groups defined for other substituents in formula (I) in the same row of the table. Similarly, it applies to other variables included in the general formula.

[0170] Particularly preferred are compounds of formula (I) selected from the following:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Particularly preferred are the compounds of formula (I) selected from: 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.

[0181] Particularly preferred are the compounds of formula (I) selected from: 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.

[0182] The present invention provides novel phenylpiperidine derivatives of formula (I), which are surprisingly potent QPCT / L inhibitors.

[0183] Another aspect of the present invention refers to compounds of formula (I), which surprisingly have potent inhibition of QPCT / L in cells associated with (but not limited to) lung diseases or cancer.

[0184] Another aspect of the present invention refers to compounds of formula (I), which are surprisingly potent cellular QPCT / L inhibitors with appropriate membrane permeability and low in vitro efflux.

[0185] Another aspect of the present invention refers to a pharmaceutical composition comprising at least one compound of formula (I) and optionally one or more inert carriers and / or diluents.

[0186] Yet another aspect of the present invention refers to compounds of formula (I) for the prevention and / or treatment of conditions associated with QPCT / L inhibition.

[0187] Another aspect of the present invention refers to a process for the preparation of the compounds of the present invention.

[0188] Those skilled in the art will appreciate other aspects of the present invention directly from the foregoing and the following description and examples.

[0189] Terms and Definitions Used

[0190] General Definitions

[0191] Terms not explicitly defined herein shall be given the meaning that would be ascribed to them by a person skilled in the art based on the disclosure and the context. However, unless specified to the contrary, the following terms as used in the specification have the indicated meanings and adhere to the following conventions.

[0192] In the groups, radicals or moieties defined below, the number of carbon atoms is usually indicated before the group, e.g., C 1-6 Alkyl means an alkyl group having 1 to 6 carbon atoms. Generally, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., a person skilled in the art can see the point of attachment of the group to the molecule from the free valence of the group itself. For a combined group containing two or more sub-groups, the last named sub-group is the point of attachment of the group, e.g., the substituent "aryl-C 1-3 -alkylene-" means aryl bonded to the C 1-3 -alkyl- group, and the latter of the substituents is bonded to the parent nucleus or to the group to which the substituent is attached.

[0193] If the compounds of the present invention are described by chemical names or described as chemical formulas, in case of any inconsistency, the chemical formula shall prevail. An asterisk may be used in the sub-formula to indicate the bond as defined connecting to the parent nuclear molecule.

[0194] The atomic numbering of substituents starts from the atom closest to the parent nucleus or to the group to which the substituent is attached.

[0195] For example, the term "3-carboxypropyl-group" represents the following substituent:

[0196]

[0197] wherein the carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" groups represent the following groups:

[0198]

[0199] An asterisk may be used in the sub-formula to indicate the bond as defined connecting to the parent nuclear molecule.

[0200] As used herein, the term "substituted" means that one or more hydrogens on a specified atom are replaced by a group selected from a 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 combination with a chemical moiety rather than a single atom, such as "substituted alkyl", "substituted aryl", etc.

[0201] Unless otherwise indicated, throughout the specification and the appended claims, given chemical formulas and names shall cover tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of individual enantiomers, mixtures of diastereomers or mixtures of any of the foregoing forms in different proportions (if such isomers and enantiomers exist), and their solvates (e.g., hydrates).

[0202] Unless otherwise indicated, the "pharmaceutically acceptable salts" as more particularly defined hereinafter shall cover their solvates (e.g., hydrates).

[0203] Generally, substantially pure stereoisomers can be obtained according to the synthetic principles known to those skilled in the art, for example, by separating the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, for example, by resolving the racemic form or by synthesis starting from optically active starting materials and / or using chiral reagents.

[0204] The enantiomerically pure compounds or intermediates of the present invention can be prepared via asymmetric synthesis, for example, by preparing and subsequently separating appropriate diastereomeric compounds or intermediates, which can 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).

[0205] In addition, it is known to those skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example, by chromatographically separating the corresponding racemic mixtures on a chiral stationary phase; or by using an appropriate resolving agent to resolve the racemic mixture, for example, by forming diastereomeric salts of the racemic compound with an optically active acid or base, subsequently resolving the salts and releasing the desired compound from the salts; or by derivatizing the corresponding racemic compound with an optically active chiral auxiliary reagent, subsequently separating the diastereomers and removing the chiral auxiliary group; or by kinetic resolution of the racemate (e.g., by enzymatic resolution); by enantioselective crystallization from a mass of enantiomorphic crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0206] As used herein, the phrase "pharmaceutically acceptable" means those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human tissue within the scope of reasonable medical judgment, and are without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0207] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines), basic or organic salts of acidic residues (such as carboxylic acids), and the like.

[0208] By way of example, such salts include those formed from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Other pharmaceutically acceptable salts can be formed using cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0209] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms 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.

[0210] Salts of other acids (such as trifluoroacetate salts) other than those mentioned above (e.g., salts that can be used for purifying or isolating the compounds of the present invention) are also part of the present invention.

[0211] The term halogen means fluorine, chlorine, bromine, and iodine.

[0212] The term "C 1-n -alkyl" (wherein n is an integer selected from 2, 3, 4, 5, or 6 (preferably 4, 5, or 6), alone or in combination with other groups) represents an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5 -alkyl encompasses the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-.

[0213] The term "C 2-m -alkynyl" is used for the group "C 2-m -alkyl" in which m is an integer selected from 3, 4, 5 or 6 (preferably 4, 5 or 6), provided that at least two carbon atoms of the group are bonded to each other by a triple bond.

[0214] The term "C 3-k -cycloalkyl" (where k is an integer selected from 3, 4, 5, 7 or 8 (preferably 4, 5 or 6), alone or in combination with other groups) represents a cyclic, saturated, unbranched hydrocarbon group having from 3 to k carbon atoms. By way of example, the term C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0215] The term "halogen" added to an "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsaturated) defines an alkyl, alkylene or cycloalkyl in which one or more hydrogen atoms are replaced by a halogen atom, where the halogen atom is selected from fluorine, chlorine or bromine (preferably fluorine and chlorine, particularly preferably fluorine). Examples include: H2FC-, HF2C-, F3C-.

[0216] The term "monoheteroaryl ring" means a monocyclic aromatic ring system that contains one or more heteroatoms selected from N, O or S and consists of 5 to 6 ring atoms.

[0217] The term "monoheteroaryl ring" is intended to include all possible isomeric forms.

[0218] Thus, the term "monoheteroaryl ring" includes the following exemplary structures (which are not described as groups as each form may optionally be covalently linked to any atom as long as the appropriate valence is maintained):

[0219]

[0220] The term "fused bicyclic heteroaryl ring" means a bicyclic aromatic ring system that contains one or more heteroatoms selected from N, O or S and consists of 9 to 10 ring atoms. 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 (which are not described as groups as each form may optionally be covalently linked to any atom as long as the appropriate valence is maintained):

[0221]

[0222] The term pyridyl refers to the group of the following ring:

[0223]

[0224] The term pyridazinyl refers to the group of the following ring:

[0225]

[0226] The term pyrimidinyl refers to a group of the following ring:

[0227]

[0228] The term 1,2-dihydropyrimidin-2-one group refers to a group of the following ring:

[0229]

[0230] The term pyrazolyl refers to a group of the following ring:

[0231]

[0232] The term thiazolyl refers to a group of the following ring:

[0233]

[0234] The term isothiazolyl refers to a group of the following ring:

[0235]

[0236] The term oxazolyl refers to a group of the following ring:

[0237]

[0238] The term isoxazolyl refers to a group of the following ring:

[0239]

[0240] The term 3H-imidazo[4,5-b]pyridinyl refers to a group of the following ring:

[0241]

[0242] The term imidazo[1,2-a]pyrimidinyl refers to a group of the following ring:

[0243]

[0244] The term 2H-pyrazolo[3,4-b]pyridinyl refers to a group of the following ring:

[0245]

[0246] The term 1H-[1,2,3]triazolo[4,5-b]pyridinyl refers to a group of the following ring:

[0247]

[0248] The term [1,2,4]triazolo[4,3-a]pyrimidinyl refers to a group of the following ring:

[0249]

[0250] The term 1H-pyrazolo[4,3-c]pyridinyl refers to a group of the following ring:

[0251]

[0252] The term [1,2,5]oxadiazolo[3,4-b]pyridinyl refers to a group of the following ring:

[0253]

[0254] The term [1,2,4]triazolo[1,5-a]pyrimidinyl refers to a group of the following ring:

[0255]

[0256] The term [1,2,5]thiadiazolo[3,4-b]pyridinyl refers to a group of the following ring:

[0257]

[0258] The term 2H-[1,3]dioxoleno[4,5-b]pyridinyl refers to a group of the following ring:

[0259]

[0260] The term imidazo[1,2-a]pyrimidinyl refers to a group of the following ring:

[0261]

[0262] The term pyrazolo[1,5-b]pyridazinyl refers to a group of the following ring:

[0263]

[0264] The term 2H,3H,4H-pyrano[2,3-b]pyridinyl refers to a group of the following ring:

[0265]

[0266] The term 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl refers to a group of the following ring:

[0267]

[0268] The term quinolinyl refers to a group of the following ring:

[0269]

[0270] Each of the above-mentioned plurality of terms can be repeatedly used independently of each other for formulas or groups and in the definitions in each case where one of the above-mentioned meanings is present.

[0271] Biological assay

[0272] Evaluation of the inhibitory activity against QPCT and QPCTL

[0273] Assay A: Biochemical QPCT and QPCTL activity assay

[0274] The activity of the compounds of the present invention can be confirmed using the following biochemical enzyme activity assays:

[0275] Monitoring of the QPCT- or QPCTL-dependent conversion of the N-terminal glutamine of CD47 to pyroglutamic acid via MALDI-TOF MS. The test compound was dissolved in 100% DMSO and serially diluted into clear 1,536-well microtiter plates. The enzyme reaction was set up in an assay buffer containing 20 mM Tris pH 7.5, 0.1 mM TCEP, 0.01% BSA, and 0.001% Tween20. 2.5 μL of 2x concentrated QPCTL (internal) or QPCT (Origine#TP700028) enzyme in assay buffer (0.5 nM final concentration, columns 1 - 23) or normal assay buffer (column 24) was added to each well. The plate was incubated in a humidified incubator at 24 °C for 10 min. Subsequently, 2.5 μL of the CD47 peptide substrate surrogate ( 19 QLLFNKTKSVEFTFC 33 )(final concentration: 10 μM for QPCTL / 20 μM for QPCT) was added to each well. The plate was mixed at 1,000 rpm for 30 sec and then incubated in a humidified incubator at 24 °C for 40 min. After incubation, the enzyme reaction was terminated by adding 1 μL of a reagent containing a stable isotope-labeled internal standard peptide 19 [Pyr]LLFN(K)TKSVEFTFC 33 (final concentration 4.0 μM) and SEN177 (final concentration 10 μM). The plate was sealed with a gel foil, mixed at 1,000 rpm for 30 s and stored at room temperature until the preparation of the MALDI target plate. The MALDI target plate was prepared as previously described. Mass spectra were obtained using a rapifleX MALDI-TOF / TOF instrument, which tracked the product ( 19 [Pyr]LLFNKTKSVEFTFC 33 m / z 1,787.9037) and the internal standard ( 19[Pyr]LLFN(K)TKSVEFTFC 33 Signal of the peptide (m / z 1,795.9179). QPCT or QPCTL activity was monitored by calculating the ratio between the product and internal standard signals and then normalizing to high (100% activity) and low (0% activity) controls. Compound potency was determined by fitting the dose-response data to a four-parameter logistic equation.

[0276] Table 2: Biological data of the compounds of the present invention obtained in Assay A.

[0277]

[0278]

[0279]

[0280] Table 3: Biological data of the prior art compounds obtained in Assay A.

[0281]

[0282] Assay B: SIRPα signal assay (using Raji or A549 cells)

[0283] The activity of the compounds of the present invention can be confirmed using the following SIRPα signaling assay, which measures SIRPα engagement induced by CD47 presented via cell-cell interaction. Two cell types were used independently: Raji cell line (a lymphoblastoid human cell line derived from B lymphocytes of a Burkitt's lymphoma patient in 1963) and A549 cells (adenocarcinoma human alveolar basal epithelial cells).

[0284] Dissolve the test compound in 100% DMSO and serially dilute it into a white 384-well microtiter cell culture plate (PerkinElmer #60076780 in the case of Raji assay; PDL-coated plate Greiner #781945 in the case of A549 assay). Add 5000 Raji cells (ATCC #CC86) or 5000 A549 cells (ATCC #CCL-185) in the assay whole cell plating reagent 30 (DiscoverX 93-0563R30B) to each well. Incubate the assay plate at 37 °C, 95% humidity and 5% CO2 for 48 h. Add 15000 reporter cells (Jurkat PathHunter SIRPαV1, DiscoverX #93-1135C19) to each well and incubate the plate at 37 °C, 95% humidity and 5% CO2 for 5 h. Use a multi-channel pipette to add the bioreagent 1 of the PathHunter bioassay detection kit (DiscoverX 93-0001) to each well of the plate, and then incubate at room temperature for 15 min. Then add the assay reagent 2, and subsequently incubate at room temperature for 60 min (incubate in the dark).

[0285] Data analysis is performed using the luminescence signal generated by β-galactosidase in the PathHunter reporter cell line. Luminescence measurements are carried out using a Pherastar multimode microplate reader. Use a 4-parameter sigmoidal dose-response to calculate the dose-response curve and IC 50 data.

[0286] Table 4: Biological data of the compounds of the present invention obtained in Assay B.

[0287]

[0288]

[0289]

[0290] Table 5: Biological data of the prior art compounds obtained in Assay B.

[0291]

[0292] Evaluation of permeability

[0293] Assay C: Permeability in Caco-2 cells

[0294] Caco-2 cells (1 - 2x10 5 cells / 1 cm 2Inoculate in the area) on a filter insert (Costar Transwell polycarbonate or PET filter, 0.4 μm pore size) and culture (DMEM) for 10 to 25 days.

[0295] Dissolve the compound in a suitable solvent (such as DMSO, 1 - 20 mM stock solution). Dilute the stock solution using HTP - 4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare the transport solution (0.1 - 300 μM compound, final DMSO <= 0.5%). Apply the transport solution (TL) to the apical or basolateral donor side respectively to measure A - B or B - A permeability (3 filter replicates). Collect samples from the donor at the start and end of the experiment and also from the receiving side at different time intervals greater than 2 hours for concentration measurement by HPLC - MS / MS or scintillation counting. Replace the sampled receiving volume with fresh receiving solution.

[0296] Efflux ratio (ER) = permeability B - A / permeability A - B

[0297] Table 7: Biological data of the compounds of the present invention obtained in Assay C.

[0298]

[0299]

[0300]

[0301] Table 8: Biological data of the prior art compounds obtained in Assay C.

[0302]

[0303] Evaluation of microsomal clearance

[0304] Microsomal clearance:

[0305] The metabolic degradation of the test compound was determined at 37 °C using pooled liver microsomes from different species. The final incubation volume of 60 μl at each time point contained TRIS buffer (0.1 M) at pH 7.6 at room temperature, magnesium chloride (5 mM), microsomal protein (1 mg / mL for humans and dogs, 0.5 mg / mL for other species), and the test compound at a final concentration of 1 μM. A short pre-incubation was then carried out at 37 °C, the reaction was initiated by adding β-nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH, 1 mM), and the reaction was terminated at different time points by transferring aliquots to the solvent. After centrifugation (10000 g, 5 min), aliquots of the supernatant were assayed by LC-MS / MS to determine the amount of the parent compound. The half-life was determined from the slope of the semi-logarithmic plot of the concentration-time profile.

[0306] The intrinsic clearance (CL_INTRINSIC) can be calculated by considering the amount of protein in the incubation:

[0307] Intrinsic clearance [μl / min / mg protein] = (Ln 2 / (half-life [min] * protein content [mg / ml])) * 1000

[0308] The in vivo intrinsic clearance (CL_INTRINSIC_INVIVO) [ml / min / kg] = (intrinsic clearance [μL / min / mg protein] × MPPGL [mg protein / g liver] × liver factor [g / kg body weight]) / 1000

[0309] Qh [%] = clearance [ml / min / kg] / hepatic blood flow [ml / min / kg])

[0310] Human hepatocyte density: 120x10e 6 cells / g liver

[0311] Human liver factor: 25.7 g / kg body weight

[0312] Human blood flow: 21 ml / (min x kg)

[0313] Evaluation of hepatocyte clearance

[0314] Hepatocyte clearance

[0315] The metabolic degradation of the test compound was determined in human hepatocyte suspensions. After recovery from cryopreservation, the human hepatocytes were diluted in Dulbecco's modified eagle medium (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, 5% human serum) to obtain a final cell density of 1.0x10 6 cells / mL.

[0316] Subsequently, the cells were pre-incubated for 30 minutes in a cell culture incubator (37 °C, 10% CO2), and the test compound solution was added to the hepatocyte suspension to obtain a final test compound concentration of 1 μM and a final DMSO concentration of 0.05%.

[0317] The cell suspension was incubated at 37 °C (cell culture incubator, horizontal shaker), and samples were removed from the incubation at 0, 0.5, 1, 2, 4, and 6 hours. The samples were quenched with acetonitrile (containing internal standard) and centrifuged to precipitate. The supernatant was transferred to a 96-well deep well plate and prepared for determination of the decline of the parent compound by HPLC-MS / MS.

[0318] The percentage of the remaining test compound was calculated using the peak area ratio (test compound / internal standard) at each incubation time point relative to the peak area ratio at the 0-hour time point. The log-transformed data were plotted against the incubation time, and the absolute value of the slope obtained by linear regression analysis was used to estimate the in vitro half-life (T1 / 2).

[0319] The in vitro intrinsic clearance (CLint) was calculated from the in vitro T1 / 2 and using a hepatocyte density of 120x10 6 cells / g liver, a human liver of 25.7 g liver / kg body weight per portion, and the in vitro incubation parameters and scaled to the whole liver using the following equation:

[0320] In vivo intrinsic clearance [mL / min / kg] = (intrinsic clearance [μL / min / 10 6 cells] × hepatocyte density [10 6 cells / g liver] × liver factor [g / kg body weight]) / 1000

[0321] The hepatic in vivo blood clearance (CL) was predicted according to the well-stirred liver model and considering the average hepatic blood flow (QH) of 20.7 mL / min / kg:

[0322] Clearance [mL / min / kg] = Intrinsic clearance in vivo [mL / min / kg] × Hepatic blood flow [mL / min / kg] / (Intrinsic clearance in vivo [mL / min / kg] + Hepatic blood flow [mL / min / kg])

[0323] Results are expressed as a percentage of hepatic blood flow:

[0324] QH [%] = Clearance [mL / min / kg] / Hepatic blood flow [mL / min / kg])

[0325] Evaluation of plasma protein binding

[0326] The equilibrium dialysis technique was used with a Dianorm Teflon dialysis cell (micro 0.2) to determine the approximate in vitro fractional binding of the test compound to plasma proteins. Each dialysis cell consists of a donor chamber and a receptor chamber separated by an ultra-thin semi-permeable membrane with a 5 kDa molecular weight cut-off. A stock solution of each test compound was prepared at 1 mM in DMSO and serially diluted to obtain a final test concentration of 1 μM. Subsequently, a dialysis solution (supplemented with NaEDTA as an anticoagulant) was prepared in plasma, and 200 μl of the test compound dialysis solution in plasma was aliquoted into the donor (plasma) chamber. 200 μl of dialysis buffer (100 mM potassium phosphate (pH 7.4), supplemented with up to 4.7% dextran) was aliquoted into the buffer (receptor) chamber. Incubation was carried out for 2 hours with rotation at 37 °C to establish equilibrium.

[0327] At the end of the dialysis period, aliquots obtained from the donor and receptor chambers were transferred separately to reaction tubes and processed for HPLC-MS / MS analysis. The analyte concentration in the sample aliquots was quantified by HPLC-MS / MS against a calibration curve.

[0328] The percentage of binding was calculated using the following formula:

[0329] Binding % = ((Plasma concentration - Buffer concentration) / Plasma concentration) × 100

[0330] Evaluation of solubility

[0331] Saturated solutions are prepared on a porous plate (the form depends on the robot) by adding an appropriate volume of a selected aqueous medium (usually in the range of 0.25 - 1.5 ml) to each well containing a known amount of solid drug substance (usually in the range of 0.5 - 5.0 mg). The wells are shaken or stirred for a predetermined time period (usually in the range of 2 - 24 h) and then filtered using an appropriate filter membrane (usually a PTFE filter membrane with a pore size of 0.45 μm). The filter membrane absorption is avoided by discarding the first few drops of the filtrate. The amount of the dissolved drug substance is determined by UV spectroscopy. In addition, the pH of the saturated aqueous solution is measured using a glass electrode pH meter.

[0332] Evaluation of the metabolism of human hepatocytes in vitro

[0333] The metabolic pathways of the test compound are studied using primary human hepatocytes in suspension. After recovery from cryopreservation, the human hepatocytes are cultured in Dulbecco's Modified Eagle Medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg / 500 ml hydrocortisone.

[0334] Subsequently, they are pre - cultured for 30 minutes in a cell culture incubator (37 °C, 10% CO2), and the test compound solution is added to the hepatocyte suspension to obtain a final cell density of 1.0*10 6 to 4.0*10 6 cells / ml (depending on the metabolic turnover rate of the compound observed using primary human hepatocytes), a final test compound concentration of 10 μM, and a final DMSO concentration of 0.05%.

[0335] The cells are cultured for 6 hours in a cell culture incubator located on a horizontal shaker, and samples are taken from the culture at 0, 0.5, 1, 2, 4, or 6 hours (depending on the metabolic turnover rate). The samples are quenched with acetonitrile and centrifuged to precipitate the samples. The supernatant is transferred to a 96 - well deep - well plate, evaporated under nitrogen and re - suspended, and then bioanalyzed by liquid chromatography - high - resolution mass spectrometry for the identification of putative metabolites.

[0336] Based on Fourier transform MS n The structures are tentatively assigned based on the data. Metabolites are reported as the percentage of the parent with a threshold of ≥4% in the human hepatocyte culture.

[0337] Evaluation of pharmacokinetic properties

[0338] The test compound is administered intravenously or orally to each test species. Blood samples are collected at several time points after the administration of the test compound, anticoagulated and centrifuged.

[0339] Quantify the concentrations of the analyte-administered compound and / or metabolite in plasma samples. Calculate PK parameters using a non-compartmental method. Normalize AUC and Cmax to a dose of 1 μmol / kg.

[0340] Treatment method

[0341] The present invention relates to compounds of general formula (I) which can be used for the prevention and / or treatment of diseases and / or conditions associated with or modulated by QPCT / L activity, including but not limited to the treatment and / or prevention of cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, and chronic kidney diseases.

[0342] The compounds of general formula (I) can be used for the prevention and / or treatment of the following diseases:

[0343] (1) Pulmonary fibrotic diseases, such as pneumonia or interstitial pneumonia associated with collagen diseases (such as lupus erythematosus, systemic scleroderma, rheumatoid arthritis, polymyositis, and dermatomyositis); idiopathic interstitial pneumonia (such as pulmonary fibrosis (IPF)); non-specific interstitial pneumonia; respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, and lymphocytic interstitial pneumonia; lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pleuroparenchymal elastosis; interstitial lung diseases with known etiology, such as interstitial pneumonia caused by occupational exposure (such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (bird) or other occupational airborne triggers (such as metal dust or mycobacteria)) or due to treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapeutic agents) or granulomatous diseases (such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis); or interstitial pneumonia caused by different etiologies (such as aspiration, inhalation of toxic gases, vapors, bronchitis, or pneumonia) or by heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis, or mucoviscidosis or α-I-antitrypsin deficiency;

[0344] (2) Other fibrotic diseases, such as hepatic bridging fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arteriosclerosis, joint fibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; spontaneous acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis or acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis caused by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, previous exacerbation and drug-induced

[0345] (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid tumors, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer, intestinal cancer, small intestine cancer, colorectal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, genitourinary cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, seminoma, teratoma, liver cancer, kidney cancer, bladder cancer, urothelial carcinoma, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma, bone sarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, thyroid follicular cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, schwannoma, glioblastoma or sarcoma, gastrointestinal cancer, gastric cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colorectal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin lymphoma (NHL), urothelial carcinoma or peritoneal cancer;

[0346] (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airway, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases (such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria); vasculitis (such as necrotizing, cutaneous and allergic vasculitis) or erythema nodosum;

[0347] (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multisystem atrophy or prion diseases.

[0348] Accordingly, in another embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0349] Furthermore, the invention relates to the use of a compound of formula (I) for the prevention and / or treatment of diseases and / or conditions associated with or modulated by QPCT / L activity.

[0350] Furthermore, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment and / or prevention of cancer, fibrotic diseases, neurodegenerative diseases, atherosclerosis, infectious diseases, chronic kidney diseases.

[0351] In addition, 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 the following diseases: (1) Pulmonary fibrosis diseases, such as pneumonia or interstitial pneumonia associated with collagen diseases (such as lupus erythematosus, systemic scleroderma, rheumatoid arthritis, polymyositis and dermatomyositis); idiopathic interstitial pneumonia (such as pulmonary fibrosis (IPF)); non-specific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia; lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pleuroparenchymal elastosis; interstitial lung diseases with known etiology, such as interstitial pneumonia caused by occupational exposure (such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (birds)) or other occupational airborne triggers (such as metal dust or mycobacteria) or due to treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapeutic agents) or granulomatous diseases (such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis); or interstitial pneumonia caused by different etiologies (such as aspiration, inhalation of toxic gases, vapors, bronchitis or pneumonia) or interstitial pneumonia caused by heart failure, X-ray, radiation, chemotherapy, Boeck's sarcoid (M. boeck) or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis or alpha-I-antitrypsin deficiency;

[0352] (2) Other fibrosis diseases, such as hepatic bridging fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arteriosclerosis, joint fibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis; spontaneous acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis or acute exacerbation of pulmonary fibrosis and progressive pulmonary fibrosis caused by infection, microaspiration, surgical lung biopsy, surgical resection, bronchoscopy (BAL, cryobiopsy), air pollution, previous exacerbation and drug-induced;

[0353] (3) Leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), lymphoma, B-cell lymphoma, T-cell lymphoma, Hodgkin's disease, non-Hodgkin lymphoma (NHL), hairy cell lymphoma, Burkitt lymphoma, multiple myeloma (MM), myelodysplastic syndrome, solid tumors, lung cancer, adenocarcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mediastinal cancer, peritoneal cancer, mesothelioma, gastrointestinal cancer, gastric cancer, stomach cancer, intestinal cancer, small intestine cancer, colorectal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, colorectal cancer, leiomyosarcoma, breast cancer, gynecological cancer, genitourinary cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, seminoma, teratoma, liver cancer, kidney cancer, bladder cancer, urothelial cancer, biliary tract cancer, pancreatic cancer, exocrine pancreatic cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma (HNSCC), skin cancer, squamous carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanoma, malignant melanoma, xeroderma pigmentosum, keratoacanthoma, bone cancer, osteosarcoma, bone sarcoma, rhabdomyosarcoma, fibrosarcoma, thyroid cancer, follicular thyroid cancer, adrenal cancer, nervous system cancer, brain cancer, astrocytoma, neuroblastoma, glioma, schwannoma, glioblastoma or sarcoma, gastrointestinal cancer, gastric cancer, stomach cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC), breast cancer, colorectal cancer, intestinal cancer, colorectal cancer, colon cancer, colon adenocarcinoma, colon adenoma, rectal cancer, ovarian cancer, pancreatic cancer, exocrine pancreatic cancer, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, lymphoma, B-cell lymphoma, non-Hodgkin lymphoma (NHL), urothelial cell carcinoma or peritoneal cancer;

[0354] (4) Inflammatory, autoimmune or allergic diseases and conditions, such as asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, non-allergic asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, emphysema; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases (such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria); vasculitis (such as necrotizing, cutaneous and allergic vasculitis) or erythema nodosum;

[0355] (5) Neurodegenerative disorders, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multisystem atrophy or prion diseases.

[0356] In another aspect, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating and / or preventing the above-mentioned diseases and conditions.

[0357] In another aspect, the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for preparing a medicament for treating and / or preventing the above-mentioned diseases and conditions.

[0358] In yet another aspect of the present invention, the present invention relates to a method for treating or preventing the above-mentioned diseases and conditions, which 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.

[0359] Combination therapy

[0360] The compounds of the present invention may further be combined with one or more, preferably one other therapeutic agent. According to one embodiment, the other therapeutic agent is selected from therapeutic agents useful for treating diseases or conditions as described above (specifically, diseases associated with cancer, fibrotic diseases, Alzheimer's disease, atherosclerosis, infectious diseases, chronic kidney diseases and autoimmune diseases).

[0361] Other therapeutic agents suitable for such combinations specifically include, for example, those that enhance the therapeutic effect of one or more active substances on one of the mentioned indications and / or permit a reduction in the dose of one or more active substances.

[0362] Accordingly, the compounds of the present invention can be combined with one or more other therapeutic agents selected from the following: chemotherapy, targeted cancer therapy, cancer immunotherapy, radiation, anti-fibrotic agents, cough suppressants, anti-inflammatory agents, anti-atopic dermatitis agents, and bronchodilators.

[0363] Chemotherapy is a type of cancer therapy that uses one or more chemical anti-cancer drugs (such as cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, etc.). Examples include folic acid (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, azacytidine, gemcitabine, alkylating agents, anti-mitotic agents, taxanes, and other prior art or standard therapeutic compounds.

[0364] 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, for example, drugs such as inhibitors of growth factors (such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4), and hepatocyte growth factor), tyrosine kinases, KRAS, BRAF, BCR-ABL, mTOR, cyclin-dependent kinases, or MDM2.

[0365] Cancer immunotherapy is a class of therapies that use substances to stimulate or inhibit the immune system to help the body fight cancer. Cancer immunotherapy includes therapeutic antibodies, such as anti-Her2 antibodies, anti-EGFR antibodies, and anti-PDGFR antibodies; anti-GD2 (ganglioside G2) antibodies. Examples include dinutuximab, olaratumab, trastuzumab, pertuzumab, ertumaxomab, cetuximab, necitumumab, nimotuzumab, panitumumab, or rituximab. Cancer immunotherapy also includes therapeutic antibodies that are checkpoint inhibitors, such as anti-PD1, anti-PD-L1 antibodies, or CTLA4 inhibitors. Examples include atezolizumab, avelumab, and durvalumab, ipilimumab, nivolumab, or pembrolizumab. Cancer immunotherapy also includes drugs that target (inhibit) the CD47-SIRPα signaling axis, such as drugs that bind to CD47 or SIRPα. Non-limiting examples include antibodies (such as anti-CD47 antibodies and anti-SIRPα antibodies) and recombinant Fc fusion proteins (such as CD47-Fc and SIRPα-Fc). Cancer immunotherapy also includes STING targeting agents or T cell engagers (such as blinatumomab).

[0366] Anti-fibrotic agents are (for example) nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors (such as roflumilast or a specific PDE4b inhibitor like BI1015550), autotaxin inhibitors (such as GLPG-1690 or BBT-877); connective tissue growth factor (CTGF) blocking antibodies (such as pamrevlumab); B-cell activating factor receptor (BAFF-R) blocking antibodies (such as lanalumab), α-V / β-6 blocking inhibitors (such as BG-00011 / STX-100), recombinant pentraxin-2 (PTX-2) (such as PRM-151); c-Jun-N-terminal kinase (JNK) inhibitors (such as CC-90001); galectin-3 inhibitors (such as TD-139); G-protein coupled receptor 84 (GPR84) inhibitors; G-protein coupled receptor 84 / G-protein coupled receptor 40 dual inhibitors (such as PBI-4050), Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitors (such as KD-025), heat shock protein 47 (HSP47) small interfering RNA (such as BMS-986263 / ND-L02-s0201); Wnt pathway inhibitors (such as SM-04646); LD4 / PDE3 / 4 inhibitors (such as tipelukast); recombinant immunomodulatory domain of histidyl-tRNA synthetase (HARS) (such as ATYR-1923), prostaglandin synthase inhibitors (such as ZL-2102 / SAR-191801); 15-hydroxy-eicosapentaenoic acid (15-HEPE, such as DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors (such as PAT-1251), PXS-5382 / PXS-5338; phosphoinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) dual inhibitors (such as HEC-68498); calpain inhibitors (such as BLD-2660); mitogen-activated protein kinase kinase kinase (MAP3K19) inhibitors (such as MG-S-2525); chitinase inhibitors (such as OATD-01), mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) inhibitors (such as MMI-0100); transforming growth factor βI (TGF-βI) small interfering RNA (such as TRKZSO / BNC-1021); or lysophosphatidic acid receptor antagonists (such as BMS986278).

[0367] The dosage of the combination ligands mentioned above is usually from 1 / 5 of the normal recommended minimum dosage to 1 / 1 of the maximum normal recommended dosage.

[0368] Accordingly, in another aspect, the present invention relates to the use of a combination of a compound of the present invention and one or more other therapeutic agents described above and below for the treatment of diseases or conditions that can be affected by or mediated by QPCT / L, particularly the diseases or conditions described above and below.

[0369] In another 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, which comprises the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents.

[0370] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents for the treatment of a disease or condition in a patient in need thereof that is affected by the inhibition of QPCT / L.

[0371] In 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, which comprises the step of administering to a patient (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more other therapeutic agents described above and below.

[0372] The use of the compound of the present invention in combination with other therapeutic agents can be carried out simultaneously or at staggered times.

[0373] Both the compound of the present invention and one or more other therapeutic agents can be present together in one formulation (such as a tablet or capsule) or separately in two identical or different formulations (such as in the form of a so-called kit-of-parts).

[0374] Accordingly, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and one or more other therapeutic agents described above and below, and optionally one or more inert carriers and / or diluents.

[0375] Other features and advantages of the present invention can be understood from the following more detailed examples, which illustrate the principles of the present invention by way of example.

[0376] Preparation

[0377] 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. Preferably, the compounds are obtained in a manner similar to the preparation methods more fully explained below (specifically as described in the experimental section). In some cases, the order of performing the reaction steps can be varied. Variations of the reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0378] Those skilled in the art will understand the general methods for preparing the compounds of the present invention after studying the following schemes. Any functional groups of the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again using methods well-known to those skilled in the art at appropriate stages within the reaction sequence.

[0379] The compounds of the present invention are prepared by the synthetic methods described below, where the substituents of the general formula have the meanings given above. These methods are intended to illustrate the present invention and not to limit the subject matter and the scope of the claimed compounds to these examples. If the preparation of the starting compounds is not described, they are commercially available or can be prepared in a manner similar to the known compounds or methods described herein. The substances described in the literature are prepared according to the disclosed synthetic methods. Abbreviations are defined as in the example section.

[0380] The compounds of formula (I) can be prepared as shown in Scheme I below.

[0381] Scheme I:

[0382]

[0383] In Scheme I, N-methyltriazolylpiperidine (Int.B; R1 = H, F, Me) undergoes a nucleophilic aromatic substitution reaction with aryl fluoride (Int.C). The reaction is typically carried out at high temperature (100 - 130 °C). The intermediate (Int.D) is then subjected to a Suzuki cross-coupling with a heteroarylboronic acid derivative in the presence of a suitable catalyst (e.g., Pd(dppf)Cl2)) and a suitable base (e.g., aqueous K2CO3) at high temperature (e.g., 100 °C) to provide the compound of formula (I).

[0384] Scheme II:

[0385]

[0386] Scheme II describes an alternative route for obtaining the compound of formula (I). The heteroarylboronic acid derivative can be prepared from the corresponding halide (R2R3A-X, where X is Cl, Br, I) using a suitable boronating agent (such as bis(pinacolato)diboron) in the presence of a suitable catalyst (such as Pd(dppf)Cl2·CH2Cl2) and a suitable base (such as KOAc) at a high temperature (e.g., 100 °C). The heteroarylboronic acid derivative (R2R3A-B(OR)2) can be isolated as the pinacol borate ester (R = CMe2 and the two Rs together with O, B, O form a five-membered ring) or boric acid (R = H) depending on the stability of the borate ester, or it can be used for subsequent Suzuki coupling after adding Int.D, a suitable catalyst (such as Pd(dppf)Cl2·CH2Cl2) and a suitable base (such as aqueous Na2CO3). If isolated, the boronic acid derivative can be converted into an example of formula I described in Scheme I.

[0387] Scheme III:

[0388] For X = C-F, C-Me:

[0389]

[0390] The intermediate Int.B (where R1 = Me, F) can be prepared by treating the corresponding piperidyl ester (Int.E) equipped with a suitable protecting group (PG, such as BOC) with a suitable hydrazine source (such as N2H4·H2O) at a high temperature (e.g., 50 °C). The obtained hydrazide (Int.F) is then activated with DMF / DMA at a high temperature (e.g., 50 °C) and subsequently treated with methylamine at a high temperature (e.g., 90 °C) to produce a triazole derivative (Int.G). The intermediate Int.B (where R1 = Me, F) can be obtained by cleaving the protecting group under suitable conditions (e.g., for PG = BOC, 4N HCl / dioxane; for PG = Bn, Pd / C under H2 atmosphere). The intermediate Int.B (where R1 = H) is obtained from a commercial source (CAS No: 297172-18-0).

[0391] Examples

[0392] Preparation

[0393] 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, using the methods described in "Comprehensive Organic Transformations", 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010 and "March’s Advanced Organic Chemistry", 7th Edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained in a manner similar to the preparation methods more fully explained below, specifically as described in the experimental section. In some cases, the order in which the reaction schemes are implemented can be changed. Variations of these reactions known to those skilled in the art but not described in detail herein can also be used. Those skilled in the art will understand the general methods for preparing the compounds of the present invention after studying the schemes below. The starting compounds are commercially available or can be prepared by the methods described in the literature or herein, or can be prepared in a similar or analogous manner. Prior to carrying out the reactions, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups can be cleaved again at appropriate stages within the reaction sequence using methods well known to those skilled in the art and described in the literature (for example, in the literature of "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" can be used interchangeably and denote a temperature of about 20 °C, for example, between 19 °C and 24 °C.

[0394] Abbreviations:

[0395]

[0396]

[0397] Preparation of Intermediates

[0398]

[0399] tert-Butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate

[0400] Suspend 4-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (160 g, 0.58 mol) in ethanol (640 mL) in a round-bottom flask. Add hydrazine hydrate (70.6 mL, 1.16 mol) to the mixture at ambient temperature. Heat the reaction mixture to 50 °C and stir for 12 h. After cooling to ambient temperature, concentrate the mixture under reduced pressure to give tert-butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate with a purity of 80%.

[0401] C 11 H 20 FN3O3 (M = 261.3 g / mol)

[0402] ESI-MS: 284.2 [M+Na]+

[0403] Rt(HPLC): 0.615 min (method A)

[0404] tert-Butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

[0405] Mix tert-butyl 4-fluoro-4-(hydrazinecarbonyl)piperidine-1-carboxylate (135 g, 0.413 mol, 80% purity) with dioxane (945 mL) in a round-bottom flask. Add N,N-dimethylformamide dimethyl acetal (137 mL, 1.03 mol) to the mixture at ambient temperature. Heat the reaction mixture to 50 °C and stir for 1 h. Add a solution of methylamine (299 g, 30% in EtOH, 2.89 mol) and acetic acid (165 mL, 2.89 mol) to the mixture. Heat the resulting reaction mixture to 90 °C and stir for 11 h. Concentrate the mixture under reduced pressure. Purify the residue by column chromatography (SiO2, PE / EtOAc gradient 20:1 to 0:1) to obtain tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate.

[0406] C 13 H 21 FN4O2 (M = 284.3 g / mol)

[0407] ESI-MS: 285.1 [M+H]+

[0408] Rt(HPLC): 0.766 min (method A)

[0409] Intermediate I: 4-Fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine

[0410] In a round-bottom flask, tert-butyl 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (90 g, 0.316 mol) was combined with MeOH (90 mL). A solution of HCl (4 M in MeOH, 450 mL, 1.79 mol) was added slowly at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 h. The desired product was collected by filtration, washed with MeOH and dried to afford 4-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine hydrochloride.

[0411] The hydrochloride (13.5 g) was added to a solution of ammonia in MeOH (7 N, 150 mL) and purified by chromatography (Biotage SNAP Cartridge KP-NH, gradient DCM / MeOH 4:1 to 7:3).

[0412] C8H 13 FN4 (M = 184.2 g / mol)

[0413] ESI-MS: 185 [M+H]+

[0414] Rt (HPLC): 0.20 min (Method B)

[0415] 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. According to the procedure described in Int. I, the hydrochloride form can be converted to the free piperidine or piperazine.

[0416] Intermediate II.1

[0417]

[0418] 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) was stirred at 130 °C for 18 h. The reaction mixture was diluted with ACN and purified directly by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to afford Intermediate II.1.

[0419] C 15 H 16 BrN5 (M = 346.2 g / mol)

[0420] ESI-MS: 346 / 348 [M+H]+

[0421] Rt (HPLC): 0.40 min (Method C)

[0422]

[0423] Intermediate III.1

[0424]

[0425] To a stirred solution of 3-bromo-5-(1-methyl-1H-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]dichloropalladium(II) (Pd(dppf)Cl2, 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 H2O. The organic phase was separated and concentrated to afford crude Int. III.1, which was used in the subsequent step without further purification.

[0426] C 15 H 20 BN3O2 (M = 203.0 g / mol)

[0427] ESI-MS: 204 [M+H]+

[0428] Rt (HPLC): 0.20 min (Method C)

[0429] Intermediate III.2

[0430]

[0431] 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]dichloropalladium(II) (Pd(dppf)Cl2, 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 H2O. The organic phase was separated and concentrated to afford crude Int. III.2, which was used in the subsequent step without further purification.

[0432] C6H4BF4NO3 (M = 224.9 g / mol)

[0433] ESI-MS: 225 / 226 [M+H]+

[0434] Rt (HPLC): 0.45 min (Method C)

[0435] Synthesis of Intermediates III.3a and III.3b

[0436]

[0437] 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

[0438] 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 methyl iodide (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 containing 0.1% NH3) to afford the corresponding methylated regioisomers.

[0439] 6-Bromo-1-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine:

[0440] C6H5BrN4 (M = 213.0 g / mol)

[0441] ESI-MS: 213 / 215 [M+H]+

[0442] Rt (HPLC): 0.36 min (Method B)

[0443] 6-Bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine (co-elutes with regioisomer 6-bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine):

[0444] C6H5BrN4 (M = 213.0 g / mol)

[0445] ESI-MS: 213 / 215 [M+H]+

[0446] Rt (HPLC): 0.44 min (Method B)

[0447] Intermediate III.3a

[0448] 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(II) 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 H2O, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to afford Intermediate III.3a.

[0449] C6H7BN4O2 (M = 178.0 g / mol)

[0450] ESI-MS: 179 [M+H]+

[0451] Rt (HPLC): 0.21 min (Method C)

[0452] Intermediate III.3b

[0453] 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 min, followed by the addition of bis(triphenylphosphine)palladium(II) chloride (CAS: 13965-03-2) (51 mg, 0.07 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 and redissolved in MeCN and H2O, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to afford a 1:1 mixture of Intermediate III.3b and the corresponding regioisomeric boronic acid, which was used without further purification.

[0454] C6H7BN4O2 (M = 178.0 g / mol)

[0455] ESI-MS: 179 [M+H]+

[0456] Rt(HPLC): 0.21 min (Method C)

[0457] Synthesis of Intermediate III.4

[0458]

[0459] 3-Bromo-4-methyl-5-(1H-pyrazol-1-yl)pyridine

[0460] A solution of 3-bromo-5-fluoro-4-methylpyridine (0.25 mL, 1.2 mmol), pyrazole (87 mg, 1.2 mmol) and Cs2CO3 (1.22 g, 3.75 mmol) in DMSO (2 mL) was stirred at 90 °C for 18 h. After cooling to ambient temperature, the mixture was diluted with MeCN / H2O and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient containing 0.1% NH3) to obtain 3-bromo-4-methyl-5-(1H-pyrazol-1-yl)pyridine.

[0461] C9H8BrN3 (M = 238.1 g / mol)

[0462] ESI-MS: 238 / 240 [M+H]+

[0463] Rt(HPLC): 0.52 min (Method C)

[0464] Intermediate III.4

[0465] 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(II) 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 and redissolved in MeCN and H2O, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient containing 0.1% TFA) to obtain Int.III.4.

[0466] C9H 10 BN3O2 (M = 203.0 g / mol)

[0467] ESI-MS: 204 [M+H]+

[0468] Rt(HPLC): 0.22 min (Method C)

[0469] Synthesis of Intermediate III.5

[0470]

[0471] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine

[0472] 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 mixture was treated with additional methanesulfonic acid (1.3 mL, 19.8 mmol). The reaction mixture was cooled to ambient temperature, concentrated, redissolved in MeCN / H2O and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to afford 5-bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine.

[0473] C 10 H 12 BrN3 (M = 254.1 g / mol)

[0474] ESI-MS: 254 / 256 [M+H]+

[0475] Rt(HPLC): 0.50 min (Method C)

[0476] Intermediate III.5

[0477] 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, then [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (190 mg, 0.23 mmol) was added. After stirring at 110 °C for 4 h, the mixture was cooled to ambient temperature, concentrated, redissolved in MeCN / H2O and purified by preparative HPLC (Xbridge C18, ACN / water gradient with 0.1% TFA) to afford Int. III.5.

[0478] C 10 H 14BN3O2 (M = 219.0 g / mol)

[0479] ESI-MS: 220 [M+H]+

[0480] Rt (HPLC): 0.27 min (Method C)

[0481] Synthesis of Intermediate III.6

[0482]

[0483] 3-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-iodopyridine

[0484] The 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), Cs2CO3 (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 purified directly via preparative HPLC (Xbridge C18, ACN / water gradient containing 0.1% TFA) to obtain 3-(3,5-dimethyl-1H-pyrazol-1-yl)-5-iodopyridine.

[0485] C 10 H 10 IN3 (M = 299.1 g / mol)

[0486] ESI-MS: 300 [M+H]+

[0487] Rt (HPLC): 0.53 min (Method C)

[0488] Intermediate III.6

[0489] 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]-dichloropalladium(II) (Pd(dppf)Cl2, 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 H2O. The organic phase was concentrated to obtain crude Int.III.6, which was used in the subsequent step without further purification.

[0490] C 10 H 12 BN3O2 (M = 217.0 g / mol)

[0491] ESI-MS: 218 [M+H]+

[0492] Rt (HPLC): 0.28 min (Method C)

[0493] Synthesis of Intermediate III.7

[0494]

[0495] 2-Azido-5-bromopyridine-3-carbaldehyde

[0496] 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) was added sodium azide (367 mg, 5.6 mmol). After stirring for 45 min, the reaction mixture was diluted with H2O, and the precipitate was collected by filtration and dried to afford 2-azido-5-bromopyridine-3-carbaldehyde, which was used in the subsequent step without further purification.

[0497] C6H3BrN4O (M = 227.0 g / mol)

[0498] ESI-MS: 227 / 229 [M+H]+

[0499] Rt (HPLC): 0.25 min (Method C)

[0500] 5-Bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine

[0501] 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 molecular sieve. 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 / H2O and purified by preparative HPLC (Xbridge C18, MeCN / water gradient containing 0.1% NH3) to afford 5-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-2H-pyrazolo[3,4-b]pyridine.

[0502] C 10H9BrF3N3 (M = 308.1 g / mol)

[0503] ESI-MS: 308 / 310 [M+H]+

[0504] Rt (HPLC): 0.62 min (Method B)

[0505] Intermediate III.7

[0506] Purge 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 (639 mg, 6.51 mmol) in 1,4-dioxane (6 mL) with Ar for 15 min, then add bis(triphenylphosphine)palladium(II) chloride (CAS: 13965-03-2) (141 mg, 0.20 mmol). Stir the mixture at 60 °C for 10 h, cool the mixture to ambient temperature, concentrate, redissolve in MeCN / H2O and purify by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to obtain Int.III.7.

[0507] C 10 H 11 BF3N3O2 (M = 273.0 g / mol)

[0508] ESI-MS: 274 [M+H]+

[0509] Rt (HPLC): 0.32 min (Method C)

[0510] Synthesis of Intermediates III.8a and III.8b

[0511]

[0512] 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

[0513] 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). The reaction mixture was stirred at 90 °C for 18 h, cooled to ambient temperature and purified directly by preparative HPLC (Xbridge C18, MeCN / H2O gradient containing 0.1% NH3) to afford the corresponding benzylated regioisomers.

[0514] 1-Benzyl-6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine:

[0515] C 12 H9BrN4 (M = 289.1 g / mol)

[0516] ESI-MS: 289 / 291 [M+H]+

[0517] Rt (HPLC): 0.52 min (method C)

[0518] 2-Benzyl-6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine (co-eluting with the regioisomer 3-benzyl-6-bromo-3H-[1,2,3]triazolo[4,5-b]pyridine):

[0519] C 12 H9BrN4 (M = 289.1 g / mol)

[0520] ESI-MS: 289 / 291 [M+H]+

[0521] Rt (HPLC): 0.59 min (method C)

[0522] Intermediate III.8a

[0523] 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(II) 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 H2O and purified by preparative HPLC (Xbridge C18, MeCN / H2O gradient containing 0.1% TFA) to afford Intermediate III.8a.

[0524] C 12 H 11 BN4O2 (M = 254.1 g / mol)

[0525] ESI-MS: 255 [M+H]+

[0526] Rt (HPLC): 0.38 min (Method C)

[0527] Intermediate III.8b

[0528] 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 min, followed by the addition of bis(triphenylphosphine)palladium(II) chloride (CAS: 13965-03-2) (75 mg, 0.11 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 H2O, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to afford Intermediate III.8b.

[0529] C 12 H 11 BN4O2 (M = 254.1 g / mol)

[0530] ESI-MS: 255 [M+H]+

[0531] Rt (HPLC): 0.41 min (Method C)

[0532] Intermediate III.9

[0533]

[0534] A mixture of 2,3-diamino-5-bromopyridine (200 mg, 1.01 mmol) and pivalic acid (2.09 g, 20.2 mmol) was heated uniformly to 120 °C over 10 h, to 140 °C over 10 h and to 150 °C over 20 h with vigorous stirring. After cooling to ambient temperature, the mixture was diluted with EtOAc and the resulting solution was washed three times with aqueous K2CO3 (2 M). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to give the desired product.

[0535] C 10 H 12 BrN3 (M = 254.1 g / mol)

[0536] ESI-MS: 254 / 256 [M+H]+

[0537] Rt (HPLC): 0.62 min (method D)

[0538] Synthesis of Intermediate III.10

[0539]

[0540] 6-Bromo-2-tert-butylimidazo[1,2-a]pyrimidine

[0541] Ethanol (2 mL) was 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 was stirred at 90 °C for 5 days. After cooling to ambient temperature, the mixture was loaded onto and purified by column chromatography (SiO2, DCM / MeOH gradient) to give the desired product.

[0542] C 10 H 12 BrN3 (M = 254.1 g / mol)

[0543] ESI-MS: 254 / 256 [M+H]+

[0544] Rt (HPLC): 0.28 min (method C)

[0545] Intermediate III.10

[0546] 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)diboron (215.0 mg, 850 mmol) and potassium acetate (167 mg, 1.70 mmol) were added and the resulting mixture was degassed by passing an argon stream through the mixture. 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 and suspended in a mixture of water and ACN and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product.

[0547] C 10 H 14 BN3O2 (M = 219.1 g / mol)

[0548] ESI-MS: 220 [M+H]+

[0549] Rt (HPLC): 0.25 min (Method C)

[0550] Synthesis of Intermediate III.11

[0551]

[0552] 6-Bromo-2-trifluoromethylimidazo[1,2-a]pyrimidine

[0553] Ethanol (2 mL) was 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 was stirred at 90 °C for 5 days. After cooling to ambient temperature, the mixture was loaded onto and purified by column chromatography (SiO2, DCM / MeOH gradient) to give the desired product.

[0554] C7H3BrF3N3 (M = 266.1 g / mol)

[0555] ESI-MS: 266 / 268 [M+H]+

[0556] Rt (HPLC): 0.38 min (Method C)

[0557] Intermediate III.11

[0558] 6-Bromo-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine (82 mg, 0.308 mmol) was added to 1,4-dioxane (1.0 mL). Bis(pinacolato)diboron (117 mg, 462 mmol) and potassium acetate (90.6 mg, 0.925 mmol) were added and the resulting mixture was degassed by passing an argon stream through the mixture. 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 and suspended in a mixture of water and can, and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product.

[0559] C7H5BF3N3O2 (M = 230.9 g / mol)

[0560] ESI-MS: 232 [M+H]+

[0561] Rt(HPLC): 0.29 min (Method C)

[0562] Synthesis of Intermediate III.12

[0563]

[0564] 5-Bromo-2-fluoro-3-{[(2-(trimethylsilyl)ethoxy]methoxy}pyridine

[0565] 5-Bromo-2-fluoropyridin-3-one (4.00 g, 20.4 mmol) and diisopropylethylamine (5.28 g, 40.8 mmol) were added to DCM (100 mL) and 2-(trimethylsilyl)ethoxymethyl chloride (3.94 g, 22.5 mmol) was added dropwise via syringe with stirring. The resulting reaction mixture was stirred at ambient temperature for 90 minutes. The mixture was concentrated and diluted with EtOAc and water. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the desired product.

[0566] C 11 H 17 BrFNO2Si (M = 322.2 g / mol)

[0567] ESI-MS: 322 / 324 [M+H]+

[0568] Rt(HPLC): 0.90 min (Method C)

[0569] Intermediate III.12

[0570] 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 min. [1,1′-Bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2; CAS: 72287-26-4) (476 mg, 0.652 mmol) was added and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated at 80 °C for 6 h. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The organic phase was separated and dried over Na2SO4. Carbon was added, the mixture was filtered through diatomaceous earth and concentrated to give the desired product which was used in the next step without further purification.

[0571] C 17 H 29 BFNO4Si (M = 369.3 g / mol)

[0572] ESI-MS: 370 [M+H]+

[0573] Rt (HPLC): 0.90 min (Method C)

[0574] Synthesis of Intermediate III.13

[0575]

[0576] 5-Bromo-2-(dibromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine

[0577] To a stirred solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (6.00 g, 28.8 mmol) in DMF (200 mL) at 0 °C was added sodium hydride (1.50 g, 34.5 mmol; 55% in mineral oil). 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 / H2O and purified directly by preparative HPLC (Xbridge C18, MeCN / water gradient containing 0.1% TFA) to afford 5-bromo-2-(bromodifluoromethyl)-2H-pyrazolo[3,4-b]pyridine.

[0578] C7H3Br2F2N3 (M = 326.9 g / mol)

[0579] ESI-MS: 326 / 328 / 330 [M+H]+

[0580] Rt (HPLC): 0.56 min (Method C)

[0581] 5-Bromo-2-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridine

[0582] 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) was stirred at 50 °C for 18 h. The reaction mixture was concentrated, redissolved in DCE (40 mL), and stirred at 80 °C for 18 h. The resulting mixture was concentrated and loaded onto it and purified by column chromatography (SiO2, DCM / MeOH gradient 100 / 0 to 1 / 1) to give the title compound.

[0583] C7H3BrF3N3 (M = 266.0 g / mol)

[0584] ESI-MS: 266 / 268 [M+H]+

[0585] Rt (HPLC): 0.47 min (Method C)

[0586] Intermediate III.13

[0587] 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 min, followed by the addition of [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2; CAS: 72287-26-4) (102 mg, 0.14 mmol). The mixture was stirred at 90 °C for 5 h, cooled to ambient temperature, concentrated, redissolved in H2O / MeCN, and purified by preparative HPLC (Xbridge C18, MeCN / water gradient with 0.1% TFA) to afford Int.III.13.

[0588] C7H5BF3N3O2 (M = 230.9 g / mol)

[0589] ESI-MS: 232 [M+H]+

[0590] Rt (HPLC): 0.30 min (Method C)

[0591] Synthesis of Intermediate III.14

[0592]

[0593] 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine

[0594] 5-tert-Butyl-4H-1,2,4-triazol-3-amine (400 mg, 2.71 mmol) and 2-bromomalonaldehyde (646 mg, 4.07 mmol) were added to acetic acid (5 mL). The reaction mixture was stirred at 60 °C for 3 h, concentrated, neutralized with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic phases were dried (Na2SO4), concentrated, and purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the title compound.

[0595] C9H 11 BrN4 (M = 255.1 g / mol)

[0596] ESI-MS: 255 / 257 [M+H]+

[0597] Rt (HPLC): 0.84 min (Method D)

[0598] Intermediate III.14

[0599] 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(II) 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 / H2O / TFA, and purified by preparative HPLC (SunFire C18, MeCN / H2O gradient containing 0.1% TFA) to afford Intermediate III.14.

[0600] C9H 13 BN4O2 (M = 220.0 g / mol)

[0601] ESI-MS: 221 [M+H]+

[0602] Rt (HPLC): 0.34 min (Method C)

[0603] Synthesis of Intermediate III.15

[0604]

[0605] 6-Bromo-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine

[0606] 5-(Trifluoromethyl)-4H-1,2,4-triazol-3-amine (500 mg, 3.12 mmol) and 2-bromomalonaldehyde (744 mg, 4.69 mmol) were added to acetic acid (5 mL). After stirring at 60 °C for 3 h, the reaction mixture was concentrated, neutralized with saturated aqueous NaHCO3 and extracted three times with DCM. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography (SiO2, CyH / EtOAc gradient) to give the title compound.

[0607] C6H2BrF3N4 (M = 267.0 g / mol)

[0608] ESI-MS: 267 / 269 [M+H]+

[0609] Rt(HPLC): 0.78 min (Method D)

[0610] Intermediate III.15

[0611] 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(II) 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 plug of silica gel. The filtrate was concentrated, redissolved in MeCN / H2O and purified by preparative HPLC (XBridge C18, MeCN / H2O gradient containing 0.1% TFA) to afford Intermediate III.15.

[0612] C6H4BF3N4O2 (M = 231.9 g / mol)

[0613] ESI-MS: 233 [M+H]+

[0614] Rt(HPLC): 0.32 min (Method C)

[0615] Synthesis of Intermediates III.16 and III.17

[0616]

[0617] 7-Bromo-1H-pyrazolo[4,3-c]pyridine (500 mg, 2.42 mmol) and potassium carbonate (838 mg, 6.06 mmol) were added to THF (10 mL). After 10 minutes, benzyl bromide (353 μL, 2.91 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered, concentrated and purified by preparative HPLC (Xbridge C18, water / MeCN gradient containing 0.1% NH3) to afford the desired separated product.

[0618] Int.III.16:

[0619] C 13 H 10 BrN3 (M = 288.1 g / mol)

[0620] ESI-MS: 288 / 290 [M+H]+

[0621] Rt (HPLC): 1.06 min (Method E)

[0622] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1H), 8.53 (s, 1H), 8.51 (s, 1H), 7.23 - 7.35 (m, 3H), 7.08 - 7.13 (m, 2H), 5.98 (s, 2H).

[0623] Int.III.17:

[0624] C 13 H 10 BrN3 (M = 288.1 g / mol)

[0625] ESI-MS: 288 / 290 [M+H]+

[0626] Rt (HPLC): 0.91 min (Method E)

[0627] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 7.31 - 7.42 (m, 5H), 5.76 (s, 2H).

[0628] Synthesis of Intermediate III.18

[0629]

[0630] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (1.00 g, 4.72 mmol) and zinc(II) trifluoromethanesulfonate (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 h. Zinc(II) trifluoromethanesulfonate (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 h. After cooling to ambient temperature, the reaction mixture was diluted with water and the organic phase was separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4, DMF (10 mL) was added and the mixture was concentrated. The residual DMF solution was purified by preparative HPLC (Sunfire C18, water / ACN gradient containing 0.1% NH3) to afford the desired product as well as other regioisomers from the trifluoromethylation reaction.

[0631] C8H5BrF3N3 (M = 280.0 g / mol)

[0632] ESI-MS: 280 / 282 [M+H]+

[0633] Rt (HPLC): 1.01 min (Method D)

[0634] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (d, J = 2.3 Hz, 1H), 8.53 (dq, J = 2.2, 1.1 Hz, 1H), 4.35 (q, J = 0.9 Hz, 3H)

[0635] Synthesis of Intermediate III.19

[0636]

[0637] 3-(3-Chlorophenyl)pyridazine

[0638] Under a nitrogen atmosphere, (3-chlorophenyl)boronic acid (0.50 g, 3.19 mmol), KOAc (0.72 g, 7.36 mmol) and Pd(dppf)Cl2*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 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc gradient) to afford 3-(3-chlorophenyl)pyridazine.

[0639] C 10 H7ClN2 (M = 190.6 g / mol)

[0640] ESI-MS: 191 [M+H]+

[0641] Rt(HPLC): 0.54 min (method F)

[0642] Methyl 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate

[0643] To a mixture of NH2OHSO3 (3.63 g, 32.1 mmol) in H2O (20 mL) was added saturated aqueous NaHCO3 solution (40 mL) to adjust the pH to 6 and heated to 70 °C. 3-(3-Chlorophenyl)pyridazine (4.00 g, 21.0 mmol) was added to the mixture. The resulting reaction mixture was stirred at 70 °C for 2 h. After cooling to ambient temperature, the pH was adjusted to pH 7 and methyl propiolate (0.45 g, 5.35 mmol) in DCM (20 mL) was added to the mixture. The resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. 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) to afford methyl 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate.

[0644] C 14 H 10 ClN3O2 (M = 287.7 g / mol)

[0645] ESI-MS: 288 [M+H]+

[0646] Rt(HPLC): 0.74 min (method F)

[0647] 6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylic acid

[0648] 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 eq, 0.88 g, 20.9 mmol) and water (30 mL). The resulting reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous phase 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 afford the desired compound which was used in the next step without further purification.

[0649] C 13 H8ClN3O2 (M = 273.7 g / mol)

[0650] ESI-MS: 274 [M+H]+

[0651] Rt(HPLC): 0.64 min (method F)

[0652] 3-bromo-6-(3-chlorophenyl)pyrazolo[1,5-b]pyridazine

[0653] 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) was added NBS (1.94 g, 10.9 mmol). The resulting reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (2x100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc gradient) to afford the desired product.

[0654] C 12 H7BrClN3 (M = 308.6 g / mol)

[0655] ESI-MS: 308 / 310 [M+H]+

[0656] Rt(HPLC): 0.81 min (method F)

[0657] Intermediate III.19

[0658] 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) under a nitrogen atmosphere, and 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).

[0659] C 18 H 19 BClN3O2 (M = 355.6 g / mol)

[0660] ESI-MS: 356 [M+H]+

[0661] Rt(HPLC): 0.90 min (method F)

[0662] Synthesis of Intermediate III.20

[0663]

[0664] 5-Bromo-2-tert-butyl-3-chloro-2H-pyrazolo[3,4-b]pyridine

[0665] 5-Bromo-2-tert-butyl-2H-pyrazolo[3,4-b]pyridine (1.00 g, 3.93 mmol) was added to acetonitrile (15 mL) and N-chlorosuccinimide (0.58 g, 4.33 mmol) was added at ambient temperature. The resulting reaction mixture was stirred at 85 °C for 12 h. After cooling to ambient temperature, the mixture was concentrated and suspended in water. Then it was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc gradient) to give the desired product.

[0666] C 10 H 11 BrClN3 (M = 288.6 g / mol)

[0667] ESI-MS: 288 / 290 [M+H]+

[0668] Rt(HPLC): 0.80 min (method R)

[0669] Intermediate III.20

[0670] The 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 N2 for 10 min, and then [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (202 mg, 0.23 mmol) was added. The mixture was stirred at 100 °C for 12 h, cooled to ambient temperature, concentrated and suspended in water. The mixture was extracted with EtOAc (3x), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (Welch Xtimate C18, acetonitrile / water gradient containing 10 mM NH4HCO3) to obtain Int.III.4.

[0671] C 10 H 13 BClN3O2 (M = 253.5 g / mol)

[0672] ESI-MS: 254 [M+H]+

[0673] Rt (HPLC): 0.71 min (method S)

[0674] Intermediate IV.1

[0675]

[0676] 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 H2O, 2 mL, 4.0 mmol). The resulting mixture was purged with argon for 15 min, then [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (0.091 g, 125 μmol) was added, and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated to 90 °C and stirred for 3 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were treated with charcoal, then filtered through diatomaceous earth and concentrated. The residue was used in the next step without further purification.

[0677] C 12 H7FN2 (M = 198.2 g / mol)

[0678] EI-MS: 199 [M+H]+

[0679] Rt (HPLC): 0.28 min (Method C)

[0680] Intermediate V.1

[0681]

[0682] 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

[0683] To a mixture of Intermediate II.1 (2.50 g, 7.22 mmol) and Intermediate III.12 (approx. 65% purity, 5.07 g, 8.9 mmol) in 1,4-dioxane (30 mL) was added cesium carbonate (2 M in H2O, 11.8 mL, 21.7 mmol). The resulting mixture was purged with argon for 15 min, then tetrakis(triphenylphosphine)palladium(0) (0.834 g, 0.722 mmol) was added and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated to 80 °C and stirred for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with diethyl ether, washed with semi-concentrated NaCl solution, dried over Na2SO4 and concentrated. The crude product was used in the next step without further purification.

[0684] C 26 H 33 FN6O2Si (M = 508.7 g / mol)

[0685] EI-MS: 509 [M+H]+

[0686] Rt (HPLC): 0.68 min (Method C)

[0687] Intermediate V.1

[0688] 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 (approx. 65% purity, 6.77 g, 8.65 mmol) was added to 1,4-dioxane (60 mL) and a solution of HCl in 1,4-dioxane (4 M, 16.6 mL, 66.5 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 66 h. The mixture was concentrated and the residue was purified by preparative HPLC (XBridge C18, ACN / water gradient 0.1% NH3) to give the desired product.

[0689] C 20 H 19FN6O (M = 378.4 g / mol)

[0690] EI-MS: 379 [M+H]+

[0691] Rt (HPLC): 0.42 min (Method C)

[0692] Intermediate V.2

[0693]

[0694] 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 H2O, 302 μL, 604 μmol). The resulting mixture was purged with argon for 15 min, then [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (22.1 mg, 30.2 μmol) was added and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated to 100 °C and stirred for 1 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, then filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC (XBridge C18, ACN / water gradient with 0.1% TFA) to give the desired compound.

[0695] C 21 H 19 FN8 (M = 402.4 g / mol)

[0696] ESI-MS: 403 [M+H]+

[0697] Rt (HPLC): 0.75 min (Method E)

[0698] Preparation of the Final Compound

[0699] Example 1

[0700]

[0701] 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 H2O, 3.2 mL, 6.5 mmol). The resulting mixture was purged with argon for 15 min, [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Pd(dppf)Cl2, CAS: 72287-26-4) (158 mg, 0.22 mmol) was added, and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated to 100 °C and stirred for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with H2O and saturated aqueous NaHCO3, then dried over Na2SO4 and concentrated. The crude product was purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to give the desired compound.

[0702] C 20 H 19 FN6 (M = 362.4 g / mol)

[0703] ESI-MS: 363 [M+H]+

[0704] Rt (HPLC): 0.42 min (method C)

[0705] 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)

[0706] The following examples were prepared with minor modifications to the procedure of Example 1:

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720] Example 34

[0721]

[0722] Intermediate V.1 (60.0 mg, 159 mmol) was added to DMF (1.0 mL) and cesium carbonate (155 mg, 476 mmol), and bromocyclobutane (98.2 mg, 634 mmol) was added. The resulting reaction mixture was heated to 100 °C and stirred at this temperature for 3 h. After cooling to ambient temperature, the reaction mixture was diluted with water and MeOH and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) to give the desired product.

[0723] C 24 H 25 FN6O (M = 432.5 g / mol)

[0724] ESI-MS: 433 [M+H]+

[0725] Rt (HPLC): 0.53 min (Method C)

[0726] 11H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1H), 7.77 (dd, J = 7.7, 1.6 Hz, 1H), 7.72 (t, J = 1.8 Hz, 1H), 7.49 - 7.56 (m, 2H), 7.27 (t, J = 7.7 Hz, 1H), 4.90 (quin, J = 7.1 Hz, 1H), 3.58 (s, 3H), 3.20 - 3.28 (m, 2H), 2.91 - 3.02 (m, 2H), 2.85 (tt, J = 11.2, 3.8 Hz, 1H), 2.43 - 2.51 (m, 2H), 2.08 - 2.20 (m, 2H), 1.55 - 1.86 (m, 6H)

[0727] The following examples were prepared with only minor modifications to the procedure of Example 34:

[0728]

[0729] Example 37

[0730]

[0731] In a microwave vial, intermediate V.1 (50.0 mg, 132 μmol) and potassium carbonate (45.7 mg, 330 μmol) were added to a mixture of DMF and water (9:1, 1.5 mL) and sodium chlorodifluoroacetate (42.0 mg, 264 μmol) was added. The vial was sealed and the resulting reaction mixture was stirred at 120 °C for 3 h. After cooling to ambient temperature, a second portion of sodium chlorodifluoroacetate (42.0 mg, 264 μmol) was added. The vial was sealed and the resulting reaction mixture was stirred at 120 °C for 2 h. After cooling to ambient temperature, the mixture was diluted with water and MeOH, filtered and purified by preparative HPLC (SunFire C18, ACN / water gradient with 0.1% TFA).

[0732] C 21 H 19 F3N6O (M = 428.4 g / mol)

[0733] ESI-MS: 429 [M+H]+

[0734] Rt (HPLC): 0.64 min (method H)

[0735] 11H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.16 (t, J = 1.6 Hz, 1H), 8.04 (dd, J = 9.4, 1.5 Hz, 1H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 72.5 Hz, 1H), 3.72 (s, 3H), 3.18 - 3.28 (m, 2H), 2.94 - 3.11 (m, 3H), 1.79 - 1.90 (m, 2H), 1.55 - 1.70 (m, 2H).

[0736] Example 38

[0737]

[0738] In a microwave vial, intermediate V.1 (50.0 mg, 132 μmol) was added to DMSO (0.5 mL) 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) were added under an argon atmosphere. The vial was sealed and the resulting reaction mixture was stirred at 100 °C for 45 min and at 130 °C for 3 h. After cooling to ambient temperature, the mixture was diluted with DCM and washed with semi-concentrated aqueous ammonia solution. The organic phase was dried, concentrated and purified by preparative HPLC (X-Bridge C18, ACN / water gradient containing 0.1% NH3) to give the desired product.

[0739] C 26 H 23 FN6O (M = 454.5 g / mol)

[0740] ESI-MS: 445 [M + H]+

[0741] Rt (HPLC): 0.86 min (Method I)

[0742] 11H NMR (400 MHz, DMSO-d6) δ = 8.33 (s, 1H), 8.03 (t, J = 1.8 Hz, 1H), 7.76 (dd, J = 7.7, 1.6 Hz, 1H), 7.59 (dd, J = 9.8, 2.0 Hz, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.39 - 7.46 (m, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.17 - 7.23 (m, 3H), 3.61 (s, 3H), 3.13 - 3.21 (m, 2H), 2.88 - 2.99 (m, 2H), 2.84 (tt, J = 11.4, 3.6 Hz, 1H), 1.72 - 1.82 (m, 2H), 1.55 - 1.68 (m, 2H).

[0743] Example 41

[0744]

[0745] 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 min. [1,1'-Bis-(diphenylphosphino)-ferrocene]-dichloro-palladium(II) dichloride DCM complex (Pd(dppf)Cl2·CH2Cl2, CAS: 95464-05-4) (14.1 mg, 0.017 mmol) was added and the mixture was purged with argon for an additional 3 min. The reaction mixture was heated to 100 °C and stirred for 4 h. After cooling to ambient temperature, Intermediate II.1 (60.0 mg, 0.173 mmol), Na2CO3 solution (2 M in H2O, 260 μL, 0.520 mmol) and (Pd(dppf)Cl2·CH2Cl2, CAS: 95464-05-4) (14.1 mg, 0.017 mmol) were added. The mixture was purged with argon for 3 min again and heated to 100 °C and stirred at 100 °C for 4 h. After cooling to ambient temperature, the reaction solution was diluted with a mixture of water / ACN, acidified with TFA, filtered and purified by preparative HPLC (SunFire C18, ACN / water gradient containing 0.1% TFA) to give the desired compound.

[0746] C 23 H 21 F3N8 (M = 466.5 g / mol)

[0747] ESI-MS: 467 [M+H]+

[0748] Rt (HPLC): 0.78 min (Method D)

[0749] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.21 - 8.27 (m, 1H), 7.82 (dd, J = 7.7, 1.5 Hz, 1H), 7.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 4.38 (s, 3H), 3.69 (s, 3H), 3.23 - 3.34 (m, 2H), 2.94 - 3.13 (m, 3H), 1.73 - 1.84 (m, 2H), 1.47 - 1.63 (m, 2H)

[0750] The following examples were prepared with only minor modifications to the procedure of Example 41:

[0751]

[0752]

[0753]

[0754] Example 55

[0755]

[0756] Intermediate V.2 (20.0 mg, 49.7 μmol) was added to THF (2.0 mL) and a solution of NaHMDS in THF (1.0 M, 49.7 μL, 49.7 μmol). The mixture was stirred at ambient temperature for 5 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (7.4 μL, 49.7 μmol) was added and the resulting reaction mixture was stirred at ambient temperature for 1 h. A second portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.4 μL, 49.7 μmol) was added and the reaction mixture was stirred for 2 h. The mixture was filtered and purified by preparative HPLC (XBridge C18, water / ACN gradient containing 0.1% NH3) to give the desired product.

[0757] C 23 H 20 F4N8 (M = 484.5 g / mol)

[0758] ESI-MS: 485 [M + H]+

[0759] Rt (HPLC): 0.65 min (Method J)

[0760] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J = 2.3 Hz, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.63 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 5.57 (q, J = 9.0 Hz, 2H), 3.68 (d, J = 1.5 Hz, 3H), 3.12 - 3.23 (m, 4H), 2.02 - 2.20 (m, 4H).

[0761] The following examples were prepared by only slightly modifying the operation of Example 55:

[0762]

[0763] Example 58

[0764]

[0765] Example 54 (30.0 mg, 60.8 μmol) and potassium carbonate (25.2 mg, 182 μmol) were added to DMF (2.0 mL), and methyl iodide (13.0 mg, 91.2 μmol) was added. The reaction mixture was stirred at ambient temperature for 4 h. It was diluted with ACN and water and purified directly by preparative HPLC (XBridge C18, ACN / water containing 0.1% TFA) to give the desired product.

[0766] C 20 H 20 FN7O (M = 393.4 g / mol)

[0767] ESI-MS: 394 [M + H]+

[0768] Rt (HPLC): 0.36 min (Method C)

[0769] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, J = 3.0 Hz, 1H), 8.56 (s, 1H), 8.43 (d, J = 3.2 Hz, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.63 (dd, J = 7.7, 1.6 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 3.76 (d, J = 1.5 Hz, 3H), 3.51 (s, 3H), 3.33 - 3.45 (m, 2H), 3.13 - 3.22 (m, 2H), 2.08 - 2.29 (m, 4H)

[0770] The following examples were prepared according to the procedure of Example 58:

[0771]

[0772] Example 65

[0773]

[0774] Intermediate IV.1 (100 mg, 0.505 mmol) was 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) were added. The resulting reaction mixture was stirred at 160 °C for 18 h. After cooling to ambient temperature, the mixture was diluted with water and purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3), and additionally purified by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% TFA) to give the desired product.

[0775] C 21 H 22 N6 (M = 358.4 g / mol)

[0776] ESI-MS: 359 [M+H]+

[0777] Rt (HPLC): 0.38 min (Method K)

[0778] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.68 (dd, J = 4.9, 1.5 Hz, 1H), 8.01 (dt, J = 7.9, 1.8 Hz, 1H), 7.80 (dd, J = 7.7, 1.6 Hz, 1H), 7.63 (dd, J = 7.8, 5.0 Hz, 1H), 7.59 (dd, J = 7.6, 1.6 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.92 - 3.13 (m, 4H), 2.04 - 2.16 (m, 2H), 1.60 - 1.72 (m, 2H), 1.30 (s, 3H).

[0779] Synthesis of Example 80

[0780]

[0781] 5-{3-Cyano-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl}pyridine-3-carboxylic acid

[0782] To a stirred solution of Example 27 (150 mg, 0.37 mmol) in MeOH (1.5 mL) was added 2 M aqueous lithium hydroxide (0.56 mL, 1.1 mmol). After stirring for 2 h, the reaction was neutralized with 4 M aqueous hydrochloric acid and concentrated. The resulting residue was suspended in H2O and filtered to afford the title compound.

[0783] C 21 H 20 N6O2 (M = 388.4 g / mol)

[0784] ESI-MS: 389 [M+H]+

[0785] Rt (HPLC): 0.44 min (Method H)

[0786] Example 80

[0787] 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 min, the reaction mixture was treated with 2 M methylamine / MeOH (0.14 mL, 0.27 mmol) and stirred for an additional 18 h. Purification by preparative HPLC (XBridge C18, ACN / water gradient containing 0.1% NH3) directly afforded Example 80.

[0788] C 22 H 23 N7O (M = 401.5 g / mol)

[0789] ESI-MS: 402 [M+H]+

[0790] Rt (HPLC): 0.47 min (Method L)

[0791] 11H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J = 2.2 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.67 (q, J = 4.1 Hz, 1H), 8.28 (s, 1H), 8.20 (t, J = 2.2 Hz, 1H), 7.80 (dd, J = 7.7, 1.6 Hz, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 3.56 (s, 3H), 3.16 - 3.23 (m, 2H), 2.91 - 3.02 (m, 2H), 2.77 - 2.88 (m, 4H), 1.70 - 1.78 (m, 2H), 1.55 - 1.69 (m, 2H)

[0792] Analysis data of synthesis examples

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819] Analytical HPLC method

[0820] Method A

[0821]

[0822] Analytical column: Kinetex EVO C18_2.1x30mm_5μm; Column temperature: 40 °C

[0823] Method B

[0824]

[0825] Instrument description: Waters Acquity; Analytical column: XBridge (Waters) BEH C18_2.1x30mm_2.5μm; Column temperature: 60 °C

[0826] Method C

[0827]

[0828] Instrument description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1x30mm_1.7μm; Column temperature: 60 °C

[0829] Method D

[0830]

[0831] Instrument description: Agilent 1200; Analytical column: Sunfire C18_3.0x30mm_2.5μm (Waters);

[0832] Column temperature: 60 °C

[0833] Method E

[0834]

[0835] Equipment description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60 °C

[0836] Method F

[0837]

[0838] Equipment description: Shimadzu LC-20ADXR; Analytical column: Halo C18_3.0x30mm_5μm; Column temperature: 40 °C

[0839] Method G

[0840]

[0841]

[0842] Equipment description: Agilent 1200; Analytical column: Zorbax (Agilent) StableBond C18_3.0x30mm_1.8μm; Column temperature: 60 °C

[0843] Method H

[0844]

[0845] Equipment description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60 °C

[0846] Method I

[0847]

[0848] Equipment description: Waters Acquity; Analytical column: XBridge BEH (Waters) C18_2.1x30mm_1.7μm; Column temperature: 60 °C

[0849] Method J

[0850]

[0851] Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60°C

[0852] Method K

[0853]

[0854]

[0855] Device description: Waters Acquity, Analytical column: Sunfire C18_3.0x30mm_2.5μm (Waters); Column temperature: 60°C

[0856] Method L

[0857]

[0858] Device description: Waters Acquity; Analytical column: XBridge C18_3.0x30mm_2.5μm (Waters); Column temperature: 60°C

[0859] Method M

[0860]

[0861] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60°C

[0862] Method N

[0863]

[0864] Device description: Agilent 1260SFC; Column: Chiral Amylose SA, 4.6x250mm, 2.5μm (YMC); Column temperature: 40°C

[0865] Method O

[0866]

[0867] Device description: Waters Acquity; Analytical column: XBridge (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60°C

[0868] Method P

[0869]

[0870] Instrument description: Waters Acquity; Analytical column: Sunfire C18_3.0x30mm_2.5μm (Waters); Column temperature: 60°C

[0871] Method Q

[0872]

[0873] Instrument description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0x30mm_2.5μm; Column temperature: 60°C

[0874] Method R

[0875]

[0876] Instrument description: Shimadzu LC-20ADXR; Analytical column: Halo C18_3.0x30mm_5μm; Column temperature: 40°C

[0877] Method S

[0878]

[0879] Instrument description: Agilent 1200 HPLC; Analytical column: Halo C18_3.0x30mm_5μm; Column temperature: 40°C.

Claims

1. A compound of formula (I), wherein A is A1a, which is a 5- or 6-membered monocyclic heteroaryl ring containing one or two heteroatom members selected from nitrogen, oxygen and sulfur; or A is A1b, which is a 9- or 10-membered fused bicyclic heteroaryl ring containing one to four heteroatom members selected from nitrogen, oxygen and sulfur, wherein at least one of the heteroatom members is nitrogen; or A is selected from the group A1c consisting of: R 1 Optionally selected from the group consisting of R1a: H, C 1-4 -alkyl and halogen; R 2 Select a group R2a consisting of: H, halogen, hydroxyl, 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-O-C(O)-, H2N-C(O)- and C 1-6 -alkyl-NH-C(O)-; or R 2 Optionally select a group R2b consisting of: phenyl, benzyl, phenoxy, and benzyloxy, where R2b is substituted with one or two R 4 substituents; or R 2 is R2c, which is a 5- or 6-membered monocyclic heteroaryl ring containing one or two heteroatom members selected from nitrogen, oxygen, and sulfur, wherein R2c is substituted with one or two R 4 substituents; or R 2 R2d consists of the following: R 3 Optionally selected from the group consisting of R3a: H, C 1-4 -alkyl and halogen; R 4 Optionally selected from the group consisting of R4a: H, C 1-4 -alkyl and halogen; or a salt thereof, especially a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, wherein A is selected from the group A4 consisting of: pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, methyl-pyrimidinone, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2-dihydropyrimidin-2-one, 3H-imidazo[4,5-b]pyridyl, imidazo[1,2-a]pyrimidinyl, 2H-pyrazolo[3,4-b]pyridyl, 1H-[1,2,3]triazolo[4,5-b]pyridyl, [1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-c]pyridyl, [1,2,5]oxadiazolo[3,4-b]pyridyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,5]thiadiazolo[3,4-b]pyridyl, 2H-[1,3]dioxoleno[4,5-b]pyridyl, imidazo[1,2-a]pyrimidinyl, pyrazolo[1,5-b]pyridazinyl, 2H,3H,4H-pyrano[2,3-b]pyridyl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazinyl and phthalazinyl; or a salt thereof.

3. The compound of formula (I) according to claim 1, wherein A is selected from the group A7 consisting of: or a salt thereof.

4. The compound of formula (I) according to any one of claims 1 to 3, wherein R 1 is selected from the group consisting of H, H3C- and F as R1d; or a salt thereof.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein R 2 is R2E of the group R2i selected from the group consisting of: H, F, Cl, hydroxy, methyl, tert-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-O-C(O)-, H2N-C(O)-, H3C-NH-C(O) Composition; or R2E is selected from the group R2j consisting of: phenyl, m-chlorophenyl, benzyl, phenoxy and benzyloxy; or R2E is selected from the group R2g consisting of: wherein R2g is substituted with H or methyl; or R2E is R2d consisting of: or a salt thereof.

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

7. The compound of formula (I) according to any one of claims 1, 4 or 5, which has the formula (1-e) or a salt thereof.

8. The compound of formula (I) according to any one of claims 1, 2, 3, 5 or 6, which has the formula (1-a) or a salt thereof.

9. The compound of formula (I) according to claim 1, which is selected from: or a salt thereof.

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

11. A pharmaceutical composition comprising one or more compounds according to one or more of claims 1 to 9 or a pharmaceutically acceptable salt thereof and optionally one or more inert carriers and / or diluents.

12. A pharmaceutical composition comprising one or more compounds according to one or more of claims 1 to 9 or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents and optionally one or more inert carriers and / or diluents.

13. The pharmaceutical composition according to claim 12, wherein the one or more other therapeutic agents are selected from anti-cancer agents and anti-fibrotic agents.

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

15. A method for treating a disease such as cancer or a fibrotic disease and a condition associated with these diseases in a patient in need thereof, the method comprising administering to the patient one or more compounds or pharmaceutically acceptable salts thereof according to one or more of claims 1 to 9.

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

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