Bicyclic pyrimidinones as inhibitors of NOX4

Abstract

The present disclosure provides bicyclic pyrimidinone derivatives that are inhibitors of NOX4 and therefore useful for the treatment of diseases treatable by inhibition of NOX4. Also provided are pharmaceutical compositions containing the same, and processes for preparing said compounds.

Description

[0001] 01-3604-FF Bicyclic pyrimidinones as inhibitors of NOX4 TECHNICAL FIELDThe present disclosure provides certain thieno- and thiazolo-pyrimidinone derivatives thatare inhibitors of NOX4, and are therefore useful for the treatment of diseases treatable by inhibition of NOX4. Furthermore, the invention relates to pharmaceutical compositions and combinations comprising these compounds, as well as their use in methods for the treatment of diseases associated with or modulated by NOX4. Particularly, the pharmaceutical com-positions of the invention are suitable for the therapy of interstitial lung diseases, e.g. idio-pathic pulmonary disease, and may also be suitable for the therapy of fibrotic diseases, al-lergic and inflammatory diseases. BACKGROUND INFORMATION Redox signaling is a critical part of a variety of cell signaling pathways involved in the reg-ulation of cell growth, differentiation, metabolism, immune regulation, and other physiolog-ical functions. It is characterized by an oxidation-reduction reaction or covalent adduct for- mation between the sensor and the second messenger. Thereby oxidation of the sensor pro-tein can modulate its activity, conformation, or susceptibility towards degradation. In caseof redox signaling the second messengers consist of a group of reactive oxygen and nitrogen species (ROS, RNS). These are generated as side products during metabolic reactions in themitochondria but also by specialized enzymes like NADPH-oxidases (NOXes). In parallel,a complex antioxidant system evolved to protect the cells from injury by ROS and RNS, ensuring a tight balance between ROS / RNS formation and degradation. In case this balance is disturbed, oxidative stress can occur leading to increased protein oxidation and aberrant redox signaling. Therefore, oxidative stress is associated with various pathophysiological conditions like interstitial lung diseases, cancer and inflammatory diseases. Several studies showed over the last decade that in interstitial lung diseases, like idiopathic pulmonary fibrosis (IPF), the redox balance is disturbed1and that NOX4 is specifically up- regulated in the lungs of IPF patients1. IPF patients experience a decline in their lung func- tion and blood oxygenation, which is caused by the remodeling of the lung parenchyma in combination with the stiffening of the lung tissue due to increased matrix deposition. Uponepithelial injury due to e.g. infection, air pollutants etc., fibroblasts are activated to enablemigration of immune cells as well as epithelial precursor cells to the site of injury. Once the injury is resolved fibroblasts as well as immune cells undergo apoptosis to allow complete 01-3604-FF restoration of the tissue. In IPF an aberrant repair is occurring leading to a progressive re- modeling of the lung parenchyma2. Recent studies using single cell sequencing allowed the identification and comparison of different cell types of lung tissue derived from IPF patients or healthy controls. These studies showed increased numbers of fibroblasts as well as a strong dedifferentiation of the epithelial cell population3. NOX4 is part of the NADPH oxidase enzyme family. NOXes are membrane bound multi- subunit protein complexes, which transfer electrons across the plasma membrane to generateROS. While the activity of all other family members (NOX1, NOX2, NOX3 and NOX5) istightly controlled and inducible, NOX4 is the only family member that is constitutively ac- tive1. It is localized in the plasma membrane, perinuclear vesicles, the endoplasmatic retic- ulum (ER), the mitochondria and the nuclear membrane. The generation of hydrogen perox- ide (H2O2) by NOX4 leads to reversible oxidation of cysteine thiol groups and / or S-glutathi- onylation1. Thereby, NOX4 is modulating TGFß signaling and other key pathways known to be involved in disease progression1. IPF fibroblasts show higher expression of NOX4 in comparison to fibroblasts isolated from healthy tissue, as well as hyperplastic alveolar cells. The role of NOX4 in fibroblast activa-tion as well as proliferation was investigated in lung fibroblasts1. Fibroblast proliferation, aswell as fibroblast activation are known processes driving disease progression. Immunohisto- chemistry on control and IPF lung samples confirmed increased NOX4 staining in fibro- blasts and showed stronger staining in bronchial and alveolar epithelial cells1. Acute respiratory distress syndrom (ARDS) and acute lung injury (ALI) are characterized by pulmonary infiltration and edema. Literature shows that NOX4 is increased in patients and plays a crucial role in cell recruitment in animal models4. Metabolic Dysfunction-associated Steatohepatitis (MASH) is characterized by an increasein lipid content and inflammation in the liver. The chronic feedback loop of lipotoxicity,increased inflammation and cell death leads to liver fibrosis. Throughout that process liver cells, namely stellate cells, dedifferentiate to an activated phenotype, of which one hallmarkis the induction of pro-fibrotic and pro-inflammatory expression pattern. As on main redox-mediating signalling pathway, the NOX-family – especially NOX4 – plays a crucial role inthat feedback loop. NOX4-dependent signalling directly leads to an induction of NFkB and 01-3604-FF MAPk transcription leading to induction of gene products, such as smooth muscle actin (SMA), collagen or tumor necrosis factor (TNF).Published literature shows that NOX4 is expressed in stellate cells and is expressed throughthe process of stellate cell activation. Vice versa, the inhibition of NOX4 on the other handleads to attenuated expression of stellate cell-activation markers.In addition to in vitro analyses, studies in NOX4 knock-out mice show reduced fibrosis and inflammation in MASH-relevant models. Aside from the prevention of fibrosis onset and progression, NOX4 plays a crucial role of endothelial integrity. Thereby, NOX4 activity fosters the nitric oxide (NO) production, lead- ing to vascular relaxation and reduced endothelial inflammation. Following, NOX4 inhibi- tion has a beneficial impact on portal hypertension. In cancer, ROS deregulation contributes to tumor development, progression, and metastasis. In some instances, this enhanced ROS, driven by various oncogenic perturbations, is re- quired for tumorigenicity leading to the acquisition of further DNA damage and genome instability in cancer cells5. Increased ROS occurs through a variety of mechanisms such as increased expression of the NOX proteins or NOX activators, or the downregulation of ROS- regulating systems. NOX4 itself has been reported to be increased in many types of tumorsleading to increased proliferation, migration, and apoptosis5. Tumor associated macrophagesare influenced by ROS and can adopt an immunosuppressive phenotype within tumors in response to ROS5. Furthermore, when fibroblasts are educated to become cancer associated fibroblasts (CAFs), NOX4 is upregulated and leads to CD8+ T cell exclusion and immune suppression in tumors. Deletion or inhibition of NOX4 in several mouse models of cancer, has reversed this immune suppression and restored immunotherapy response to anti-PD-1therapy (PD1 being programmed cell death protein 1)5. Therefore, specific inhibition ofNOX proteins in tumor cells themselves or stromal cells, is a tractable target for anti-tumor therapies. The list of the references cited above can be found here: 1. Veith, C., Boots, A. W., Idris, M., Schooten, F.-J. van & Vliet, A. van der. Redox Imbal- ance in Idiopathic Pulmonary Fibrosis: A Role for Oxidant Cross-Talk Between NADPH Oxidase Enzymes and Mitochondria. Antioxid Redox Sign 31, 1092–1115 (2019). 01-3604-FF 2. Hinz, B. & Lagares, D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 16, 11–31 (2020). 3. Habermann, A. C. et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci Adv 6, eaba1972 (2020). 4. Lee, S. H. et al. NADPH oxidase 4 signaling in a ventilator-induced lung injury mouse model. Respir Res 23, 73 (2022). 5. Cheung, E. C. & Vousden, K. H. The role of ROS in tumour development and progression. Nat Rev Cancer 22, 280–297 (2022). DETAILED DESCRIPTION OF THE INVENTIONThe present invention discloses novel thieno- and thiazolo-pyrimidinone derivatives that areinhibitors of NOX4, possessing appropriate pharmacological and pharmacokinetic proper- ties enabling their use as medicaments for the treatment of conditions and / or diseases treat- able by inhibition of NOX4.PCT / EP2024 / 054867 (i.e. WO2024 / 180018) discloses thiazolo-pyrimidinone derivatives asNOX4-inhibitors and particularly discloses a thiazole-pyrimidinone substituted with a 2-hy-droxy-pyrimidine as example 69.WO2016207785 discloses benzoxazole and benzthiazole based NOX4 inhibitors with the following generalized structural formula , of which example 1, example 15 and example 80 are reported with the following IC50values in an assay on modified human embryonic kidney (HEK) cells using Amplex Red as detect- ing reagent: 01-3604-FF Example as dis-NOX4 IC50 [µM] closed in Structure as disclosed in WO2016207785 WO2016207785 10.34O O H 15N N0.40ON O OOO80N N0.31H N O When tested in an assay for metabolic stability as described herein below, examples 1, 15and 80 show a clearance in human hepatocytes of 52 % QH, 29 % QH and 46 % QH, re-spectively. Another patent application, WO2005049613 discloses bicyclic pyrimidin-4-(3H)-one based modulators of the vanilloid-1 receptor (VR1) of the following generalized structural formula . Examples 19, 20, 30, 59 and 63 from WO2005049613 have been tested for their activity onNOX4 inhibition with the assay described herein below, resulting in the following IC50 val-ues: 1-3604-FFExample as disclosedStructure NOX4 IC50 [µM]in WO2005049613 Cl F 19 >99S N O N S Cl F 20 >99S N O N S Cl F 30 >99S N O N NH N 01-3604-FF F 59S N79N N O Cl Cl F 63 55S N O N S N As visible from the above data, the tested compounds of WO2005049613 show low activity as inhibitors of NOX4. Surprisingly it was found that the exchange of the para-chloro substituent in example 63 from WO2005049613 with a para-hydroxy substituent increases the inhibition of NOX4from 55 µM to 0.66 µM with respect to IC50 as tested in the NOX4-inhibition assay describedherein below, as shown by the following reference compound and the following examples 3 01-3604-FF Example Structure NOX4 IC50 [µM]OH Reference Example 0.56S N O F N S N Example 3 of the0.84 present invention OH N Example 57 of theN 0.10 present invention S N O F N S NThe effect of the hydroxy group in this position on the NOX4 inhibitory activity of othercompounds of the present invention is also shown in the following table: 1-3604-FF Example Structure NOX4 IC50 [µM]F N FReference ExampleSN O8.47N S N Example 4 of the0.24 present invention OH F F NExample 61 of theF 0.064 present invention S N O N S NReference Example 3.81 01-3604-FF Example 6 of the0.036 present inventionIt is therefore the aim of the present invention to provide thiazolo- and thieno-pyrimidinoneswhich are potent, metabolically stable and selective NOX4 inhibitors. Such thiazolo- andthieno-pyrimidinones of the invention may also be represented as thiazolo- and thieno-2-hydroxypyrimidines. The compounds of the present invention according to general formula (I) wherein A is N or CH; X is N or CR1c; Y is N or CH; R1a, R1band R1cis H or F; Q is selected from among a group consisting of 01-3604-FF ;R2, R3, R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl,-O-C1-4-alkyl, -CN, -SF5 and -N3; R7 is -Cl or -CF3; or salts thereof, exhibit several advanta-geous properties such as high potency, high metabolic stability and high selectivity forNOX4 and against NOX1, NOX2, NOX3 and NOX5. The compounds according to the invention typically show inhibition of NOX4 with IC50- values below 600 nM, preferably below 400 nM, more preferably below 200 nM, most pref-erably below 100 nM (see assay description herein below and table 1). High potency canenable lower doses for pharmacological efficacy. Lower doses have the advantages of lower "drug load" or "drug burden" (parent drug and metabolites thereof) for the patient causing potentially less side effects, and lower production costs for the drug product. In a further aspect of the invention, the compounds according to the invention are selective NOX4-inhibitors, and are selective against NOX1, NOX2, NOX3 and NOX5. Preferred are compounds in which the IC50 on NOX4 is 10x lower than the IC50 on either of NOX1, NOX2, NOX3 or NOX5. More preferred are compounds in which the IC50 on NOX4 is 30x lower than the IC50on either of NOX1, NOX2, NOX3 or NOX5. Most preferred are compounds in which the IC50 on NOX4 is 100x lower than the IC50 on either of NOX1, NOX2, NOX3 or NOX5 (see assay description herein below and table 2).Furthermore, the compounds according to the invention are metabolically stable as shownin human hepatocytes. Metabolic stability in human hepatocytes in this respect is defined asbelow or equal to 45 % QH, preferably below or equal to 30 % QH, more preferably belowor equal to 20 % QH (see assay description herein below and table 3 and the definition ofhow to calculate the % QH = hepatic blood flow herein below). Therefore, the compoundsof the present invention are expected to have a favorable in vivo clearance and thus the fa-vourably long duration of action in humans. Stability in human hepatocytes refers to thesusceptibility of compounds to biotransformation in the context of selecting and / or designing drugs with favorable pharmacokinetic properties, as the primary site of metabolism for many 01-3604-FFdrugs is the liver. Human hepatocytes contain the cytochrome P450 (CYPs) and additionalenzymes for phase II metabolism (e.g. phosphatases and sulfatases), and thus represent amodel system for studying in vitro how a drug is metabolised. Stability in hepatocytes isassociated with several advantages, including improved bioavailability and half-life, which can allow lower and less frequent dosing in patients. Thus, stability in hepatocytes is a fa- vorable characteristic for compounds that are to be used as drugs in the treatment of a dis- ease. USED TERMS AND DEFINITIONS General Definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the mean- ing indicated and the following conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often spec- ified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general in groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more sub- groups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkylene" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. In case a chemical bond at the end of moiety is indicated with a “-“, this “-“ signals the attachment point of the group to the molecule. In case a compound of the present invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail. A wavy line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. For example, the term "3-carboxypropyl-group" represents the following substituent: 01-3604-FF wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups: The wavy line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Term Substituted The term "substituted" as used herein, means that one or more hydrogens on the designated atom are replaced by a group selected from a defined group of substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. Likewise, the term “substituted” may be used in connection with a chem- ical moiety instead of a single atom, e.g. “substituted alkyl”, “substituted aryl” or the like. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E / Z isomers etc…) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as solvates thereof such as for instance hydrates. Unless specifically indicated, also “pharmaceutically acceptable salts” as defined in more detail below shall encompass solvates thereof such as for instance hydrates. Salts The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. 01-3604-FF As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed com- pounds wherein the parent compound is modified by making acid or base salts thereof. Ex-amples of pharmaceutically acceptable salts include, but are not limited to, mineral or or-ganic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesul- fonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Fur- ther pharmaceutically acceptable salts can be formed with cations from ammonia, L-argi-nine, calcium, 2,2’-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine , potas-sium, sodium and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical meth- ods. 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 in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also com- prise a part of the invention. Halogen The term halogen denotes fluorine, chlorine, bromine and iodine. Alkyl The term "C1-n-alkyl", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, 01-3604-FF 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)-.Alkylene The term "C1-n-alkylene" wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-4-alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-,-CH(CH2CH2CH3)- , -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.Alkenyl The term "C2-m-alkenyl" is used for a group "C2-m-alkyl" wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a double bond. Alkenylene The term "C2-m-alkenylene" is used for a group "C2-m-alkylene", wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a double bond. Alkynyl The term "C2-m-alkynyl" is used for a group "C2-m-alkyl" wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a triple bond. Alynylene The term "C2-m-alkynylene" is used for a group "C2-m-alkylene" wherein m is an integer se- lected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. 01-3604-FF Cycloalkyl The term "C3-k-cycloalkyl", wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to k C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Halo-(alkyl, alkylene or cycloalkyl) The term "halo" added to an "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsatu- rated) defines an alkyl, alkylene or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, prefera- bly fluorine and chlorine, particularly preferred is fluorine. Examples include: F3C-, H2FC-, HF2C. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.The term „bicyclic ring systems” means groups consisting of 2 joined cyclic substructuresincluding spirocyclic, fused, and bridged ring systems. PREFERRED EMBODIMENTS In another embodiment the invention relates to compounds of general formula (Ia) wherein X is N or C-R1c, wherein R1a, R1b and R1c is H or F; and wherein R2, R3, R4, R5, R6are, independently of each other, selected from among a group consisting of -H, -halogen, - 01-3604-FF C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al- kyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a saltthereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F, provided that R1a andR1b cannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently of eachother, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; providedthat at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F, provided that R1a andR1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4- 01-3604-FFalken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H andR5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F, provided that R1a andR1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3 is H and R5 is H; ora salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F, provided that R1a andR1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2,-C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N or C-R1c, wherein R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a saltthereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, independentlyof each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclo- propyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; 01-3604-FF or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, independentlyof each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclo- propyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3;provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N and wherein R1a and R1b is H or F, provided that R1a and R1b cannot be F simultane-ously; and wherein R2, R4, R6 are, independently of each other, selected from among a groupconsisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N and wherein R1a and R1b is H or F, provided that R1a and R1b cannot be F simultane-ously; and wherein R2, R4, R6 are, independently of each other, selected from among a groupconsisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H,-CF2Cl and -OCH3-CN, -SF5 and -N3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is N and wherein R1a and R1b is H or F, provided that R1a and R1b cannot be F simultane-ously; and wherein R2, R4, R6 are, independently of each other, selected from among a groupconsisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3is H and R5is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is CR1c and R1c is H and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are,independently of each other, selected from among a group consisting of -H, -halogen, -C1-4- alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al- kyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) wherein 01-3604-FFX is CR1c and R1c is H and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are,independently of each other, selected from among a group consisting of -H, -halogen, -C1-4- alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al-kyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is CR1c and R1c is H and wherein R1a and R1b is H or F, provided that R1a and R1b cannotbe F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at leasttwo of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ia) whereinX is CR1c and R1c is H and wherein R1a and R1b is H or F, provided that R1a and R1b cannotbe F simultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H; or a saltthereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is CR1c and R1c is H and wherein R1a and R1b is H or F, provided that R1a and R1b cannotbe F simultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ia) whereinX is CR1c and R1c is H and wherein R1a and R1b is H or F, provided that R1a and R1b cannotbe F simultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3,-CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (I) 01-3604-FF wherein Q is selected from among a group consisting of ;wherein A is N, X is N, and Y is CH; and wherein R1a and R1b is H or F; and wherein R2,R3, R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; and wherein R7 is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ; wherein A is N, X is N, and Y is CH; and wherein R1aand R1bis H or F; and wherein R2,R3, R4, R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O- 01-3604-FFC1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; andwherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ; A is N, X is N, and Y is CH; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other,selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided thatat least two of R2, R3, R4, R5, R6 are H; and wherein R7 is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ; A is N, X is N, and Y is CH; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H;and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (I) Q is se- lected from among a group consisting of 01-3604-FF ; A is N, X is N, and Y is CH; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopro- pyl, -CH=CH2,-C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ; A is N, X is N, and Y is CH; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH,-CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; and wherein R7 is -Cl or -CF3; or asalt thereof. In another embodiment the invention relates to compounds of general formula (I) 01-3604-FF wherein Q is selected from among a group consisting of ;wherein A is N, X is CR1c, R1c is H and Y is CH; and wherein R1a and R1b is H or F; andwherein R2, R3, R4, R5, R6 are, independently of each other, selected from among a groupconsisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ;A is N, X is CR1c, R1c is H and Y is CH; and wherein R1a and R1b is H or F; and wherein R2,R3, R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4- 01-3604-FFhaloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6are H; and wherein R7 is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of ; A is N, X is CR1c, R1cis H and Y is CH; and wherein R1aand R1bis H or F, provided thatR1a and R1b cannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently ofeach other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopro- pyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3;provided that at least two of R2, R3, R4, R5, R6 are H; and wherein R7 is -Cl or -CF3; or a saltthereof. In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of A is N, X is CR1c, R1c is H and Y is CH; and wherein R1a and R1b is H or F, provided thatR1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of eachother, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H andR5is H; and wherein R7is -Cl or -CF3; or a salt thereof. 01-3604-FF In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of A is N, X is CR1c, R1cis H and Y is CH; and wherein R1aand R1bis H or F, provided thatR1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of eachother, selected from among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopro- pyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (I) wherein Q is selected from among a group consisting of A is N, X is CR1c, R1cis H and Y is CH; and wherein R1aand R1bis H or F, provided thatR1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of eachother, selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; and wherein R7 is-Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) 01-3604-FF wherein X is N or CR1c; and wherein R1a, R1b and R1c is H or F; and wherein R2, R3, R4, R5,R6are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al- kyl, -CN, -SF5 and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H; and wherein R2, R3,R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl,-O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or asalt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H, provided that R1aand R1b cannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently ofeach other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl,-C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; pro-vided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof. 01-3604-FF In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H, provided that R1aand R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H andR5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H, provided that R1aand R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, - CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N or CR1c; and wherein R1aand R1bis H or F and R1cis H, provided that R1aand R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other,selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2,-C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, inde-pendently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b are, independently of each other, H or F; andwherein R2, R3, R4, R5, R6 are, independently of each other, selected from among a groupconsisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof; with the proviso that suchcompounds of general formula (Ib) are not compounds of general formula (Ib) wherein X is 01-3604-FFN; R1a and R1b are H; R2, R4, and R6 are, independently of each other, -H or -F; and R3 andR5 are H.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b are, independently of each other, H or F; andwherein R2, R3, R4, R5, R6 are, independently of each other, selected from among a groupconsisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof; with the proviso that thecompound is not . In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, inde-pendently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and-N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at leasttwo of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4- 01-3604-FFalkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H; or a saltthereof. In another embodiment the invention relates to compounds of general (Ib) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3,-CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b are, independently of each other, H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently ofeach other, selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3is H and R5is H; or a salt thereof;with the proviso that such compounds of general formula (Ib) are not compounds of generalformula (Ib) wherein X is N; R1a and R1b are H; R2, R4, and R6 are, independently of eachother, -H or -F; and R3 and R5 are H.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is N; and wherein R1a and R1b are, independently of each other, H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently ofeach other, selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3is H and R5is H; or a salt thereof; with the proviso that the compound is not 01-3604-FF (disclosed in WO2024 / 180018). In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5,R6are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al- kyl, -CN, -SF5 and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5,R6are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-al-kyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other,selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided thatat least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H;or a salt thereof. 01-3604-FF In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, - C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ib)wherein X is CR1c, R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH,-CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ic) wherein R1a and R1b is H or F; and wherein X is N or C-R1c; and wherein R1c is H; andwherein R7 is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ic) wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein Xis N or C-R1c; and wherein R1c is H; and wherein R7 is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ic) wherein X is N; and wherein R1aand R1bis H or F; and wherein R7is -Cl or -CF3; or a salt thereof. 01-3604-FF In another embodiment the invention relates to compounds of general formula (Ic) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Ic) wherein X is CR1c, R1cis H; and wherein R1aand R1bis H or F; and wherein R7is -Cl or -CF3; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Ic) wherein X is CR1c, R1cis H; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be F simultaneously; and wherein R7is -Cl or -CF3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id) wherein X is N or CR1c; and wherein R1cis H; and wherein R1aand R1bis H or F; and whereinR2, R3, R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is N or CR1c; and wherein R1c is H; and wherein R1a and R1b is H or F; and whereinR2, R3, R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, 01-3604-FF-O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or asalt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is N or CR1c; and wherein R1c is H; and wherein R1a and R1b is H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, inde-pendently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id) wherein X is N or CR1c; and wherein R1cis H; and wherein R1aand R1bis H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently ofeach other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, -cyclopro-pyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id) wherein X is N or CR1c; and wherein R1cis H; and wherein R1aand R1bis H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently ofeach other, selected from among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, -cy- clopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id) formula(Id) wherein X is N or CR1c; and wherein R1c is H and wherein R1a and R1b is H or F, providedthat R1a and R1b cannot be F simultaneously; and wherein R2, R4, R6 are, independently ofeach other, selected from among a group consisting of -H, -F, -Cl, -C1-2-alkyl, -cyclopropyl,-CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id)wherein X is N; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, inde-pendently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, 01-3604-FF cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is N; and wherein R1a and R1b is H or F; and wherein R2, R3, R4, R5, R6 are, inde-pendently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at leasttwo of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -halogen, -C1-4-alkyl, -cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H; or a saltthereof. In another embodiment the invention relates to compounds of general formula (Id) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, -cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5 and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected from 01-3604-FF among a group consisting of -H, -F, -Cl, -C1-2-alkyl, -cyclopropyl, -CH=CH2, -C^CH, -CF3,-CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id) wherein X is N; and wherein R1aand R1bis H or F, provided that R1aand R1bcannot be Fsimultaneously; and wherein R2, R4, R6 are, independently of each other, selected fromamong a group consisting of -H, -F, -Cl, -C1-2-alkyl, -cyclopropyl, -CF3, and -CF2H; R3 is Hand R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3, R4,R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F; and wherein R2, R3, R4,R5, R6 are, independently of each other, selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, R6 are H; or a saltthereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R3, R4, R5, R6 are, independently of each other,selected from among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided thatat least two of R2, R3, R4, R5, R6 are H; or a salt thereof.In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, - 01-3604-FFC2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R3 is H and R5 is H; or asalt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -Br, -I, -C1-2-alkyl, cyclopropyl, -CH=CH2, - C^CH, -CF3, -CF2H, -CF2Cl, -OCH3, -CN, -SF5and -N3; R3is H and R5is H; or a salt thereof. In another embodiment the invention relates to compounds of general formula (Id)wherein X is CR1c and R1c is H; and wherein R1a and R1b is H or F, provided that R1a and R1bcannot be F simultaneously; and wherein R2, R4, R6 are, independently of each other, selectedfrom among a group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH,-CF3, -CF2H, -CF2Cl and -OCH3; R3 is H and R5 is H; or a salt thereof.In another embodiment, the invention relates to a compound selected from among the groupconsisting of 01-3604-FF in its salt-free form. In another embodiment, the invention relates to a compound selected from among the group consisting of 01-3604-FF or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound selected from among the group consisting of 01-3604-FF in its salt-free form. In another embodiment, the invention relates to a compound selected from the group con- sisting of 01-3604-FFin its salt-free form or a salt thereof or a pharmaceutically acceptable salt thereof.In another embodiment, the invention relates to a compound selected from the group con- sisting of in its salt-free form or a salt thereof or a pharmaceutically acceptable salt thereof.BIOLOGICAL ASSAYS Assay to determine inhibition of NOX4Cell line generation for NOX4 inhibition assayThe synthetic gene phNOX4_DNA3_1_Zeo (Accession: AAF68973) is assembled fromsynthetic oligonucleotides and / or PCR products. The fragment is cloned into pcDNA3.1_Zeo_A011 using NheI and XhoI cloning sites. The plasmid DNA is purifiedfrom transformed bacteria and its concentration is determined by UV spectroscopy. The finalconstruct is verified by sequencing. The plasmid is transfected via electroporation (Amaxaelectroporation device) in comibination with Nucleofector Kit V. Selection of NOX4 over-expressing genes is achieved using selection antibiotic Zeocin.NOX4 inhibition assay (HyPerBluTM)The inhibitory activity of the example compounds of the invention is determined using thefollowing procedure: 01-3604-FFNOX4 inhibition is assessed utilizing HEK293 cells stably overexpressing human NOX4(hNOX4), generating constitutively high levels of hydrogen peroxide (H2O2). Cells are cul-tured in the Dulbecco's Modified Eagle Medium (DMEM) media containing 4.5g / L glucosesupplemented with 10% fetal calf serum and 250µg / ml Zeocin in an incubator at 37°C with5% CO2. For the assay, cells are seeded in 384 well plates. After 24h cells are washed andtreated with several concentrations (10nM-30µM) of the test compounds (diluted in DMSO)or 100µM diphenyleneiodonium chloride (DPI, used as positive control) in assay buffer con-sisting of phosphate-buffered saline (PBS) with 4-(2-hydroxyethyl)-1-piperazineethanesul-fonic acid (HEPES), and incubated for 2 hours at 24°C in a humidified incubator. Afterincubation Lumigen HyPerBluTM is added and cells are incubated for additional 30 min at24°C in a humidified incubator. Next, luminescence is measured using an Envision Multi-mode Plate reader to determine levels of produced H2O2 in the wells. Results are visible inTable 1.

[0002] 01-3604-FF Table 1: Example IC50(NOX4) Example IC50(NOX4) Number [nM] Number [nM] 153 29 772 114 30 773 838 31 1334 243 32 415 51 33 386 36 34 627 77 35 498 56 36 719 34 37 4410 52 38 2911 62 39 17412 25 40 8913 50 41 6314 57 42 5015 52 43 4116 25 44 6417 31 45 7318 22 46 5819 40 47 17220 34 48 2421 232 49 4722 67 50 3723 66 51 17524 90 52 11225 60 53 5426 51 54 19627 23 55 6028 181 56 33 01-3604-FF Example IC50 (NOX4) Example IC50 (NOX4) Number [nM] Number [nM] 57 101 72 4758 28 73 5059 45 74 6960 55 75 8461 64 76 8662 81 77 8863 136 78 3564 176 79 5465 288 80 6966 111 81 7567 85 82 8368 25 83 5769 53 84 8470 46 85 11371 58 86 14387 180Assays to determine the selectivity against NOX1, NOX2, NOX3, NOX5Cell line generation Plasmids are purchased from Vectorbuilder.- for HEK-hNOX1 all necessary subunits are cloned accordingly:▪ pLV-CMV-hNOX1-puro (NM_007052.5)▪ pLV-CMV-hNOXO1-blas (NM_172168.3)▪ pLV-CMV-hp22phox-hygro (NM_000101.4)▪ pLV-CMV-hNOXA1-neo (NM_006647.2)- for HEK-hNOX3▪ pLV-CMV-hNOX3-puro (NM_015718.3)3rd generation lentiviral particles are produced in HEK293 suspension cells by transient transfection of three helper and expression plasmids. Crucial lentivirus supernatants are 01-3604-FF harvested, clarified by filtration and concentrated by precipitation. Lentivirus titers are de- termined in transducing units in (TU / mL) by transduction of HT1080 cells and colony form-ing assay. Parental HEK293 cells, purchased from CLS GmbH, are transduced with replica-tion-incompetent 3rd generation lentiviral particles (MOI 2) and expanded for at least two weeks before cryopreservation of tested lots. During cultivation, medium is changed threetimes per week and cells are sub-cultured at least once per week. Selection antibiotics areadded according to the plasmids (1 μg / ml puromycin, 1.5 μg / ml blasticidin, 200 μg / ml G418 and 100 μg / ml hygromycin). For HEK-hNOX5The synthetic gene hNOX5 (Accession: Q96PH1) is cloned into pcDNA3.1_Zeo. The plas-mid DNA is purified from transformed bacteria and its concentration is determined by UV spectroscopy. The final construct is verified by sequencing. The plasmid is transfected via electroporation (Amaxa electroporation device) in comibination with Nucleofector Kit V. Selection of NOX5 overexpressing genes is achieved using selection antibiotic Zeocin.NOX1 inhibition assay (L-012)Evaluation of the NOX4 inhibitors on NOX1 activity is assessed in HEK293 cells stablyoverexpressing human NOX1 (hNOX1).Cells are cultured in the DMEM media containing 4.5g / L glucose supplemented with 10%fetal calf serum (FCS), Puromycin1µg / mL, Blasticidin 1,5µg / mL, Geneticin (G418)200µg / mL and Hygromycin 100µg / mL in an incubator at 37°C with 5% CO2. For the assaycells are seeded in 384 well plates in DMEM media with 10% FCS. After 24h, cells arewashed, treated for 30mins with several concentrations (30nM-100µM) of test compoundsand then stimulated with phorbol myristate acetate (PMA) at 1µM to induce NOX1-depend-ent ROS production (except wells used as a positive control). Lastly, 8-amino-5-chloro-2,3-dihydro-7-phenyl-pyrido[3,4-d]pyridazine-1,4-dione sodium salt (L-012, CAS 143556-24-5) is added at 400µM to all wells, and cells are incubated in an incubator for an additional3h. Afterwards luminescence is measured with a SpectraMax Paradigm Microplate Reader.Data can be found in table 2.NOX2 inhibition assay (L-012) 01-3604-FFEvaluation of the NOX4 inhibitors on NOX2 activity is assessed in human blood-derivedgranulocytes.Different concentrations of the test compounds (30nM-100µM), DMSO (as a negative con-trol) or diphenyleneidonium chloride (DPI; 30µM, as a positive control), prepared in assaybuffer (PBS containing CaCl2 and MgCl2 +0.1% bovine serum albumin (BSA)), are placedin 384 well plates. Afterwards, freshly isolated granulocytes are added to the wells contain-ing the compounds in assay buffer and incubated for 1h at 37°C. Next, a solution ofN-formylmethionine-leucyl-phenylalanine (fMLP; 730nM), phorbol myristate acetate(PMA, 100nM) (stimuli of ROS production) and L-012 (200uM, ROS indicator) is added tothe wells and the cells are incubated for additional 30mins at 37°C. Afterwards luminescenceis measured in a SpectraMax M5 microplate reader. Data can be found in table 2.NOX3 inhibition assay (L-012)Evaluation of the NOX4 inhibitors on NOX3 activity is assessed in HEK293 cells stably overexpressing human NOX3 (hNOX3). Cells are cultured in the DMEM media containing 4.5g / L glucose supplemented with 10%fetal calf serum (FCS), Puromycin 1µg / mL and Blasticidin 1,5µg / mL in an incubator at 37°Cwith 5% CO2. Cells are seeded in 384 well plates for 2 days. For the assay cells are washedand treated with several concentrations (10nM-30µM) of test compound (diluted in DMSO)or 100µM DPI (as a positive control in assay buffer consisting of PBS), and incubated for 2hours at 24°C in a humidified incubator. Cells are then stimulated with PMA at 0.1µM to induce NOX3-dependent ROS production. Finally, L-012 is added at 100µM and incubated for 2 hours at 24°C in a humidified incubator. Luminescence is measured with anPHERAstar multimode reader. Data can be found in table 2.NOX5 inhibition assay (L-012)Evaluation of the NOX4 inhibitors on NOX5 activity is assessed in HEK293 cells stably overexpressing human NOX5 (hNOX5). Cells are cultured in the DMEM media containing 4.5g / L glucose supplemented with 10%fetal calf serum and 250µg / ml Zeocin in an incubator at 37°C with 5% CO2. Cells are seededin 384 well plates over-night. For the assay cells are washed and treated with several con-centrations (10nM-30µM) of test compounds (diluted in DMSO and added to assay bufferconsisting of PBS) or 100µM DPI as a positive control and incubated for 2 hours at 24°C in 01-3604-FF a humidified incubator. Cells are then stimulated with PMA at 0.1µM to induce NOX5- dependent ROS production. Finally, L-012 is added at 100µM and incubated for 2 hours at 24°C in a humidified incubator. Luminescence is measured with an PHERAstar multimodereader. Data can be found in table 2.Table 2: Example NOX1 IC50NOX2 IC50NOX3 IC50NOX5 IC50Number [µM] [µM] [µM] [µM] 15 >100 27 352 N / A >100 N / A N / A4 32 >100 >100 286 >100 >100 >100 >1007 >100 >100 >100 >1008 >100 >100 >100 >1009 >100 88 10 >10010 57 >100 28 >10011 66 >100 >100 >10012 44 >100 25 6113 52 >100 18 12014 >100 >100 >100 >10015 >100 >100 31 >10016 >100 >100 19 >10017 56 >100 47 8618 32 >100 2.8 6519 9.3 >100 3 4420 31 >100 N / A N / A21 36 >100 N / A N / A22 60 >100 >100 >10023 >100 84 >100 >10024 19 >100 27 >10025 30 >100 >100 >100 1-3604-FF Example NOX1 IC50 NOX2 IC50 NOX3 IC50 NOX5 IC50 Number [µM] [µM] [µM] [µM] 26 38 188 91 8127 68 >100 2 8628 72 >100 >100 >10029 17 >100 7 2530 29 >100 4.2 >10031 30 >100 12 >10032 55 >100 12 >10033 27 >100 4 3034 65 >100 38 8735 40 >100 12 7436 34 >100 2 3237 44 >100 21 >10038 38 >100 1 >10039 42 >100 84 >10040 32 >100 >100 >10041 49 >100 5 >10042 30 >100 1 >10043 18 >100 7 6944 5 >100 2 2245 37 >100 23 6246 86 >100 >100 >10047 >100 >100 64 >10048 >100 >100 6 7649 26 >100 2 4350 >100 >100 3 >10051 >100 >100 >100 >10052 95 N / A 1 8553 72 >100.0 13 >10054 28 >100 >100 >10055 19 >100 35 43 1-3604-FF Example NOX1 IC50 NOX2 IC50 NOX3 IC50 NOX5 IC50 Number [µM] [µM] [µM] [µM] 56 30 >100 100 3557 58 >100 >100 >10058 >100 >100 37 >10059 >100 >100 33 5360 >100 >100 34 4861 66 >100 >100 >10062 >100 >100 >100 6863 N / A N / A N / A N / A64 66 >100 36 6165 N / A N / A N / A N / A66 10 >100 51 3767 74 >100 52 6368 46 >100.0 >100 5269 9.8 >100 >100 >10070 59 >100 63 9471 30 >100 32 2172 68 >100 >100 10073 33 >100 >100 >10074 >100 >100 >100 >10075 >100 >100 >100 >10076 22 >100 49 2377 87 >100 >100 >10078 >100 >100 55 8979 >100 >100 19 >10080 >100 >100 57 5281 >100 >100 >100 >10082 >100 >100 39 >10083 63 >100.0 >100 8484 N / A N / A >100 13085 >100 >100 >100 88 01-3604-FF Example NOX1 IC50 NOX2 IC50 NOX3 IC50 NOX5 IC50 Number [µM] [µM] [µM] [µM] 86 >100 N / A >100 11087 79 N / A >100 50*N / A: not available Evaluation of Hepatocyte Clearance The metabolic degradation of the test compound is assayed in a hepatocyte suspension. Hepatocytes (cryopreserved) are incubated in Dulbecco´s modified eagle medium (supple- mented with 3.5µg glucagon / 500mL, 2.5mg insulin / 500mL and 3.75mg / 500mL hydrocorti- sone) containing 5% human serum. Following a 30 min preincubation in an incubator (37°C, 10% CO2) 5 µl of test compound solution (80 µM; from 2mM in DMSO stock solution diluted 1:25 with medium) are addedinto 395 µl hepatocyte suspension (cell density in the range 0.25-5 Mio cells / mL, typically1 Mio cells / mL; final concentration of test compound 1µM, final DMSO concentration 0.05%). The cells are incubated for six hours (incubator, orbital shaker) and samples (25µl) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by cen- trifugation (5 min). The supernatant is transferred to a new 96-deepwell plate, evaporated under nitrogen and resuspended. Decline of parent compound is analyzed by HPLC-MS / MS. CLint is calculated as follows: CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD + clast / k) x 1000 / 60. C0: initial concentration in the incubation [µM], CD: cell density of vital cells [106cells / mL], AUD: area under the data [µM x h], clast: concentration of last data point [µM], k: slope of the regression line for parent decline [h-1]. The calculated in vitro hepatic intrinsic clearance can be scaled up to the intrinsic in vivo hepatic clearance and used to predict hepatic in vivo blood clearance (CL) by the use of a liver model (well stirred model). CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [µL / min / 106cells] x hepatocel- lularity [106cells / g liver] x liver factor [g / kg bodyweight]) / 1000 01-3604-FF CL [ml / min / kg] = CL_INTRINSIC_INVIVO [ml / min / kg] x hepatic blood flow [ml / min / kg] / (CL_INTRINSIC_INVIVO [ml / min / kg] + hepatic blood flow [ml / min / kg]) Qh [%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg]) Hepatocellularity, human: 120x106cells / g liver Liver factor, human: 25.7 g / kg bodyweightBlood flow, human: 21 ml / (min x kg)The resulting data are visible in table 3. Table 3 ExampleQh [%]ExampleQh [%]Number Number 159 24 152 38 25 126 12 26 197 12 27 88 17 30 229 12 34 1010 26 35 3211 8 36 1512 14 37 3213 9 38 714 9 42 1315 15 43 816 18 46 2617 10 48 1318 24 49 2219 11 50 3420 12 53 522 30 55 1323 19 56 10 -3604-FF ExampleQh [%]ExampleQh [%]Number Number 57 14 73 658 8 74 <459 15 75 1360 11 76 561 13 77 1062 10 78 1863 12 79 2366 15 80 1667 21 81 3368 35 82 1969 9 83 1570 21 84 1371 14 85 972 11

[0003] 01-3604-FF METHOD OF TREATMENTThe present invention is directed to compounds of general formula (I) which are useful inthe prevention and / or treatment of a disease and / or condition associated with or modulatedby NOX4 activity, including but not limited to the treatment and / or prevention of chronicliver diseases, portal hypertension, viral infections, cancer, interstitial lung diseases, retinop-athies, acute and chronic inflammation as well as fibrotic diseases. Particularly, the pharma-ceutical compositions of the invention are suitable for the therapy of interstitial lung dis- eases, e.g. idiopathic pulmonary disease, and may also be suitable for the therapy of fibrotic diseases, allergic and inflammatory diseases.The compounds of general formula (I) are useful for the prevention and / or treatment of:vascular inflammation, atherosclerosis, interstitial lung diseases (e.g. idiopathic pulmonaryfibrosis, progressive pulmonary fibrosis), liver fibrosis, pulmonary hypertension, portal hy-pertension, liver cirrhosis, acute on chronic liver failure (ACLF), sepsis, multi-organ failure,diabetic retinopathies, wet age-related macular degeneration (AMD), dry AMD, cardiovas-cular diseases, NOX4+ cancer associated fibroblast rich tumors (pancreatic, lung, breast,colon, head and neck tumors), systemic sclerosis, inflammatory bowel disease, Duchennemuscular dystrophy, COVID-19, acute respiratory distress syndrome, influenza, ischemicand hemorrhagic stroke.Accordingly, the present invention relates to a compound of general formula (I) for use as amedicament. Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and / or prevention of a disease and / or condition associated with or modu-lated by NOX4 activity.Furthermore, the present invention relates to the use of a compound of general formula (I)for the treatment and / or prevention of chronic liver diseases, viral infections, cancer, inter-stitial lung diseases, retinopathies, acute and chronic inflammation as well as fibrotic dis- eases. 01-3604-FF Particularly, the pharmaceutical compositions of the invention are suitable for the therapy of interstitial lung diseases, e.g. idiopathic pulmonary disease, and may also be suitable for the therapy of fibrotic, allergic and inflammatory diseases. Furthermore, the present invention relates to the use of a compound of general formula (I)for the treatment and / or prevention of: vascular inflammation, atherosclerosis, interstitiallung diseases, e.g. idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, liver fi- brosis, pulmonary hypertension, portal hypertension, liver cirrhosis, acute on chronic liver failure (ACLF), sepsis, multi-organ failure, diabetic retinopathies, wet age-related macular degeneration (AMD), dry AMD, cardiovascular diseases, NOX4+ cancer associated fibro- blast rich tumors (pancreatic, lung, breast, colon, and head and neck tumors), systemic scle- rosis, inflammatory bowel disease, Duchenne muscular dystrophy, COVID-19, acute respir- atory distress syndrome, influenza, pulmonary hypertension, ischemic and hemorrhagic stroke, heart failure, cardio myopathies, hypertension, progression of interstitial lung dis-eases, chronic lung disease, chronic obstructive pulmonary disease (COPD), asthma, dia-betic nephropathy, acute kidney injury, obstructive nephropathy, hypertensive nephropathy,and neurodegenerative diseases.In a further aspect the present invention relates to a compound of general formula (I) for usein the treatment and / or prevention of above mentioned diseases and conditions. In a further aspect the present invention relates to the use of a compound of general formula(I) for the preparation of a medicament for the treatment and / or prevention of above men-tioned diseases and conditions. In a further aspect of the present invention the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method com-prises the administration of an effective amount of a compound of general formula (I) to ahuman being. The dose range of the compounds of general formula (I) applicable per day is usually from 0.00001 to 100 mg per kg body weight, for example from 0.00001 to 10 mg per kg body weight of the patient. Each dosage unit may conveniently contain from 0.001 to 1000 mg, for example from 0.001 to 100 mg. 01-3604-FF The actual pharmaceutically effective amount or therapeutic dosage will usually depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compounds will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient’s unique condition. PHARMACEUTICAL COMPOSITION Suitable preparations for administering the compounds of formula (I) will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, supposi- tories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalables and pow- ders etc.. Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients, for example inert diluents, carriers, disintegrants, ad- juvants, surfactants, binders and / or lubricants. COMBINATION THERAPY The compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent. According to one embodiment the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or condi- tions described hereinbefore, in particular associated with chronic liver diseases, viral infec- tions, cancer, interstitial lung diseases, retinopathies, acute and chronic inflammation as well as fibrotic diseases. According to another embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described here- inbefore, in particular associated with vascular inflammation, atherosclerosis, interstitial lung diseases (e.g. idiopathic pulmonary fibrosis, progressive pulmonary fibrosis), liver fi- brosis, pulmonary hypertension, portal hypertension, liver cirrhosis, acute on chronic liver failure (ACLF), sepsis, multi-organ failure, diabetic retinopathies, wet age-related macular degeneration (AMD), dry AMD, cardiovascular diseases, NOX4+ cancer associated fibro- blast rich tumors (pancreatic, lung, breast, colon, head and neck tumors), systemic sclerosis, 01-3604-FF inflammatory bowel disease, Duchenne muscular dystrophy, COVID-19, acute respiratory distress syndrome, influenza, ischemic and hemorrhagic stroke. Additional therapeutic agents that are suitable for such combinations include in particular those, which, for example, potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and / or allow the dosage of one or more active substances to be reduced. Therefore, a compound of the invention may be combined with one or more additional ther-apeutic agents selected from the group consisting of antifibrotics (e.g. Ofev, PDE4i); of im-munotherapeutics (e.g. PD-1, aCTLA-4); of T cell engagers; of sGC activators; of ATX-inhibitors; of SGLT2 inhibitors (e.g. dapagliflozin, empagliflozin); of THRb inhibitors; ofGLP1 agonists and GLP1 agonist combinations; of FGF-analogs, such as FGF21 or FGF19;of KRAS-G12C-inhibitors (e.g. sotorasib); of KRAS-G12D-inhibitors; of MDM2-p53-an-tagonists; of Her2-inhibitors; of platinum derivatives (e.g. cisplatin, oxaliplatin, car-boplatin); of alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil,busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such asfor example carmustin and lomustin, thiotepa); of antimitotic agents (e.g. Vinca alkaloidse.g. vinblastine, vindesin, vinorelbin and vincristine); of taxanes such as paclitaxel, docet-axel, nab-paclitaxel (Abraxane); of angiogenesis inhibitors (e.g. tasquinimod, bevacizumab);of tubuline inhibitors; of DNA synthesis inhibitors; of PARP inhibitors; of topoisomeraseinhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, tenipo-side, amsacrin, topotecan, irinotecan, mitoxantrone); of antimetabolites (e.g. methotrexate,raltitrexed, 5-fluorouracil (5-FU), capecitabine, floxuridine, gemcitabine, mercaptopurine,thioguanine, cladribine, pentostatin, cytarabine (ara C), fludarabine, combination of tri-fluridine and tipiracil (= TAS102)); of antitumor antibiotics (e.g. anthracyclins such as dox-orubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylatedliposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin,dactinomycin, plicamycin, streptozocin); of inhibitors of vascular endothelial growth factor. Furthermore, the compounds according to the present invention can be combined with aradiotherapy regime.Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described herein- before and hereinafter for the treatment of diseases or conditions which may be affected or 01-3604-FF which are mediated by NOX4, in particular diseases or conditions as described hereinbefore and hereinafter. In a further aspect this invention relates to a method for treating a disease or condition whichcan be influenced by the inhibition of NOX4 in a patient that includes the step of adminis-tering to the patient in need of such treatment a therapeutically effective amount of a com- pound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents. In a further aspect this invention relates to the use of a compound of formula (I) or a phar- maceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of diseases or conditions which can be influenced by the inhibitionof NOX4 in a patient in need thereof.In yet another aspect the present invention relates to a method for the treatment of a diseaseor condition mediated by NOX4 activity in a patient that includes the step of administeringto the human patient, in need of such treatment a therapeutically effective amount of a com- pound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter. The use of the compound according to the invention in combination with the additional ther- apeutic agent may take place simultaneously or at staggered times. The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or sepa-rately in two identical or different formulations, for example as a so-called kit-of-parts.Consequently, in another aspect, this invention relates to a pharmaceutical composition that comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and / or diluents. 01-3604-FF Other features and advantages of the present invention will become apparent from the fol- lowing more detailed examples which illustrate, by way of example, the principles of the invention. PREPARATION The compounds according to the invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the sequence adopted in carrying out the reaction schemes may be varied. Variants of these reactions that are known to the skilled artisan but are not described in detail herein may also be used. The general processes for preparing the compounds according to the invention will become apparent to the skilled man on studying the schemes that follow. Starting compounds are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Before the reaction is carried out, any corresponding functional groups in the starting compounds may be protected using conventional protecting groups. These pro- tecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man and described in the literature. The terms "ambient tem- perature" and "room temperature" are used interchangeably and designate a temperature of about 20 °C, e.g. between 19 and 24 °C. Scheme 1: 01-3604-FFIntermediates II (Step 1, intermediates I intermediates II) can be prepared by treatingintermediates I with a suitable thiocarbonylation reagent, for example 1,1'-thiocarbonyl-bis(pyridin-2(1H)-one), in a suitable solvent, for example acetonitrile (Scheme 1). Preferredreaction temperatures are between room temperature and 75 °C. Formation of the thiourea(Step 2, intermediates II intermediates III) can be achieved by reacting intermediates IIwith an aniline-RE.1-NH2either in the presence of a suitable base, such as triethylamine or N,N-diisopropylethylamine, or without base, in a suitable solvent, such as acetonitrile or 2-methyltetrahydrofuran. The cyclization (Step 3, intermediates III intermediates IV) canbe achieved by treating intermediates III with a suitable base, such as potassium tert-butox-ide or aqueous sodium hydroxide in an appropriate solvent, such as acetonitrile, methanol,or water. Compounds according to the present invention V (step 4, intermediates IV com-pounds of the invention V) can be prepared by reaction of intermediates IV with a benzylhalide (i.e. chloride or bromide) RE.2-CH2-Z (Z is halide) and a suitable base, such as N,N-diisopropylethylamine or triethylamine, in a suitable solvent, for example acetonitrile, pro-pan-2-ol, N,N-dimethylacetamide or N,N-dimethylformamide.Scheme 2: Alternatively, compounds of the present invention V can directly be obtained by reactingintermediates III with a benzyl halide, such as benzyl chloride or benzyl bromide, and asuitable base, such as N,N-diisopropylethylamine or aqueous lithium hydroxide in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, at temperatures between roomtemperature and 40 °C (Scheme 2). 01-3604-FF Abbreviations: ACN acetonitrileAq. aqueousBoc tert-butyloxycarbonyl°C degree celsiusCDI carbonyl diimidazoleCyH / CH cyclohexaneconc. concentratedDCM dichloromethaneDIPEA N,N-diisopropylethylamineDMA N,N-dimethylacetamideDMF N,N-dimethylformamideDMSO dimethyl sulfoxideESI-MS electrospray ionisation mass spectrometryEtOAc ethyl acetateEtOH ethanolex exampleequiv equivalentFA formic acidh hourHATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri-dinium 3-oxid hexafluorophosphate HCl hydrochloric acidHPLC high performance liquid chromatographyInt. intermediateK2CO3 potassium carbonate KotBu potassium tert-butoxideL literLiOH*H2O lithium hydroxide monohydrateM Molar (mol / L) 1-3604-FFMeOH methanolMgSO4magnesium sulphatemin minutemL milliliterMTBE tert-butylmethyletherMW molecular weightNaOEt sodium ethoxideNH3 ammoniaPMB para-methoxybenzylPrep. PreparativeRP reversed phaseRfRetardation factor Rt retention timesat. saturatedscCO2 supercritical CO2SFC supercritical fluid chromatographyTBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluorob-orateTCDI 1,1-thiocarbonyldiimidazoleTEA triethylamineTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTBS tert-butyldimethylsilylTMS trimethylsilylTMS-Cl trimethylsilyl chlorideXphosPdG3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonateXPhosPdG4 methanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) 01-3604-FF Nomenclature The names of the compounds described in the experimental section were generated using PerkinElmer ChemDraw®Software (Version 22.2.0.330). Preparation of starting materials Unless stated otherwise, the starting materials are commercially available and used without further purification.

[0004] 01-3604-FF Preparation of intermediates Intermediate 1 Ethyl 4-isothiocyanatothiazole-5-carboxylate 1,1'-Thiocarbonylbis(pyridin-2(1H)-one) (28.3 g, 122 mmol, 1.10 equiv) is added to a solu-tion of ethyl 4-aminothiazole-5-carboxylate (20.0 g, 116 mmol, 1 equiv) in acetonitrile(110 mL), and the reaction mixture is heated at 75 °C. After 3 h, the reaction mixture ispoured on ice-water, and the mixture is extracted with tert-butylmethylether. The phases are separated, and the organic phase is washed with water and dried over sodium sulfate. All volatiles are removed under reduced pressure, and the residue is purified by flash column chromatography (silica gel, gradient cyclohexane to cyclohexane / EtOAc 70:30) to provide the product.C7H6N2O2S2 (MW = 214.0 g / mol)ESI 215 [M+H]+Rt (HPLC) 0.96 min (Z018_S04)Intermediate 2 6-Fluoro-5-methoxypyrazin-2-amine Step 1: 5-Bromo-3-fluoro-2-methoxypyrazine 3-Nitrobezenesulfonic acid (150 mg, 724 µmol, 0.100 equiv) and 1,3-dibromo-5,5-dime-thylhydantoin (1.30 g, 4.41 mmol, 0.600 equiv) are added to a solution of 2-fluoro-3-meth-oxypyrazine (1.00 g, 7.42 mmol, 1 equiv) in 1,1,1,3,3,3-hexafluoropropan-2-ol (5 mL), andthe reaction mixture is heated at 60 °C. After 18 h, the reaction mixture is concentrated under 01-3604-FFreduced pressure (50 °C, 84 mbar). The residue is dissolved in dichloromethane, and theorganic phase is washed with water. The organic layer is concentrated under reduced pres-sure (50 °C, 84 mbar), and the residue is purified by flash column chromatography (silicagel, gradient cyclohexane to cyclohexane / EtOAc 90:10) to yield the desired product.C5H4BrFN2O (MW = 205.9 g / mol)ESI not detectedRt (HPLC) 0.93 min (Z018_S04)Step 2: 6-Fluoro-5-methoxypyrazin-2-amine Under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (1 M inTHF, 4.35 mL, 4.35 mmol, 3.00 equiv) is added dropwise to a mixture of 5-bromo-3-fluoro-2-methoxypyrazine (step 1, 300 mg, 1.45 mmol, 1 equiv) and bis(di-tert-butyl(4-dimethyla-minophenyl)phosphine)dichlorpalladium(II) (67.0 mg, 145 µmol, 0.10 equiv) in 1,4-diox-ane (6 mL). After complete addition, the reaction mixture is heated at 110 °C. After 18 h,the reaction mixture is cooled at room temperature and concentrated under reduced pressure(50 °C, 180 mbar). The residue is purified by flash column chromatography (silica gel, gra-dient cyclohexane to cyclohexane / EtOAc 65:35) to yield the desired product.C5H6FN3O (MW = 143.0 g / mol)ESI 144 [M+H]+Rt (HPLC) 0.58 min (Z018_S04) 01-3604-FF Intermediate 3 6-(6-Fluoro-5-methoxypyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]py- rimidin-7(6H)-one A mixture of ethyl 4-isothiocyanatothiazole-5-carboxylate (intermediate 1, 150 mg,700 µmol, 1 equiv), and 6-fluoro-5-methoxypyrazin-2-amine (intermediate 2, 100 mg,699 µmol, 1 equiv) in acetonitrile (3 mL) is stirred for 24 h at room temperature. Potassiumtert-butoxide (78.0 mg, 695 µmol, 1 equiv) is added, and the mixture is stirred for 4 h.1-(Bromomethyl)-4-(trifluoromethyl)benzene (170 mg, 697 µmol, 1 equiv) is added, and themixture is stirred for 15 min. Dichloromethane and water are added, and the layers are sep-arated. The organic layer is concentrated under reduced pressure. The residue is purified byreversed phase HPLC (Agilent SunfireTM-C18, gradient of acetonitrile in water, 0.1% TFA) to yield the desired product.C18H11F4N5O2S2 (MW = 469.0 g / mol)ESI 470 [M+H]+Rt (HPLC) 1.10 min (Z018_S04)The following compounds are prepared using procedures analogous to those described forintermediate 3, using appropriate starting materials. As is appreciated by those skilled in theart, the analogous examples may involve variations in general reaction conditions. 01-3604-FF HPLC retention timeIntermediate Structure ESI-MS[min] (method) 4456 [M+H]+ 1.07 (Z018_S04)5 401 [M+H]+ 0.98 (Z018_S04)6 433 [M+H]+ 0.98 (Z018_S04)Intermediate 7 5-Ethoxy-3-fluoropyrazin-2-amine Step 1 Tert-butyl (5-ethoxypyrazin-2-yl)carbamate 01-3604-FFUnder an atmosphere of nitrogen, 4-dimethylamino-pyridine (658 mg, 5.39 µmol,0.100 equiv) is added to a mixture of 5-ethoxypyrazin-2-yl-amine (7.50 g, 53.9 mmol,1 equiv) in tetrahydrofuran (5 mL), and the mixture is stirred at room temperature for 1h.Di-tert-butyldicarbonate (17.6 g, 80.8 mmol, 1.50 equiv) is added, and the mixture is heatedat reflux for 14 h. The mixture is cooled at room temperature and poured into water (5 mL).The mixture is extracted with ethyl acetate (3 x), and the combined organic layers are con-centrated under reduced pressure. The residue is purified by flash column chromatography(silica gel, gradient petroleum ether EtOAc 20:1 to petroleum ether / EtOAc 5:1) to yield thedesired product.C11H17N3O3 (MW = 239.3 g / mol)Rf (silica gel) 0.6 (dichloromethan / MeOH 20:1)Step 2: Tert-butyl (5-ethoxy-3-fluoropyrazin-2-yl)carbamate 1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate(Selectfluor) (5.70 g, 16.1 mmol, 3.90 equiv) is added to a solution of tert-butyl (5-ethoxy-pyrazin-2-yl)carbamate (step 1, 980 mg, 4.10 mmol, 1 equiv) in acetonitrile (10 mL). After5 d, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure.The residue is purified by flash column chromatography (silica gel, gradient cyclohexane to cyclohexane / EtOAc 2:1) to yield the desired product.C11H16FN3O3 (MW = 257.1 g / mol)ESI not detectedRt (HPLC) 0.97 min (Z018_S04) 01-3604-FF Step 3: 5-Ethoxy-3-fluoropyrazin-2-amine Trifluoroacetic acid (1 mL) is added to a solution of tert-butyl (5-ethoxy-3-fluoropyrazin-2-yl)carbamate (step 3, 70.0 mg, 272 µmol, 1 equiv) in dichloromethane (2 mL). After 1 h, thereaction mixture is concentrated under reduced pressure to yield the desired product.C6H8FN3O (MW = 157.1 g / mol)ESI 158 [M+H]+Rt (HPLC) 0.69 min (Z018_S04)Intermediate 8 6-(5-Ethoxy-3-fluoropyrazin-2-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]pyrimidin-7(4H)- one A mixture of ethyl 4-isothiocyanatothiazole-5-carboxylate (intermediate 1, 27.0 mg,126 µmol, 1 equiv), and 5-ethoxy-3-fluoropyrazin-2-amine TFA salt (intermediate 7,27.0 mg, 80.0 µmol, 0.600 equiv) in acetonitrile (2 mL) is stirred at room temperature. After24 h, triethylamine (40 µL, 287 µmol, 2.30 equiv) is added. After 24 h, potassium tert-butoxide (55.0 mg, 490 µmol, 3.90 equiv) is added. After 30 min, the reaction mixture isacidified with acetic acid and purified by reversed phase HPLC (Agilent SunfireTM-C18,gradient of acetonitrile in water, 0.1% TFA) to yield the desired product.C11H8FN5O2S2 (MW = 325.0 g / mol)ESI 326 [M+H]+ 01-3604-FFRt (HPLC) 0.86 min (Z018_S04)Intermediate 9 2-Bromo-5-((4-methoxybenzyl)oxy)pyrazine Sodium hydride (60% in mineral oil, 9.90 g, 248 mmol, 1.10 equiv) is slowly added to asolution of 4-methoxybenzylalcohol (31.5 mL, 248 mmol, 1.10 equiv) in tetrahydrofuran(550 mL) keeping the temperature between 30–38 °C. After 30 min, 2,5-dibromopyrazine(54.6 g, 225 mmol, 1 equiv) is added. After 1.5 h water is added, and the precipitate is fil-tered and dried to yield the desired product.C12H11BrN2O2S2 (MW = 294.0 g / mol)ESI 295 / 297 [M+H]+ (bromine isotope pattern)Rt (HPLC) 0.67 min (X012_S01)Intermediate 10 5-((4-Methoxybenzyl)oxy)pyrazin-2-amine A solution of lithium-bis-(trimethylsilyl)-amide in tetrahydrofuran (1 M, 163 mL,163 mmol, 1.20 equiv) is added dropwise to a mixture of 2-bromo-5-((4-methoxybenzyl)-oxy)pyrazine (intermediate 9, 40.0 g, 136 mmol, 1 equiv) and XphosPdG3 (3.00 g,3.50 mmol, 0.0250 equiv) in toluene (450 mL) under argon atmosphere. After complete ad-dition, the reaction mixture is heated at 110 °C. After 3 h, the reaction mixture is allowed tocool to room temperature. Water is added, and the mixture is filtered through a pad ofCelite®. The filter cake is washed with toluene. The layers are separated, and the organiclayer is washed with water and concentrated under reduced pressure. The residue is dissolvedin a mixture of methanol (200 mL) and acetic acid (0.5 mL), and the mixture is stirred at 01-3604-FFroom temperature. After 4 h, the mixture is filtered through a pad of Celite®, and the filtrateis concentrated under reduced pressure. The residue is purified by flash column chromatog- raphy (silica gel, gradient cyclohexane / EtOAc 80:20 to cyclohexane / EtOAc 60:40) to yield the desired product.C12H13N3O2 (MW = 231.1 g / mol)ESI 232 [M+H]+Rt (HPLC) 0.49 min (X011_S05)Intermediate 11 Ethyl 4-(3-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)thioureido)thiazole-5-carboxylate 5-((4-Methoxybenzyl)oxy)pyrazin-2-amine (intermediate 10, 7.19 g, 30.1 mmol, 1 equiv) isadded to a solution of ethyl 4-isothiocyanatothiazole-5-carboxylate (intermediate 1, 6.46 g,30.1 mmol, 1 equiv) in acetonitrile (70 mL), and the mixture is stirred at room temperature.After 18 h, the precipitate is filtered and dried to yield the desired product.C19H19N5O4S2 (MW = 445.1 g / mol)ESI 446 [M+H]+Rt (HPLC) 1.15 min (Z018_S04) 01-3604-FF Intermediate 12 6-(5-((4-Methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]pyrimidin- Ethyl 4-(3-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)thioureido)thiazole-5-carboxylate (in-termediate 11, 16.0 g, 28.7 mmol, 1 equiv) is added in small portions to a mixture of aqueoussodium hydroxide solution (4 M, 28.7 mL, 113 mmol, 4.00 equiv) and methanol (160 mL),and the mixture is stirred at room temperature for 2 h. Water is added, and the mixture isneutralized with aqueous hydrochloric acid (4 M, 28.7 mL), and the precipitate is filteredand washed with water. The crude product is treated with a mixture of dichloro-methane / methanol (400 mL, 95:5) and filtered, and the filtrate is concentrated under reducedpressure to yield the product.C17H13N5O3S2 (MW = 399.0 g / mol)ESI 400 [M+H]+Rt (HPLC) 0.91 min (Z018_S04)

[0005] 01-3604-FFIntermediate 13 (general procedure A)6-(5-((4-Methoxybenzyl)oxy)pyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo- [4,5-d]pyrimidin-7(6H)-one A solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (2.65 g, 10.9 mmol, 1 equiv) andN,N-diisopropylethylamine (6.00 mL, 33.6 mmol, 3.10 equiv) in propan-2-ol (10 mL) isadded to a mixture of 6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydrothia-zolo[4,5-d]pyrimidin-7(4H)-one (intermediate 12, 4.34 g, 10.9 mmol, 1 equiv) and propan-2-ol (70 mL). After 30 min water is added, and the precipitate is filtered and dried to yieldthe desired product.C25H18F3N5O3S2 (MW = 557.1 g / mol)ESI 558 [M+H]+Rt (HPLC) 1.13 min (Z018_S04)Intermediate 14 (general procedure B)5-((4-(Difluoromethyl)benzyl)thio)-6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)thiazolo- [4,5-d]pyrimidin-7(6H)-one 1-(Bromomethyl)-4-(difluoromethyl)benzene (277 mg, 1.25 mmol, 1 equiv) is added to asolution of 6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]-pyrimidin-7(4H)-one (intermediate 12, 500 mg, 1.25 mmol, 1 equiv) and triethylamine 01-3604-FF(536 µL, 3.87 mmol, 3.10 equiv) in N,N-dimethylacetamide (3 mL). After 30 min, water isadded, and the precipitate is filtered and dried to yield the desired product.C25H19F2N5O3S2 (MW = 539.1 g / mol)ESI 540 [M+H]+Rt (HPLC) 1.09 min (Z018_S04)The following intermediates are prepared using procedures analogous to the general proce-dures A and B described for intermediates 13 and 14, using appropriate starting materials.As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. General HPLC retention Interme- proce-Structure ESI-MStime [min] diate dure (method) 526 15 B1.08 (Z018_S04) [M+H]+524 / 526 16 B+1.10 (Z018_S04)[M+H] 558 17 B+1.09 (Z018_S04)[M+H] -3604-FF 57618 B 1.11 (Z018_S04)[M+H]+558 / 56019 B+1.19 (Z018_S04)[M+H] 57620 B 1.16 (Z018_S04)[M+H]+59421 B+1.16 (Z018_S04)[M+H] 50822 B+1.10 (Z018_S04)[M+H] -3604-FF 542 / 54423 B 1.15 (Z018_S04)[M+H]+542 / 54424 B+1.14 (Z018_S04)[M+H] 538 / 54025 B 1.17 (Z018_S04)[M+H]+53626 B+1.16 (Z018_S04)[M+H] 52227 B+1.13 (Z018_S04)[M+H] -3604-FF 61628 A 0.80 (X012_S01)[M+H]+52229 A+0.75 (X012_S01)[M+H] 51430 A+0.75 (X012_S01)[M+H] 55031 B+1.09 (X018_S03)[M+H]

[0006] 01-3604-FF Intermediate 32 Ethyl 4-(3-(5-fluoro-6-hydroxypyridin-3-yl)thioureido)thiazole-5-carboxylate Ethyl 4-isothiocyanatothiazole-5-carboxylate (intermediate 1, 2.00 g. 9.37 mmol, 1 equiv)is added to a solution of 5-amino-3-fluoropyridin-2-ol (1.50 g, 9.37 mmol, 1 equiv) in 2-me-thyltetrahydrofuran (15 mL). After 18 h, tert-butylmethylether is added, and the precipitateis filtered to yield the product.C12H11FN4O3S2 (MW = 342.0 g / mol)ESI 343 [M+H]+Rt (HPLC) 0.89 min (Z020_S01)Intermediate 33 6-(5-Fluoro-6-hydroxypyridin-3-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]pyrimidin-7(4H)- one Ethyl 4-(3-(5-fluoro-6-hydroxypyridin-3-yl)thioureido)thiazole-5-carboxylate (intermediate32, 525 mg, 1.53 mmol, 1 equiv) is added in small portions to a solution of sodium hydrox-ide in water (0.1 M, 12 mL, 1.53 mmol, 1 equiv), and the mixture is stirred at room temper-ature. After 30 min, the reaction mixture is poured on aqueous potassium bisulfate solution,and the precipitate is filtered and washed with water to yield the product.C10H5FN4O2S2 (MW = 296.0 g / mol)ESI 297 [M+H]+Rt (HPLC) 0.60 min (Z020_S01) 01-3604-FF Intermediate 34 3-(5-((4-Methoxybenzyl)oxy)pyrazin-2-yl)-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin- 4(1H)-one Step 1: 1,1'-Thiocarbonylbis(pyridin-2(1H)-one) (15.1 g, 64.8 mmol, 1.05 equiv) is added to a solu-tion of methyl 3-aminothiophene-2-carboxylate (10.0 g, 61.7 mmol, 1 equiv) in acetonitrile(50 mL), and the reaction mixture is heated at 75 °C. After 2 h, the reaction mixture is pouredon ice-water, and the mixture is extracted with tert-butylmethylether. The phases are sepa-rated, and the organic phase is washed with water and dried over magnesium sulfate. Allvolatiles are removed under reduced pressure, and the residue is purified by flash column chromatography (silica gel, gradient cyclohexane to cyclohexane / EtOAc 70:30) to provide the product.C7H5NO2S2 (MW = 199.2 g / mol)ESI not detectedRt (HPLC) 1.07 min (Z020_S01)

[0007] 01-3604-FF Step 2: 3-(5-((4-Methoxybenzyl)oxy)pyrazin-2-yl)-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin- 4(1H)-one A mixture of 5-((4-Methoxybenzyl)oxy)pyrazin-2-amine (intermediate 10, 1.71 g,7.15 mmol, 1 equiv) and methyl 3-isothiocyanatothiophene-2-carboxylate (step 1, 1.50 g,7.15 mmol, 1 equiv) in acetontrile (50 mL) is stirred at room temperature over night and thenheated at 50 °C for 1.5 h. Potassium tert-butoxide (802 mg, 7.15 mmol, 1 equiv) is added,and the mixture is stirred for 2 h and then cooled at room temperature. Water is added, andthe mixture is neutralized with aqueous hydrochloric acid. The precipitate is filtered anddried. The residue is triturated with acetonitrile and dried to obtain the desired product.C10H5FN4O2S2 (MW = 398.1 g / mol)ESI 399 [M+H]+Rt (HPLC) 0.57 min (X012_S01)Intermediate 35 Methyl 3-(3-(5-fluoro-6-hydroxypyridin-3-yl)thioureido)thiophene-2-carboxylate Step 1: 1,1'-Thiocarbonylbis(pyridin-2(1H)-one) (15.1 g, 64.8 mmol, 1.05 equiv) is added to a solu-tion of methyl 3-aminothiophene-2-carboxylate (10.0 g, 61.7 mmol, 1 equiv) in acetonitrile 01-3604-FF(50 mL), and the reaction mixture is heated at 75 °C. After 2 h, the reaction mixture is pouredon ice-water, and the mixture is extracted with tert-butylmethylether. The phases are sepa- rated, and the organic phase is washed with water and dried over magnesium sulfate. All volatiles are removed under reduced pressure, and the residue is purified by flash column chromatography (silica gel, gradient cyclohexane to cyclohexane / EtOAc 70:30) to provide the product.C7H5NO2S2 (MW = 199.2 g / mol)ESI not detectedRt (HPLC) 1.07 min (Z020_S01)Step 2: Methyl 3-(3-(5-fluoro-6-hydroxypyridin-3-yl)thioureido)thiophene-2-carboxylate A mixture of 3-fluoro-5-nitropyridin-2-ol (500 mg, 3.10 mmol, 1 equiv), palladium on car-bon (10%, 50 mg) and ammonia (2M in MeOH, 155µL, 310 µmol, 0.100 equiv) in methanol(10 ml) is stirred under hydrogen atmosphere (3 bar). After 24 h, the mixture is filtered,1-methyl-2-pyrolidinon (3 mL) is added to the filtrate and methanol is distilled off underreduced pressure. The residue is diluted with 2-methyltetrahydrofuran (3 mL) and methyl3-isothiocyanatothiophene-2-carboxylate (step 1, 617 mg, 3.00 mmol, 1 equiv) is added. Af-ter 72 h, methyl tert-butyl ether is added, and the precipitate is filtered and dried to yield thedesired product.C12H10FN3O3S2 (MW = 327.0 g / mol)ESI 328 [M+H]+Rt (HPLC) 0.43 min (X012_S01) 01-3604-FF Intermediate 36 3-(5-fluoro-6-hydroxypyridin-3-yl)-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one A solution of sodium hydroxide in water (2M, 1.71 mL, 3.42 mmol, 2.00 equiv) is added toa mixture of methyl 3-(3-(5-fluoro-6-hydroxypyridin-3-yl)thioureido)thiophene-2-carbox-ylate (intermediate 35, 559 mg, 1.71 mmol, 1 equiv) in water (10 mL). After 30 min, thereaction mixture is acidified with hydrochloric acid (2M), and the precipitate is filtered and dried to yield the desired product.C11H6FN3O2S2 (MW = 295.0 g / mol)ESI 296 [M+H]+Rt (HPLC) 0.30 min (X012_S01)Intermediate 37 6-(5-((4-Methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydro-[1,2,3]thiadiazolo[4,5-d]- pyrimidin-7(4H)-one A mixture of ethyl 4-amino-1,2,3-thiadiazole-5-carboxylate (1.50 g, 8.23 mmol, 1 equiv)and 1,1'-thiocarbonylbis(pyridin-2(1H)-one) (2.21 g, 9.05 mmol, 1.10 equiv) in acetonitrileis heated at 70 °C. After 1.5 h, 5-((4-methoxybenzyl)oxy)pyrazin-2-amine (intermediate 10,2.00 g, 8.64 mmol, 1.10 equiv) is added. After 30 min, the reaction mixture is cooled at room 01-3604-FFtemperature, and concentrated under reduced pressure. The residue is dissolved in methanol(40 mL), and potassium tert-butoxide is added. After 20 min, the reaction mixture is acidi-fied with aqueous hydrochloric acid, and the mixture is extracted with ethyl acetate. Theorganic phase is washed with water and dried over magnesium sulfate. The dried solution isfiltered, and the filtrate is concentrated under reduced pressure to yield the desired product.C16H12N6O3S2 (MW = 400.4 g / mol)ESI 401 [M+H]+Rt (HPLC) 0.57 min (X012_S01)Intermediate 38 6-(5-Fluoro-6-methoxypyridin-3-yl)-5-thioxo-5,6-dihydro-[1,2,3]thiadiazolo[4,5-d]pyrim- idin-7(4H)-one Intermediate 38 is prepared using procedures analogous to those described for intermediate37, using appropriate starting materials.C10H6FN5O2S2 (MW = 311.3 g / mol)ESI 312 [M+H]+Rt (HPLC) 0.45 min (X012_S01)

[0008] 01-3604-FF Preparation of Final Compounds Example 1 6-(6-Fluoro-5-hydroxypyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]py- rimidin-7(6H)-one Sodium iodide (45.0 mg, 300 µmol, 2.60 equiv) and trimethylsilyl chloride (100 µL,788 µmol, 6.70 equiv) are added to a solution of 6-(6-fluoro-5-methoxypyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]pyrimidin-7(6H)-one (intermediate 3, 55.0 mg,117 µmol, 1 equiv) in acetonitrile (3 mL). After 18 h, additional trimethylsilyl chloride(30.0 µL, 236 µmol, 2.02 equiv) is added. After 1 h, the reaction mixture is filtered, and thefiltrate is purified by reversed phase HPLC (Agilent SunfireTM-C18, gradient of acetonitrile in water, 0.1% TFA) to yield the desired product.C17H9F4N5O2S2 (MW = 455.0 g / mol)ESI 456 [M+H]+Rt (HPLC) 0.94 min (Z018_S04)The following examples are prepared using procedures analogous to those described for ex- ample 1, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. 1-3604-FF HPLC retentionExample Structure ESI-MStime [min] (method) 2442 [M+H]+ 0.89 (Z018_S04)3 387 [M+H]+ 0.78 (Z018_S04)4 419 [M+H]+ 0.80 (Z018_S04)

[0009] 01-3604-FF Example 3 5-((3-Fluorobenzyl)thio)-6-(6-hydroxypyridin-3-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one Potassium iodide (37.0 mg, 223 µmol, 0.900 equiv) and trimethylsilyl chloride (140 µL,1.10 µmol, 4.60 equiv) are added to a solution of 5-((3-fluorobenzyl)thio)-6-(6-methoxypyr-idin-3-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one (intermediate 5, 95.0 mg, 237 µmol, 1 equiv)in acetonitrile (2 mL). After 18 h, acetic acid and methanol are added, and the reaction mix-ture is purified by reversed phase HPLC (Agilent SunfireTM-C18, gradient of acetonitrile inwater, 0.1% TFA) to yield the desired product.C17H11FN4O2S2 (MW = 386.0 g / mol)ESI 387 [M+H]+Rt (HPLC) 0.78 (Z018_S04)The following examples are prepared using procedures analogous to those described for ex- ample 3, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. HPLC retention time Example Structure ESI-MS[min] (method) 4419 [M+H]+ 0.80 (Z018_S04) 01-3604-FF Example 5 6-(3-fluoro-5-hydroxypyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]py- rimidin-7(6H)-one 1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.75 mg, 28.0 µmol, 1 equiv) and triethyla-mine (10.0 µL, 72.0 µmol, 2.60 equiv) are added to a solution of 6-(5-ethoxy-3-fluoropyra-zin-2-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]pyrimidin-7(4H)-one (intermediate 8,9.00 mg, 28.0 µmol, 1 equiv) in acetonitrile (3 mL). After 45 min, the reaction mixture isconcentrated under reduced pressure. Pyridinium hydrochloride (9.59 mg, 83.0 µmol,3.00 equiv) is added to the residue and the mixture is heated at 250 °C for 2 minutes with aheatgun. The mixture is cooled at room temperature and purified by reversed phase HPLC(Agilent SunfireTM-C18, gradient of acetonitrile in water, 0.1% TFA) to yield the desired product.C17H9F4N5O2S2 (MW = 455.0 g / mol)ESI 456 [M+H]+Rt (HPLC) 1.00 min (Z018_S04)

[0010] 01-3604-FFExample 6 (general procedure C)6-(5-Hydroxypyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]pyrimidin- Amberlyst® 15(H) (58 mg, 267 µmol, 2.5 equiv) is added to a solution of 6-(5-((4-methox-ybenzyl)oxy)pyrazin-2-yl)-5-((4-(trifluoromethyl)benzyl)thio)thiazolo[4,5-d]pyrimidin-7(6H)-one (intermediate 13, 58mg, 104 µmol, 1 equiv) in methanol (1 mL), and the reactionmixture is heated at reflux. After 2.5 h, the reaction mixture is filtered, and the filtrate iscooled at room temperature and concentrated under reduced pressure. The residue is tritu-rated with dichloromethane and dried to yield the product.C17H10F3N5O2S2 (MW = 437.0 g / mol)ESI 436 [M–H]-Rt (HPLC) 0.88 min (Z018_S04)Example 7 (general procedure D)5-((4-(Difluoromethyl)benzyl)thio)-6-(5-hydroxypyrazin-2-yl)thiazolo[4,5-d]pyrimidin- 7(6H)-one A mixture of 5-((4-(difluoromethyl)benzyl)thio)-6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one (intermediate 14, 690 mg, 1.28 mmol, 1 equiv) andacetic acid (5 mL) is heated at 120 °C for 2h. The mixture is concentrated under reduced 01-3604-FF pressure and the residue is purified by reversed phase HPLC (Gilson SunfireTM-C18, gradi- ent of acetonitrile in water, 0.1% TFA) to yield the desired product.C17H11F2N5O2S2 (MW = 419.0 g / mol)ESI 420 [M+H]+Rt (HPLC) 0.81min (Z018_S04)The following examples are prepared using procedures analogous to the general proceduresC and D described for examples 6 and 7, using appropriate starting materials. As is appreci-ated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. General HPLC retention ExampleStructure ESI-MSprocedure time [min] (method) 406 8C0.81 (Z018_S04) [M+H]+404 9C+0.84 (Z018_S04) [M+H] 438 10 D+0.83 (Z018_S04) [M+H] -3604-FF 45611 D0.84 (Z018_S04) [M+H]+438 / 44012 D+ 0.90 (Z018_S04) [M+H] 45613 D0.89 (Z018_S04) [M+H]+47414 D+0.90 (Z018_S04) [M+H] 38815 D+0.78 (Z018_S04)[M+H] -3604-FF 422 / 42416 C0.84 (Z018_S04) [M+H]+422 / 42417 D+0.86 (Z018_S04)[M+H] 418 / 42018 C0.88 (Z018_S04) [M+H]+41619 C+0.88 (Z018_S04) [M+H] 40220 C+0.84 (Z018_S04) [M+H] -3604-FF 49621 C0.56 (X012_S01) [M+H]+40222 C+ 0.49 (X012_S01) [M+H] 39423 C+0.47 (X012_S01) [M+H] 43024 C+0.70 (X018_S03) [M+H]

[0011] 01-3604-FF Example 25 5-((2-Chloro-4,6-difluorobenzyl)thio)-6-(5-hydroxypyrazin-2-yl)thiazolo[4,5-d]pyrimidin- 7(6H)-one 2-(Bromomethyl)-1-chloro-3,5-difluorobenzene (21.2 mg, 88.0 µmol, 1 equiv) is added to asolution of 6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydrothiazolo[4,5-d]-pyrimidin-7(4H)-one (intermediate 12, 35 mg, 88.0 µmol, 1 equiv) and triethylamine(37.5 µL, 271 µmol, 3.10 equiv) in N,N-dimethylacetamide (2.5 mL). After 1 h, Amberlyst®15(H) (95.2 mg, 438 mmol, 5.00 equiv) is added, and the reaction mixture is heated at 60 °C.After 18 h, the reaction mixture is filtered, and the filtrate is purified by reversed phaseHPLC (Waters XBridgeTM-C18, gradient of acetonitrile in water, 0.1% NH3) to yield thedesired product.C16H8ClF2N5O2S2 (MW = 439.0 g / mol)ESI 440 [M+H]+Rt (HPLC) 0.49 min (X012_S01)The following examples are prepared using procedures analogous to those described for ex- ample 25, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions.

[0012] 1-3604-FF HPLC retention timeExample Structure ESI-MS[min] (method) 26 466 [M+H]+ 0.72 (007_CA11)27 466 [M+H]+ 0.76 (007_CA11)28 413 [M+H]+ 0.61 (007_CA02)29 472 [M+H]+ 0.44 (008_CA02) -3604-FF30 436 [M+H]+ 0.70 (007_CA02)31 424 [M+H]+ 0.67 (007_CA02)32 396 [M+H]+ 0.73 (007_CA02)33 462 [M+H]+ 0.41 (008_CA02)

[0013] -3604-FF34 444 [M+H]+ 0.76 (007_CA02)35 416 [M+H]+ 0.79 (007_CA02)36 410 [M+H]+ 0.40 (008_CA02)37 454 [M+H]+ 0.81 (007_CA02)

[0014] -3604-FF38 484 [M+H]+ 0.76 (007_CA02)39 409 [M+H]+ 0.62 (007_CA11)40 384 [M+H]+ 0.67 (007_CA11)41 398 [M+H]+ 0.75 (007_CA11)42 420 [M+H]+ 0.72 (007_CA02) -3604-FF43 456 [M+H]+ 0.79 (007_CA02)44 456 [M+H]+ 0.77 (007_CA02)45 452 [M+H]+ 0.82 (007_CA02)46 384 [M+H]+ 0.71 (007_CA02)47 400 [M+H]+ 0.44 (X012_S01) -3604-FF48 496 [M+H]+ 0.77 (007_CA02)49 482 [M+H]+ 0.81 (007_CA02)50 440 [M+H]+ 0.50 (X012_S01)51 402 [M+H]+ 0.50 (X012_S01)52 412 [M+H]+ 0.82 (007_CA02) -3604-FF53 410 [M+H]+ 0.48 (X012_S01)54 423 [M+H]+ 0.38 (X011_S03)55 420 [M+H]+ 0.52 (X012_S01)56 411 [M+H]+ 0.49 (X012_S01)57 388 [M+H]+ 0.86 (Z018_S04) 01-3604-FF Example 58 5-((4-(Difluoromethyl)-2,6-difluorobenzyl)thio)-6-(5-fluoro-6-hydroxypyridin-3-yl)thiazo- lo[4,5-d]pyrimidin-7(6H)-one 2-(Bromomethyl)-5-(difluoromethyl)-1,3-difluorobenzene (187 mg, 729 µmol,0.900 equiv) is added to a solution of 6-(5-fluoro-6-hydroxypyridin-3-yl)-5-thioxo-5,6-di-hydrothiazolo[4,5-d]pyrimidin-7(4H)-one (intermediate 33, 300 mg, 810 µmol, 1 equiv) andtriethylamine (337 µL, 2.43 mmol, 3.00 equiv) in dimethylformamide (7 mL). After1 h, the reaction mixture is filtered, and the filtrate is purified by reversed phase HPLC (Gil-son XBridgeTM-C18, gradient of acetonitrile in water, 0.1% TFA) to yield the desired prod- uct.C18H9F5N4O2S2 (MW = 472.0 g / mol)ESI 473 [M+H]+Rt (HPLC) 0.50 min (X012_S01)The following examples are prepared using procedures analogous to those described for ex- ample 58, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions.

[0015] 1-3604-FF HPLC retention time [min]Example Structure ESI-MS(method) 59 455 [M+H]+ 0.49 (X012_S01)60 491 [M+H]+ 0.54 (X012_S01)61 437 [M+H]+ 0.48 (X012_S01)62 447 [M+H]+ 0.40 (X011_S04) -3604-FF63 426 [M+H]+ 0.89 (Z018_S04)64 471 [M+H]+ 0.56 (X012_S01)65 440 [M+H]+ 0.71 (007_CA02)66 461 [M+H]+ 0.53 (X012_S01)67 427 [M+H]+ 0.94 (Z018_S04) 01-3604-FF 68 501 [M+H]+ 0.77 (X018_S03)69 428 [M+H]+ 0.50 (X012_S01)Example 70 2-((4-Chlorobenzyl)thio)-3-(5-hydroxypyrazin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one 1-(Bromomethyl)-4-chlorobenzene (27.0 mg, 127 µmol, 1 equiv) is added to a solution of3-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4-(1H)-one (intermediate 34, 50 mg, 125 µmol, 1 equiv) and triethylamine (54.0 µL,390 µmol, 3.10 equiv) in N,N-dimethylacetamide (2 mL). After 16 h, Amberlyst® 15(H)(274 mg, 1.26 µmol, 10.0 equiv) and methanol (0.5 mL) are added, and the reaction mixtureis heated at 80 °C. After 18 h, the reaction mixture is filtered, and the filtrate is purified byreversed phase HPLC (Waters XBridgeTM-C18, gradient of acetonitrile in water, 0.1% NH3) to yield the desired product.C17H11ClN4O2S2 (MW = 402.0 g / mol)ESI 403 [M+H]+ 01-3604-FFRt (HPLC) 0.58 min (X012_S01)The following examples are prepared using procedures analogous to those described for ex- ample 70, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. HPLC retention time Example Structure ESI-MS[min] (method) 71 437 [M+H]+ 0.96 (Z018_S04)72 405 [M+H]+ 0.81 (007_CA11)73 423 [M+H]+ 0.82 (007_CA11)74 387 [M+H]+ 0.79 (007_CA11) 01-3604-FF 75 419 [M+H]+ 0.80 (007_CA11)76 455 [M+H]+ 0.90 (007_CA11)Example 77 3-(5-Fluoro-6-hydroxypyridin-3-yl)-2-((2,4,6-trifluorobenzyl)thio)thieno[3,2-d]pyrimidin- 4(3H)-one Example 77 is prepared using procedures analogous to those described for example 58, usingappropriate starting materials.C18H9F4N3O2S2 (MW = 439.0 g / mol)ESI 440 [M+H]+Rt (HPLC) 0.57 min (X012_S01) 01-3604-FF Example 78 5-((4-Chlorobenzyl)thio)-6-(5-hydroxypyrazin-2-yl)-[1,2,3]thiadiazolo[4,5-d]pyrimidin- 7(6H)-one Step 1: 5-((4-Chlorobenzyl)thio)-6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-[1,2,3]thiadia- zolo[4,5-d]pyrimidin-7(6H)-one 1-(Bromomethyl)-4-chlorobenzene (89.0 mg, 425 µmol, 1 equiv) is added to a solution of6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-5-thioxo-5,6-dihydro-[1,2,3]thiadiazolo[4,5-d]-pyrimidin-7(4H)-one (intermediate 37, 200 mg, 425 µmol, 1 equiv) and triethylamine(178 µL, 1.27 mmol, 3.00 equiv) in N,N-dimethylacetamide (2 mL). After 2 h, water andethyl acetate are added, the layers are separated, and the aqueous layer is extracted with ethylacetate. The combined organic layers are dried over magnesium sulfate, filtered, and con-centrated under reduced pressure to yield the desired product. Step 2: 5-((4-Chlorobenzyl)thio)-6-(5-hydroxypyrazin-2-yl)-[1,2,3]thiadiazolo[4,5-d]pyrimidin- A mixture of 5-((4-chlorobenzyl)thio)-6-(5-((4-methoxybenzyl)oxy)pyrazin-2-yl)-[1,2,3]-thiadiazolo[4,5-d]pyrimidin-7(6H)-one (step 1, 228 mg, 434 µmol, 1 equiv) and acetic acid(2 mL) is heated at 120 °C for 2h. The mixture is concentrated under reduced pressure and 01-3604-FF the residue is purified by reversed phase HPLC (Waters XBridgeTM-C18, gradient of ace- tonitrile in water, 0.1% TFA) to yield the desired product.C15H9ClN6O2S2 (MW = 404.0 g / mol)ESI 405 [M+H]+Rt (HPLC) 0.55min (X012_S01)The following examples are prepared using procedures analogous to those described for ex- ample 78, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions.

[0016] 1-3604-FF HPLC retention timeExample Structure ESI-MS[min] (method) 79 425 [M+H]+ 0.53 (X012_S01)80 439 [M+H]+ 0.59 (X012_S01)81 407 [M+H]+ 0.52 (X012_S01)82 421 [M+H]+ 0.57 (X012_S01) 01-3604-FF Example 83 5-((4-Chlorobenzyl)thio)-6-(5-fluoro-6-hydroxypyridin-3-yl)-[1,2,3]thiadiazolo[4,5-d]py- rimidin-7(6H)-one 1-(Bromomethyl)-4-chlorobenzene (98.5 mg, 470 µmol, 1.10 equiv) is added to a mixtureof 6-(5-fluoro-6-methoxypyridin-3-yl)-5-thioxo-5,6-dihydro-[1,2,3]thiadiazolo[4,5-d]py-rimidin-7(4H)-one (intermediate 38, 133 mg, 427 µmol, 1 equiv), and triethylamine(179 µL, 1.28 mmol, 3.00 equiv) in N,N-dimethylacetamide (2 mL). After 3 h, ethyl acetateis added, and the mixture is washed with water. The organic layer is dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residue is dissolved in ace-tonitrile (10 mL) and treated with chlorotrimethylsilane (162 µL, 1.28 mmol, 3.00 equiv)and sodium iodide (128 mg, 854 µmol, 2.00 equiv). After 2 h, the precipitate is filtered,washed with water, and dried to yield the desired product.C16H9ClFN5O2S2 (MW = 421.0 g / mol)ESI 422 [M+H]+Rt (HPLC) 0.74 min (X012_S01)The following examples are prepared using procedures analogous to those described for ex- ample 83, using appropriate starting materials. As is appreciated by those skilled in the art, the analogous examples may involve variations in general reaction conditions. 1-3604-FF HPLC retentionExample Structure ESI-MStime [min] (method) 84 442 [M+H]+ 0.54 (X012_S01)85 424 [M+H]+ 0.53 (X012_S01)86 438 [M+H]+ 0.54 (X012_S01)87 456 [M+H]+ 0.59 (X012_S01) 01-3604-FF Analytical HPLC methods Method Name: X011_S03Device description: Waters Acquity with DA- and MS-DetectorColumn: XBridge BEH C18_2.1 x 30 mm_1.7 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] NH3] 0.0 95.0 5.0 1.3 60.00.02 95.0 5.0 1.3 60.01.0 0.0 100.0 1.3 60.01.1 0.0 100.0 1.3 60.0Method Name: X011_S04Device description: Waters Acquity with DA- and MS-DetectorColumn: XBridge BEH C18_2.1 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] NH3] 0.0 95.0 5.0 1.3 60.00.02 95.0 5.0 1.3 60.01.0 0.0 100.0 1.3 60.01.1 0.0 100.0 1.3 60.0Method Name: X011_S05Device description: Waters Acquity with DA- and MS-DetectorColumn: XBridge BEH C18_2.1 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] NH3] 0.0 95.0 5.0 1.3 60.00.02 95.0 5.0 1.3 60.01.0 0.0 100.0 1.3 60.01.3 0.0 100.0 1.3 60.0 -3604-FFMethod Name: X012_S01Device description: Waters Acquity with DA- and MS-DetectorColumn: XBridge BEH C18_2.1 x 30 mm_1.7 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] TFA (v / v)]0.0 99.0 1.0 1.6 60.00.02 99.0 1.0 1.6 60.01.0 0.0 100.0 1.6 60.01.1 0.0 100.0 1.6 60.0Method Name: X018_S03Device description: Waters Acquity with DA- and MS-DetectorColumn: Sunfire C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] TFA (v / v)]0.0 95.0 5.0 1.5 60.01.3 0.0 100.0 1.5 60.01.5 0.0 100.0 1.5 60.0Method Name: Z018_S04Device description: Agilent 1200 with DA- and MS-DetectorColumn: Sunfire C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] TFA (v / v)]0.0 97.0 3.0 2.2 60.00.2 97.0 3.0 2.2 60.01.2 0.0 100.0 2.2 60.01.25 0.0 100.0 3.0 60.01.4 0.0 100.0 3.0 60.0Method Name: Z020_S01Device description: Agilent 1200 with DA- and MS-DetectorColumn: Sunfire C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] FA (v / v)]0.0 97.0 3.0 2.2 60.00.2 97.0 3.0 2.2 60.01.2 0.0 100.0 2.2 60.01.25 0.0 100.0 3.0 60.01.4 0.0 100.0 3.0 60.0 -3604-FFMethod Name: 007_CA11Device description: Waters Acquity, QDa DetectorColumn: Sunfire C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile Flow [ml / min] Temp [°C]Time [min] TFA (v / v)] 0.08% TFA (v / v)]0.0 95.0 5.0 1.5 60.01.3 0.0 100.0 1.5 60.01.5 0.0 100.0 1.5 60.01.6 95.0 5.0 1.5 60.0Method Name: 007_CA02Device description: Waters Acquity, QDa DetectorColumn: Sunfire C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile Flow [ml / min] Temp [°C]Time [min] TFA (v / v)] 0.08% TFA (v / v)]0.0 95.0 5.0 1.5 60.01.3 0.0 100.0 1.5 60.01.5 0.0 100.0 1.5 60.01.6 95.0 5.0 1.5 60.0Method Name: 008_CA02Device description: Waters Acquity, QDa DetectorColumn: XBridge C18_3.0 x 30 mm_2.5 µmColumn producer: WatersDescription: Gradient / Solvent% Sol [Water 0.1% % Sol [Acetonitrile] Flow [ml / min] Temp [°C]Time [min] NH3]0.0 95.0 5.0 1.5 60.01.3 0.0 100.0 1.5 60.01.5 0.0 100.0 1.5 60.01.6 95.0 5.0 1.5 60.0

[0017] 01-3604-FFThe invention encompasses the followingITEMS1. A compound of formula (I) wherein A is N or CH; X is N or CR1c; Y is N or CH; R1a, R1band R1cis H or F; Q is selected from among a group consisting of R2, R3, R4, R5, R6 are, independently of each other, selected from among a group consistingof -H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; R7is -Cl or -CF3; or a salt thereof; provided that the compound is not 01-3604-FF .2. A compound according to item 1, wherein A is CH, Y is CH, R1c is H andQ is ; or a salt thereof.3. A compound according to item 1, wherein A is N, Y is CH and R1c is H; or a saltthereof.4. A compound according to item 1, wherein A is N, Y is N, R1c is H andQ is ; or a salt thereof.5. A compound according to item 3, whereinQ is 01-3604-FF ; or a salt thereof.6. A compound according to item 3, whereinQ is ; or a salt thereof.7. A compound according to any one of items 3, 4, 5 or 6 wherein X is N; or a saltthereof.8. A compound according to any one of items 3, 4, 5 or 6 wherein X is CH; or a saltthereof.9. A compound according to item 1 selected from among the group consisting of 01-3604-FF 10. A compound according to any one of the items 1-9 in its salt free form.11. A compound according to any one of items 1-9 or a pharmaceutically acceptable saltthereof for use as a medicament.12. A compound according to any one of items 1 to 9 or a pharmaceutically acceptablesalt thereof for use in the treatment and / or prevention of a disease selected from among the group consisting of chronic liver diseases, portal hypertension, viral infections, cancer, in- terstitial lung diseases, retinopathies, acute and chronic inflammation as well as fibrotic dis- eases. interstitial lung diseases.13. A compound according to any one of items 1 to 9 or a pharmaceutically acceptablesalt thereof for use in the treatment of and / or prevention of a disease selected from among the group consisting ofvascular inflammation, atherosclerosis, interstitial lung diseases (e.g. idiopathic pulmonary fibrosis, progressive pulmonary fibrosis), liver fibrosis, pulmonary hy- pertension, portal hypertension, liver cirrhosis, acute on chronic liver failure (ACLF), sepsis, multi-organ failure, diabetic retinopathies, wet age-related macular degeneration (AMD), 01-3604-FF dry AMD, cardiovascular diseases, NOX4+ cancer associated fibroblast rich tumors (pan- creatic, lung, breast, colon, head and neck tumors), systemic sclerosis, inflammatory bowel disease, Duchenne muscular dystrophy, COVID-19, acute respiratory distress syndrome, in- fluenza, ischemic and hemorrhagic stroke. 14. A pharmaceutical composition comprising at least one compound according to anyone of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. 15. A medicament combination which comprises, besides one or more compoundsaccording to one or more of items 1 to 9, or a pharmaceutically acceptable salt thereof asfurther active substances a substance selected from the group consisting of antifibrotics, im- munotherapeutics, sGC activators, ATX-inhibitors, SGLT2-inhibitors, THRb inhibitors,GLP1 agonists and GLP1 agonist combinations, FGF-analogs, KRAS-G12C-inhibitors,KRAS-G12D-inhibitors, MDM2-p53-antagonists, of Her2-inhibitors and chemotherapeu- tics.16. A compound of formula (I) wherein A is N or CH; X is N or CR1c; Y is N or CH; R1a, R1band R1cis H or F; Q is 01-3604-FF ;R2, R3, R4, R5, R6 are, independently of each other, selected from the group consisting of -H,-halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof.17. A compound of formula (I) wherein A is N or CH; X is N or CR1c; Y is N or CH; R1a, R1band R1cis H or F; Q is ; 01-3604-FFR2, R3, R4, R5, R6 are, independently of each other, selected from the group consisting of -H,-halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof; provided that the compound is not provided that when A is N and Y is CH, X is not CR1c.

Claims

01-3604-FF CLAIMS1. A compound of formula (I)wherein A is N or CH; X is N or CR1c; Y is N or CH; R1a, R1band R1care, independently of each other, H or F; Q is;R2, R3, R4, R5, and R6 are, independently of each other, selected from the group consisting of-H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, - O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof; provided that the compound is not01-3604-FFprovided that when A is N and Y is CH, X is not CR1c.

2. The compound according to claim 1, wherein the compound is according to formula(Ib)wherein X is N; R1aand R1bare, independently of each other, H or F;R2, R3, R4, R5, and R6 are, independently of each other, selected from the group consisting of-H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, - O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof; provided that the compound is not01-3604-FF.

3. The compound according to claim 1, wherein the compound is according to formula(Ia)wherein X is N or CR1c; R1cis H;R1a and R1b are, independently of each other, H or F;R2, R3, R4, R5, and R6 are, independently of each other, selected from the group consisting of-H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, - O-C1-4-alkyl, -CN, -SF5 and -N3; or a salt thereof.

4. The compound according to claim 1, wherein the compound is according to formula(Id)01-3604-FFwherein X is N or CR1c; R1cis H;R1a and R1b are, independently of each other, H or F;R2, R3, R4, R5, and R6 are, independently of each other, selected from the group consisting of-H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, - O-C1-4-alkyl, -CN, -SF5and -N3; or a salt thereof.

5. The compound according to any one of the preceding claims, whereinR1aand R1bare, independently of each other, H or F, provided that R1aand R1bcannot be F simultaneously;R2, R3, R4, R5, and R6 are, independently of each other, selected from the group consisting of-H, -halogen, -C1-4-alkyl, cyclopropyl, -C2-4-alken-1-yl, -C2-4-alkyn-1-yl, -C1-4-haloalkyl, -O-C1-4-alkyl, -CN, -SF5 and -N3; provided that at least two of R2, R3, R4, R5, and R6 are H; ora salt thereof.

6. The compound according to any one of the preceding claims, whereinR1aand R1bare, independently of each other, H or F, provided that R1aand R1bcannot be F simultaneously;R2, R4, and R6 are, independently of each other, selected from the group consisting of -H, -F, -Cl, -C1-2-alkyl, cyclopropyl, -CH=CH2, -C^CH, -CF3, -CF2H, -CF2Cl and -OCH3;R3 is H; and R5 is H; or a salt thereof.01-3604-FF7. The compound according to claim 1 or 2, wherein the compound is selected from thegroup consisting of8. The compound according to claim 7, wherein the compound is in a salt form or in apharmaceutically acceptable salt form.

9. The compound according to any one of claims 1-7 or a pharmaceutically acceptablesalt thereof for use as a medicament.

10. The compound according to any one of claims 1-7 or a pharmaceutically acceptablesalt thereof for use in the treatment and / or prevention of a disease selected from the groupconsisting of chronic liver diseases, portal hypertension, viral infections, cancer, interstitiallung diseases, retinopathies, acute and chronic inflammation, fibrotic diseases.01-3604-FF11. The compound according to any one of claims 1-7 or a pharmaceutically acceptablesalt thereof for use in the treatment of and / or prevention of a disease selected in the groupconsisting of vascular inflammation, atherosclerosis, interstitial lung diseases, idiopathicpulmonary fibrosis, progressive pulmonary fibrosis, liver fibrosis, pulmonary hypertension,portal hypertension, liver cirrhosis, acute on chronic liver failure (ACLF), sepsis, multi-or- gan failure, diabetic retinopathies, wet age-related macular degeneration (AMD), dry AMD,cardiovascular diseases, NOX4+ cancer associated fibroblast rich tumors, NOX4+ cancerassociated fibroblast rich tumors wherein the tumor is selected in the group consisting ofpancreatic, lung, breast, colon, head and neck tumors, systemic sclerosis, inflammatory bowel disease, Duchenne muscular dystrophy, COVID-19, acute respiratory distress syn-drome, influenza, ischemic and hemorrhagic stroke, heart failure, cardio myopathies, hyper-tension, progression of interstitial lung diseases, chronic lung disease, chronic obstructivepulmonary disease (COPD), asthma, diabetic nephropathy, acute kidney injury, obstructivenephropathy, hypertensive nephropathy, and neurodegenerative diseases.

12. A pharmaceutical composition comprising at least one compound according to anyone of claims 1-7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically ac-ceptable carrier.

13. A medicament combination which comprises, besides one or more compoundsaccording to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, as furtheractive substances a substance selected in the group consisting of antifibrotics, immunother- apeutics, sGC activators, ATX-inhibitors, SGLT2-inhibitors, THRb inhibitors, GLP1 ago-nists and GLP1 agonist combinations, FGF-analogs, KRAS-G12C-inhibitors, KRAS-G12D-inhibitors, MDM2-p53-antagonists, of Her2-inhibitors and chemotherapeutics.

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