Tetrazole derivatives as TRPA1 inhibitors

Abstract

This disclosure describes certain tetrazole derivatives that inhibit the transient ankyrin receptor 1 (TRPA1) potential and are therefore useful for the treatment of diseases that can be treated by TRPA1 inhibition. Pharmaceutical compositions containing these derivatives and procedures for their preparation are also provided.

Description

Tetrazole derivatives as TRPA1 inhibitors FIELD OF INVENTION This disclosure provides certain tetrazole derivatives that are transient receptor potential ankyrin 1 (TRPA1) inhibitors and are therefore useful for the treatment of diseases that can be treated by TRPA1 inhibition. Pharmaceutical compositions containing these derivatives and processes for preparing these compounds are also provided. BACKGROUND INFORMATION Transient receptor potential (TRP) channels are a group of voltage-gated ion channels located mostly in the plasma membrane of numerous mammalian cell types. There are approximately 30 structurally related TRP channels classified into groups: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. The transient receptor potential cation channel, subfamily A, member 1 (TRPA1), also known as transient receptor potential ankyrin 1, is the sole member of the TRPA gene subfamily. Structurally, TRPA channels are characterized by multiple N-terminal ankyrin repeats (~14 at the N-terminus of human TRPA1), hence the "A" in the ankyrin designation (Montell, 2005). TRPA1 is highly expressed in the plasma membrane of sensory neurons in the dorsal root and nodose ganglia that serve both the skin and the lung, as well as in the small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder and lymphocytes (https: / / www.proteinat-las.org / ) as well as in human lung fibroblasts. TRPA1 is best known as a sensor for environmental irritants, giving rise to somatosensory modalities such as pain, cold, and itching. TRPA1 is activated by a number of electrophilic, reactive stimuli (e.g., allyl isothiocyanate, reactive oxygen species), as well as non-reactive compounds (e.g., icilin), implicated in cough associated with asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or post-viral or chronic idiopathic cough, as well as cough in sensitive patients (Song and Chang, 2015; Grace and Belvisi, 2011). TRPA1 inhibitors are useful in the treatment of IPF in which cough is highly prevalent due to the link between cough and lung injury, based on studies showing cough-induced elevation of TGF-β (Xie et al., 2009; Froese et al., 2016; Tschumperlin et al., 2003; Yamamoto et al., 2002; Ahamed et al., 2008).TRPA1 antagonists inhibit calcium signaling triggered by cough triggers such as oxidative stress from cigarette smoke extract (CSE), release of inflammatory mediators, and downregulated antioxidant gene expression (Lin et al., 2015; Wang et al., 2019). TRPA1 antagonists are effective in studies of atopic dermatitis (Oh et al., 2013; Wilson et al., 2013), contact dermatitis (Liu et al., 2013), psoriasis-associated itching (Wilson et al., 2013), and IL-31-dependent itching (Cevikbas et al., 2014). A gain of function in human TRPA1 has been associated with familial episodic pain syndrome (Kremeyer et al., 2010). A TRPA1 antagonist was effective in a behavioral model of migraine-related allodynia (Edelmayer et al., 2012).TRPA1 is selectively increased in trigeminal ganglia innervating damaged teeth compared to TRPA1 expression in trigeminal ganglia innervating healthy teeth (Haas et al., 2011). Several anesthetics are known to be TRPA1 agonists, including isoflurane (Matta et al., 2008), providing a rationale for TRPA1 inhibitors for postoperative pain relief. TRPA1-inactivated mice and wild-type mice treated with a TRPA1 antagonist exhibited anxiolytic- and antidepressant-like phenotypes (de Moura et al., 2014). TRPA1 inhibitors are expected to have a benefit in the treatment of diabetic neuropathy based on studies showing a mechanistic inverse regulatory link between AMPK and TRPA1 (Hiyama et al., 2018; Koivisto and Pertovaara, 2013; Wang et al., 2018).TRPA1-inactivated mice exhibit smaller myocardial infarct sizes compared to wild-type mice (Conklin et al., 2019). TRPA1 inactivation and pharmacological intervention inhibited TNBS-induced colitis in mice (Engel et al., 2011). In a mouse model of cerebral ischemia, TRPA1 inactivation and TRPA1 antagonists reduce myelin damage (Hamilton et al., 2016). Urate crystals and joint inflammation are reduced in TRPA1-inactivated mice in a monosodium urate mouse model of gout (Moilanen et al., 2015). TRPA1 deletion in rats improved joint inflammation and hyperalgesia in a rat model of acute gout attacks (Trevisan et al., 2014). Activation of TRPA1 triggers an inflammatory response in osteoarthritic chondrocytes (Nummenmaa et al., 2016).Inhibition and genetic deletion of TRPA1 reduce inflammatory mediators in chondrocytes of osteoarthritic mice and murine cartilage (Nummenmaa et al., 2016). Finally, TRPA1-inactivated mice showed improvements in weight-bearing in the osteoarthritic limb in a model of knee swelling induced by MIA (Horvath et al., 2016). TRPA1 is differentially expressed in the bladder epithelium of rats (Du et al., 2007) and of patients with bladder outlet obstruction (Du et al., 2008). Modulation of the TRPA1 receptor attenuates bladder hyperactivity in a rat model of spinal cord injury (Andrade et al., 2011) and intrathecal administration of TRPA1 antagonists attenuates cyclophosphamide-induced cystitis in hyperreflexia micturition rats (Chen et al., 2016). Therefore, it is desirable to provide potent TRPA1 inhibitors. TRPA1 inhibitors of various structural classes are reviewed in S. Skerratt, Progress in Medicinal Chemistry, 2017, volume 56, 81-115 and in D. Preti, G. Saponaro, A. Szallasi, Pharm. Pat. Anal. (2015) 4 (2), 75-94. Document WO2017 / 060488 discloses compounds that are TRPA1 antagonists, which have the generalized structural formula The TRPA1 activity of Examples 28 and 29, which contain a tetrazolyl ring, is not disclosed. L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809, disclose quinazolinone-based TRPA1 antagonists that include compounds of the generalized structural formula of which compound 31, in which R is OH, is reported to have a TRPA1 antagonistic CI5058 nM activity in a FLIPR assay and to have an intrinsic clearance in human liver microsomes of <14 |jl / min / kg. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses novel tetrazole derivatives that are transient receptor potential ankyrin 1 (TRPA1) inhibitors, exhibiting appropriate pharmacological and pharmacokinetic properties that enable their use as drugs for the treatment of conditions and / or diseases that can be treated by TRPA1 inhibition. The compounds of the present invention may provide several advantages, such as enhanced potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein binding, enhanced bioavailability, suitable pharmacokinetic profiles, and the possibility of forming stable salts. The compounds of the invention The present invention provides novel tetrazole derivatives that are surprisingly potent TRPA1 inhibitors (assay A), further characterized by - improved stability in human liver microsomes (assay B) - improved stability in human hepatocytes (assay C). The compounds of the present invention differ structurally from Examples 28 and 29 in WO2017 / 060488 because they contain a monocyclic dioxodihydropyrimidine core with N-substituents, amide substituents, and substituents adjacent to a secondary aliphatic alcohol. The compounds of the present invention further differ structurally from Example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809, because they possess a tetrazolyl ring. These structural differences unexpectedly lead to a favorable combination of (i) TRPA1 inhibition, (ii) stability in human liver microsomes, and (iii) stability in human hepatocytes. Therefore, the compounds of the invention are superior to those disclosed in the prior art in terms of the combination of the following parameters: - potency as TRPA1 inhibitors - stability in human liver microsomes - stability in human hepatocytes Stability in human liver microsomes refers to the susceptibility of compounds to biotransformation in the context of drug selection and / or design with favorable pharmacokinetic properties as a first step in screening. The liver is the primary site of metabolism for many drugs. Human liver microsomes contain cytochrome P450s (CYPs) and therefore represent a model system for studying in vitro phase I drug metabolism. Enhanced stability in human liver microsomes is associated with several advantages, including increased bioavailability and a suitable half-life, which can enable lower and less frequent dosing for patients. Therefore, enhanced stability in human liver microsomes is a desirable characteristic for compounds intended for use as drugs.Therefore, it is expected that the compounds of the present invention, in addition to being able to inhibit TRPA1, will have a favorable in vivo clearance and therefore the desired duration of action in humans. Stability in human hepatocytes refers to the susceptibility of compounds to biotransformation in the context of drug selection and / or design with favorable pharmacokinetic properties. The liver is the primary site of metabolism for many drugs. Human hepatocytes contain cytochrome P450s (CYPs) and other drug-metabolizing enzymes, and therefore represent a model system for studying drug metabolism in vitro (importantly, in contrast to liver microsome assays, the hepatocyte assay also covers phase II biotransformations as well as processes mediated by specific liver transporters, and thus represents a more comprehensive system for drug metabolism studies).Enhanced stability in human hepatocytes is associated with several advantages, including increased bioavailability and a suitable half-life, which can allow for lower and less frequent dosing in patients. Therefore, enhanced stability in human hepatocytes is a favorable characteristic for compounds intended for use as drugs. The present invention provides novel compounds according to formula (I) in which A is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl or benzofuranyl, unsubstituted or substituted with one, two or three members of the R3 group consisting of halogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cyclofluoroalkyl, -O-C1-4 alkyl, -O-cyclopropyl and NC-; either A is selected from the group consisting of and R1 is selected from the group consisting of C1-4 alkyl, C1-4 fluoroalkyl, C3-6 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; where m is 1 or 2; n is 2; R4 is C3-6 cycloalkyl; R5 is -O-C1-4 alkyl or -O-C1-4 fluoroalkyl; R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cyclofluoroalkyl, HO-C1-4 alkyl-, C1-4 fluoroalkyl, R6-(H2C)p-, R7-(H2C)q-, R6-(H(R8)C)p- and R7-(H(R9)C)q-; where p is 1 or 2; q is 2; R6 is selected from the group consisting of HO-C1-2-alkyl, C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl is unsubstituted or substituted with C1-4 alkyl or C1-4 fluoroalkyl; R7 is selected from the group consisting of C1-4 -O-alkyl, C1-4 -O-fluoroalkyl, C1-4-alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, N-morpholinyl is not substituted or is substituted with C1-4 alkyl or C1-4 fluoroalkyl; R8 and R9 are independently selected from H or C1-4 alkyl. Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl or benzofuranyl, unsubstituted or substituted with one or two members of group R3 consisting of halogen, C1-4 alkyl, -O-C1-4 alkyl and NC-; or A is R1 is selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; where m is 1 or 2; n is 2; R4 is C3-6 cycloalkyl; R5 is -O-C1-4 alkyl; R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl-, C1-4 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; where p is 1 or 2; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl is either unsubstituted or substituted with C1-4 alkyl; R7 is selected from the group consisting of -O-C1-4 alkyl, -O-C1-4 fluoroalkyl, C1-4-alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, N-morpholinyl is unsubstituted or substituted with a C1-4 alkyl group. Another embodiment of the present invention relates to a compound of formula (I) wherein A is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl or benzofuranyl, unsubstituted or substituted with one or two members of the R3 group consisting of Cl, F, Br, H3C, H3C-O- and NC-; either A is and the substituents R1 and R2 are defined as in the previous embodiment. Another embodiment of the present invention relates to a compound of formula (I) in which A is selected from the group consisting of and unsubstituted or substituted with one or two members of the R3 group consisting of Cl, F, Br, H3C, H3C-O- and NC-, or A is and the substituents R1 and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group consisting of and and the substituents R1 and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R1 is selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; n where m is 1; n is 2; R4 is C3-6 cycloalkyl; R5 is -O-C1-4 alkyl; and the substituents A and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), in which R1 is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; wherein m is 1; n is 2; R4 is C3-4 cycloalkyl; R5 is -O-C1-4 alkyl; and the substituents A and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R1 is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; wherein m is 1; n is 2; R4 is C3-4 cycloalkyl; R5 is H3C-O-; and the substituents A and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R1 is selected from the group consisting of H3C, H3CH2C, H3COH2CH2C, and the substituents A and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R1 is H3C; and the substituents A and R2 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl, C1-4 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; where p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl is either unsubstituted or substituted with C1-4 alkyl; R7 is selected from the group consisting of -O-C1-4 alkyl, -O-C1-4 fluoroalkyl, C1-4-alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, N-morpholinyl is unsubstituted or substituted with C1-4 alkyl; and the substituents A and R1 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl-, C1-2 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; where p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl is either unsubstituted or substituted with H3C; R7 is selected from the group consisting of H3C-O-, -O-fluoromethyl, H3C-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, N-morpholinyl is not substituted or is substituted with H3C; and the substituents A and R1 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl-, C1-2 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; where p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, and R7 is selected from the group consisting of H3C-O, -O-fluoromethyl, H3C-S (O) 2-, and and the substituents A and R1 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R2 is selected from the group consisting of H, H3C, H3CH2C, H3COH2CH2C, F2HCH2C, F3CH2C, FH2CH2C, H3C (O) 2SH2CH2C, F3COH2CH2C, and and the substituents A and R1 are defined as in any of the preceding claims. Another embodiment of the present invention relates to a compound of formula (I), wherein R2 is H; and the substituents A and R1 are defined as in any of the preceding claims. A compound of formula (I) is preferred, selected from the group consisting of and the substituent A is defined as in any of the preceding claims. The compound according to formula (I) selected from is preferred and the substituent A is defined as in any of the preceding claims. Particularly preferred is the compound according to formula (I) selected from the group consisting of TERMS USED AND DEFINITIONS Terms not specifically defined herein should be understood as those given to them by a person skilled in the art in light of the relevant information and context. As used in the descriptive report, however, unless otherwise specified, the following terms have the meanings indicated and the following conventions are observed. In the groups, radicals, or residues defined below, the number of carbon atoms is often specified after the group; for example, "C1-6 alkyl" means an alkyl group or radical having from 1 to 6 carbon atoms. Generally, in groups such as HO, H2N, (O)S, (O)2S, NC(cyano), HOOC, F3C, or the like, a person skilled in the art can determine the point(s) of radical attachment to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last-mentioned subgroup is the point of radical attachment; for example, the substituent "C1-3 aryl-alkyl" means an aryl group attached to a C1-3 alkyl group, the latter being attached to the nucleus or group to which the substituent is attached. In the event that a compound of the present invention is represented in the form of a chemical name and as a formula, in the event of any discrepancy the formula shall prevail.An asterisk may be used in subformulas to indicate the bond that is connected to the core molecule as defined. The numbering of the atoms of a substituent begins with the atom that is closest to the nucleus or the group to which the substituent is attached. For example, the term "3-carboxypropyl group" represents the following substituent: where the carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl", "2,2-dimethylpropyl", or "cyclopropylmethyl" represent the following groups: The asterisk can be used in subformulas to indicate the bond that is connected to the core molecule as defined. The term "C1-n alkyl", where n is an integer selected from 2, 3, 4, or 5, either alone or in combination with another radical, designates an acyclic, saturated, branched, or linear hydrocarbon radical with 1 to n carbon atoms. For example, the term C1-5 alkyl encompasses the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C (CH3) 2-, H3C-C (CH3) 2-CH2-, H3C-CH (CH3) -CH (CH3) - and H3C-CH2-CH (CH2CH3) -. The term "fluoro" added to an "alkyl," "alkylene," or "cycloalkyl" group (saturated or unsaturated) means an alkyl or cycloalkyl group of this type in which one or more hydrogen atoms are replaced by a fluorine atom. Examples include, but are not limited to: H₂FC₆, HF₂C₆, and F₃C₆. The term "C3-n cycloalkyl", where n is an integer from 4 to n, either alone or in combination with another radical, designates a cyclic, saturated, unbranched hydrocarbon radical with 3 to n carbon atoms. For example, the term C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term halogen generally refers to fluorine, chlorine, bromine, and iodine. The term "phenyl" refers to the radical of the next ring The term "thiophenyl" refers to the radical of the next ring The term "benzothiophenyl" refers to the radical of the following ring The term "benzofuranyl" refers to the radical of the next ring The term "tetrazolyl" refers to the radical of the next ring The term "dioxodihydropyrimidincarboxamide" refers to the radical of the following nucleus The term "C-morpholinyl" refers to the radical of the next ring The term "C-imidazolyl" refers to the radical of the next ring The term "C-pyrazolyl" refers to the radical of the next ring The term "N-morpholinyl" refers to the radical of the next ring The term "N-imidazolyl" refers to the radical on the next ring The term "N-pyrazolyl" refers to the radical of the next ring The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valency of the designated atom is not exceeded and the substitution results in a stable compound. Unless specifically stated throughout the descriptive memorandum and appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures in different proportions of the independent enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates including solvates of the free compounds or solvates of a salt of the compound. In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the art, for example, by separating corresponding mixtures, using stereochemically pure starting materials, and / or by stereoselective synthesis. The preparation of optically active forms is known in the art, such as by resolving racemic forms or by synthesis, for example, starting from optically active starting materials and / or using chiral reagents. Enantiomerically pure compounds of this invention or intermediate products can be prepared by means of asymmetric synthesis, for example, by the preparation and subsequent separation of diastereomeric compounds or suitable intermediate products that can be separated by known methods (for example, by chromatographic separation or crystallization) and / or using chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliary agents. Furthermore, the person skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolving a racemic mixture using an appropriate resolving agent, for example, by forming the diastereomeric salt of the racemic compound with optically active acids or bases, subsequently resolving the salts and releasing the desired compound from the salt; or by derivatizing the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequently separating the diastereomers and removing the chiral auxiliary group; or by kinetic resolution of a racemate (for example, by enzymatic resolution);by enantioselective crystallization from an agglomerate of enantiomorphic crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary agent. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, to the best of sound medical judgment, suitable for use without toxicity, irritation, excessive allergic response, or other problems or complications, and proportionate to a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound forms a salt or complex with an acid or a base. Examples of acids that form a pharmaceutically acceptable salt with a parent compound containing a basic moiety include mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Examples of cations and bases that form a pharmaceutically acceptable salt with a parent compound containing an acid moiety include Na+, K+, Ca2+, Mg2+, NH4+, L-arginine, 2,2'-iminobisethanol, L-lysine, N-methyl-D-glucamine, or tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of acids other than those mentioned above, which, for example, are useful for purifying or isolating the compounds of the present invention (e.g., trifluoroacetate salts), are also part of the present invention. BIOLOGICAL ASSAYS Evaluation of TRPA1 activity Trial A: TRPA1 trial The activity of the compounds of the invention can be demonstrated using the following in vitro TRPA1 cell assay: Method: A human HEK293 cell line overexpressing the human TRPA1 ion channel (Perkin Elmer, product no. AX-004-PCL) is used as a test system for the compound's efficacy and potency. The compound's activity is determined by measuring the effect of the compound on intracellular calcium concentration induced by AITC (allyl isothiocyanate) agonism in a FLIPRtetra system (Molecular Devices). Cell culture: The cells are obtained as frozen cells in cryovials and stored until use at -150°C. Cells are grown in culture medium (MEM / EBSS medium with 10% FCS and 0.4 mg / ml geneticin). It is important that the density does not exceed 90% confluence. For subculture, cells are detached from the flasks using Versene. The day before the assay, the cells are detached, washed twice with medium (MEM / EBSS medium with 10% FCS), and 20,000 cells are seeded into 20 µl / well in 284-well biocoated plates coated with poly-D-lysine (black, light background, cat. 356697) from Corning. The plates are incubated for 24 hours at 37°C / 5% CO2 before use in the assay. Preparation of the compounds The test compounds are dissolved in 100% DMSO to a concentration of 10 mM and, in a first step, diluted in DMSO to a concentration of 5 mM, followed by serial dilution steps in 100% DMSO. The dilution factor and the number of dilution steps can be varied according to requirements. Typically, eight different concentrations are prepared by 1:5 dilutions. Additional intermediate dilutions (1:20) of the substances are carried out with HBSS / HEPES buffer (1xHEPES, Gibco cat. 14065, HEPES 20 mM, cat. 83264 from SIGMA, 0.1% BSA cat.11926 from Invitrogen, pH 7.4 FLIPR Trial: On the day of the assay, cells are washed 3x with assay buffer, leaving 20 jl of buffer in the wells after washing. 10 jl of Ca6 loading buffer kit (cat. R8191 Molecular Devices) in HBSS / HEPES is added to the cells, and the plates are incubated with a lid for 120 minutes at 37°C / 5% CO2. 10 jl of compound or controls in HBSS / HEPES / 5% DMSO buffer from the intermediate dilution plate are carefully added to the wells. Luminescence (indicating calcium influx or release) is read on the FLIPRtetra device for 10 minutes to monitor compound-induced effects (e.g., agonism). Finally, 10 µL of the AITC agonist 50 µM dissolved in HBSS / HEPES / 0.05% DMSO buffer (final concentration 10 µM) are added to the wells, followed by an additional reading on the FLIPRtetra device for 10 minutes. The area under the signal curve (AUC) after the addition of AITC is used for IC50 / % inhibition calculations. Data evaluation and calculation: Each assay microtiter plate contains wells with vehicle controls (1% DMSO) instead of compound as controls for AITC-induced luminescence (100%CTL; high controls) and wells with vehicle controls without AITC as controls for non-specific changes in luminescence (0%CTL; low controls). Data analysis is performed by calculating the area under the signal curve for individual wells. Based on this value, the percentage value for each substance concentration is calculated: (AUC (sample) - AUC (low)) * 100 / (AUC (high) - AUC (low)) using MegaLab software (in-house developed). IC50 values ​​are calculated from the control values ​​in % using MegaLab software. Calculation: [y = (ad) / (1 + (x / c) Ab) + d], where a = low value, d = high value; x = concentration (M); c = IC50 (M); b = slope; y = % control Table 1: Biological data for the compounds of the invention as obtained in assay A Table 2: Biological data for prior art compounds (examples 28 and 29 in document WO2017 / 060488) as obtained in assay A. Table 3: Biological data for prior art compounds (example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in test A. Evaluation of microsomal clearance Assay B: Microsomal clearance: The metabolic degradation of the test compound is assayed at 37°C using pooled liver microsomes. The final incubation volume of 100 µl per time point contains TRIS buffer pH 7.6 at TA (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / ml), and the test compound at a final concentration of 1 µM. After a short pre-incubation period at 37°C, the reactions are initiated by the addition of reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated by transferring an aliquot to solvent at different time points (0, 5, 15, 30, 60 min). Additionally, NADPH-independent degradation is monitored in NADPH-free incubations, terminated at the last time point. The percentage of test compound remaining after NADPH-independent incubation is reflected by the parameter c (control) (metabolic stability). The terminated incubations are pelleted by centrifugation (10,000 g, 5 min). An aliquot of the supernatant is then analyzed by LC-MS / MS for the amount of parent compound. The half-life (t1 / 2 IN VITRO) is determined by the slope of the semi-logarithmic graph of the concentration-time profile. Intrinsic clearance (CL_INTRINSIC) is calculated considering the amount of protein in the incubation: CL_INTRINSIC [jl / min / mg of protein] = (Ln 2 / (half-life [min] * protein content [mg / ml]) ) * 1000 CL_INTRINSIC_LIVE [ml / min / kg] = (CL_INTRINSIC [jl / min / mg of protein] x MPPGL [mg of protein / g of liver] x liver factor [g / kg of body weight]) / 1000 Q h [% ] = CL [ml / m in / kg ] / hepatic blood flow [ml / m in / kg ] ) Hepatocellularity, human: 120x10e6 cells / g of liver Liver factor, human: 25.7 g / kg of body weight Blood flow, human: 21 ml / (min x kg) Table 4: Biological data for compounds of the invention as obtained in assay B Table 5: Biological data for prior art compounds (examples 28 and 29 in WO2017 / 060488) as obtained in assay B. Table 6: Biological data for prior art compounds (example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in test B. Evaluation of hepatocyte clearance Assay C: Hepatocyte Clearance The metabolic degradation of the test compound is assayed in a hepatocyte suspension. The (cryopreserved) hepatocytes are incubated in Dulbecco's modified Eagle medium (supplemented with 3.5 µg of glucagon / 500 ml, 2.5 mg of insulin / 500 ml and 3.75 mg / 500 ml hydrocortisone) containing 5% or 50% species serum. After a 30 min pre-incubation in an incubator (37°C, 10% CO2), 5 jl of test compound solution (80 jM; from 2 mM in DMSO stock solution diluted 1:25 with medium) are added to 395 jl of hepatocyte suspension (cell density in the range of 0.25-5 million cells / ml depending on the species, normally 1 million cells / ml; final concentration of test compound 1 jM, final DMSO concentration 0.05%). Cells were incubated for six hours (incubator, orbital shaker) and samples (25 J / L) were taken at 0, 0, 5, 1, 2, 4, and 6 hours. The samples were transferred to acetonitrile and pelleted by centrifugation (5 min). The supernatant was transferred to a new 96-well deep plate, evaporated under nitrogen, and resuspended. The decrease in parental compound was analyzed by HPLC-MS / MS. CLint is calculated as follows CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD + cultim. / k) x 1000 / 60. C0: initial concentration at incubation [jM ], CD: cell density of live cells [10e6cells / ml], AUD: area under the data [jM xh], cultim.: concentration of the last data point [jM ], k: slope of the regression line for parental decline [h-1]. The calculated in vitro intrinsic hepatic clearance can be scaled up to the in vivo intrinsic hepatic clearance and used to predict in vivo hepatic blood clearance (CL) using a liver model (well-shaken model). CLJNTRÍNSECOJNVIVO [ml / min / kg] = (CL_INTRÍNSECO [ml / min / 10e6cells] x hepatocellularity [10e6 cells / g of liver] x liver factor [g / kg of body weight]) / 1000 CL [ml / min / kg] = CLJNTRÍNSECOJNVIVO [ml / min / kg] x hepatic blood flow [ml / min / kg] / (CLjNTRÍNSECOJNVIVO [ml / min / kg] + hepatic blood flow [ml / min / kg]) Q h [% ] = CL [ml / m in / kg ] / hepatic blood flow [ml / m in / kg ] ) Hepatocellularity, human: 120x10e6 cells / g of liver Liver factor, human: 25.7 g / kg of body weight Blood flow, human: 21 ml / (min x kg) Table 7: Biological data for compounds of the invention as obtained in assay C Table 8: Biological data for prior art compounds (examples 28 and 29 in WO2017 / 060488) as obtained in assay C. Table 9: Biological data for prior art compounds (example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in test C. Permeability assessment Caco-2 cells (1 - 2 x 105 cells / 1 cm2 area) are seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 |jm pore size) and cultured (DMEM) for 10 to 25 days. The compounds are dissolved in an appropriate solvent (such as DMSO, 1-20 mM stock solutions). The stock solutions are diluted with HTP-4 buffer (NaCl 128.13 mM, KCl 5.36 mM, MgSO4 1 mM, CaCl2 1.8 mM, NaHCO3 4.17 mM, Na2HPO4 x 7H2O 1.19 mM, NaH2PO4xH2O 0.41 mM, HEPES 15 mM, glucose 20 mM, BSA 0.25%, pH 7.2) to prepare the carrier solutions (compound 0.1-300 jM, final DMSO <= 0.5%). The transport solution (TL) is applied to the apical or basolateral donor side to measure AB or BA permeability (3 filter replicates), respectively. Samples are collected from the donor side at the beginning and end of the experiment, and at various time intervals for up to 2 hours, also from the recipient side, for concentration measurement by HPLC-MS / MS or scintillation counting. Sampled recipient volumes are replaced with fresh recipient solution. Evaluation of plasma protein binding This equilibrium dialysis (ED) technique is used to determine the approximate in vitro fractional binding of test compounds to plasma proteins. Dianorm Teflon dialysis cells (micro 0.2) are used. Each cell consists of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a molecular weight limit of 5 kDa. Stock solutions for each test compound are prepared in 1 mM DMSO and diluted to a final concentration of 1.0 jM. Subsequent dialysis solutions are prepared in pooled human or rat plasma (with NaEDTA) from male and female donors. 200 jL aliquots of dialysis buffer (100 mM potassium phosphate, pH 7.4) are dispensed into the buffer chamber. 200 jL aliquots of the test compound dialysis solution are dispensed into the plasma chambers. An incubation is carried out for 2 hours under rotation at 37°C. At the end of the dialysis period, the dialysate is transferred to reaction tubes. The buffer fraction tubes contain 0.2 mL of ACN / water (80 / 20). 25 JL aliquots of the plasma dialysate are transferred to deep-well plates and mixed with 25 JL of ACN / water (80 / 20), 25 JL of buffer, 25 JL of calibration solution, and 25 JL of internal standard solution. Protein precipitation is performed by adding 200 JL of ACN. 50 JL aliquots of the buffer dialysate are transferred to deep-well plates and mixed with 25 JL of blank plasma, 25 JL of internal standard solution, and 200 JL of ACN. The samples are measured on HPLC-MS / MS systems and evaluated using Analyst software. The percentage of binding is calculated with the formula: % bound = (plasma concentration - buffer concentration / plasma concentration) X 100. Solubility assessment Saturated solutions are prepared in well plates (the format depends on the robot) by adding an appropriate volume of selected aqueous media (typically in the range of 0.2–1.5 mL) to each well containing a known amount of solid drug substance (typically in the range of 0.5–5.0 mg). The wells are shaken or agitated for a predefined period (typically in the range of 2–24 h) and then filtered using appropriate filter membranes (typically PTFE filters with a 0.45 µm pore size). Filter absorption is prevented by discarding the first few drops of filtrate. The amount of dissolved drug substance is determined by UV spectroscopy. In addition, the pH of the saturated aqueous solution is measured using a glass electrode pH meter. Evaluation of pharmacokinetic characteristics in rodents The test compound is administered either intravenously to fed rats or orally to fasted rats. Blood samples are taken at various time points after administration of the test compound, anticoagulated, and centrifuged. The concentration of analytes—the administered compound and / or metabolites—is quantified in plasma samples. PK parameters are calculated using non-compartmentalized methods. AUC and Cmax are normalized to a dose of 1 µmol / kg. Evaluation of metabolism in human hepatocytes in vitro The metabolic pathway of a test compound is investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, the human hepatocytes are incubated in Dulbecco's modified Eagle medium containing 5% human serum and supplemented with 3.5 g of glucagon / 500 ml, 2.5 mg of insulin / 500 ml, and 3.75 mg / 500 ml of hydrocortisone. After a 30 min pre-incubation in a cell culture incubator (37°C, 10% CO2), the test compound solution is added in a known amount to the hepatocyte suspension to obtain a final cell density of 1.0*106 to 4.0*106 cells / ml (depending on the metabolic turnover rate of the compound observed with primary human hepatocytes), a final test compound concentration of 10 jM, and a final DMSO concentration of 0.05%. The cells are incubated for six hours in a cell culture incubator on a horizontal shaker, and the samples are removed from incubation after 0, 0.5, 1, 2, 4, or 6 hours, depending on the metabolic turnover rate. The samples are quenched with acetonitrile and pelleted by centrifugation. The supernatant is transferred to a 96-well deep plate, evaporated under nitrogen, and resuspended before bioanalysis by high-resolution liquid chromatography-mass spectrometry for the identification of putative metabolites. Structures are provisionally assigned based on Fourier-MSn transform data. Metabolites are reported as a percentage of the parental incubated human hepatocytes with a threshold of >4%. TREATMENT METHOD The present invention relates to compounds of general formula 1 that are useful in the prevention and / or treatment of a disease and / or condition associated with or modulated by TRPA1 activity, including, but not limited to, the treatment and / or prevention of fibrotic disease, inflammatory and immunoregulatory disorders, respiratory or gastrointestinal diseases or discomfort, ophthalmic diseases, inflammatory diseases of the joints and inflammatory diseases of the nasopharynx, eyes and skin, and pain and neurological disorders.These disorders, diseases, and discomforts include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic, asthmatic, or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, as well as inflammatory and immunoregulatory disorders such as rheumatoid arthritis and atherosclerosis, as well as pain and neurological disorders such as acute pain, surgical pain, chronic pain, and depression and bladder disorders. Compounds with general formula 1 are useful for the prevention and / or treatment of: (1) Cough such as chronic idiopathic cough or chronic resistant cough, cough associated with asthma, COPD, lung cancer, postviral infection and idiopathic pulmonary fibrosis and other interstitial lung diseases. (2) Fibrotic lung diseases such as pneumonitis or interstitial pneumonitis associated with collagenosis, for example, lupus erythematosus, systemic scleroderma, rheumatoid arthritis, polymyositis and dermatomyositis, idiopathic interstitial pneumonias such as pulmonary fibrosis of the lung (FpI), nonspecific interstitial pneumonia, interstitial lung disease associated with respiratory bronchiolitis, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, limongioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known cause such as interstitial pneumonitis as a result of occupational exposures such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold),Pigeon (bird) breeder's lung or other occupational airborne triggers such as metal dust or mycobacteria, or as a result of treatment such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapeutic agents, or for granulomatous disease, such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonitis caused by various origins, e.g., aspiration, inhalation of toxic gases, fumes, bronchitis or pneumonitis or interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis, or alpha-1-antitrypsin deficiency. (3) Other fibrotic diseases such as bridging liver fibrosis, liver cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis. (4) Inflammatory, autoimmune or allergic diseases and conditions such as allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal polyposis, chronic rhinosinusitis, acute rhinosinusitis, asthma, pediatric asthma, allergic bronchitis, alveolitis, overactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, non-allergic asthma; exercise-induced bronchoconstriction; chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, cough, pulmonary emphysema;Systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporin), eosinophilic syndrome / myalgia due to ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenia (ITP in adults, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug-induced), Evans syndrome (immune cytopenias of platelets and red blood cells), Rh disease of the newborn, Goodpasture syndrome (anti-GBM disease), celiac disease, juvenile-onset diabetes due to autoimmune cardiomyopathy; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease;Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell-mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis, cancers with leukocyte infiltration of the skin or organs;ophthalmic diseases such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema, keratitis, eosinophilic keratitis, keratoconjunctivitis, vernal keratoconjunctivitis, scars, anterior segment scars, blepharitis, blepharoconjunctivitis, bullous disorders, cicatricial pemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye, episcleritis, glaucoma, gliosis, granuloma annulare, Graves' ophthalmopathy, intraocular melanoma, pinguecula, proliferative vitreoretinopathy, pterygium, scleritis, uveitis, acute gout attacks, gout or osteoarthritis.; (5) Pain such as chronic idiopathic pain syndrome, neuropathic pain, dysesthesia, allodynia, migraine, dental pain and post-surgical pain. (6) Depression, anxiety, diabetic neuropathy and bladder disorders such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemia injury. Therefore, the present invention relates to a compound of general formula 1 for use as a medicament. Furthermore, the present invention relates to the use of a compound of general formula 1 for the treatment and / or prevention of a disease and / or condition associated with or modulated by TRPA1 activity. Furthermore, the present invention relates to the use of a compound of general formula 1 for the treatment and / or prevention of fibrotic disease, inflammatory and immunoregulatory disorders, respiratory or gastrointestinal diseases or discomforts, ophthalmic diseases, inflammatory diseases of the joints and inflammatory diseases of the nasopharynx, eyes and skin, pain and neurological disorders. Such disorders, diseases and discomforts include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic, asthmatic or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, as well as inflammatory and immunoregulatory disorders, such as rheumatoid arthritis and atherosclerosis, as well as pain and neurological disorders, such as acute pain, surgical pain, chronic pain and depression, and bladder disorders. Furthermore, the present invention relates to the use of a compound of general formula 1 for the treatment and / or prevention of: (1) Cough such as chronic idiopathic cough or chronic resistant cough, cough associated with asthma, COPD, lung cancer, postviral infection and idiopathic pulmonary fibrosis and other interstitial lung diseases. (2) Fibrotic lung diseases such as pneumonitis or interstitial pneumonitis associated with collagenosis, for example, lupus erythematosus, systemic scleroderma, rheumatoid arthritis, polymyositis and dermatomyositis, idiopathic interstitial pneumonias, such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, interstitial lung disease associated with respiratory bronchiolitis, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung diseases of known cause, such as interstitial pneumonitis as a result of occupational exposures such as asbestosis, silicosis, miner's lung (coal dust), lung of farmer (hay and mold),Pigeon (bird) breeder's lung or other occupational airborne triggers such as metal dust or mycobacteria, or as a result of treatment such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapeutic agents, or for granulomatous disease, such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonitis caused by various origins, e.g., aspiration, inhalation of toxic gases, fumes, bronchitis or pneumonitis or interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, M. boeck or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis, or alpha-1-antitrypsin deficiency. (3) Other fibrotic diseases such as bridging liver fibrosis, liver cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arterial stiffness, arthrofibrosis, Dupuytren's contracture, keloid, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis. (4) Inflammatory, autoimmune or allergic diseases and conditions such as allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal polyposis, chronic rhinosinusitis, acute rhinosinusitis, asthma, pediatric asthma, allergic bronchitis, alveolitis, overactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, non-allergic asthma; exercise-induced bronchoconstriction; chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, cough, pulmonary emphysema;Systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporin), eosinophilic syndrome / myalgia due to ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenia (ITP in adults, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug-induced), Evans syndrome (immune cytopenias of platelets and red blood cells), Rh disease of the newborn, Goodpasture syndrome (anti-GBM disease), celiac disease, juvenile-onset diabetes due to autoimmune cardiomyopathy; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease;Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell-mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis, cancers with leukocyte infiltration of the skin or organs;ophthalmic diseases such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema, keratitis, eosinophilic keratitis, keratoconjunctivitis, vernal keratoconjunctivitis, scars, anterior segment scars, blepharitis, blepharoconjunctivitis, bullous disorders, cicatricial pemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye, episcleritis, glaucoma, gliosis, granuloma annulare, Graves' ophthalmopathy, intraocular melanoma, pinguecula, proliferative vitreoretinopathy, pterygium, scleritis, uveitis, acute gout attacks, gout or osteoarthritis.; (5) Pain such as chronic idiopathic pain syndrome, neuropathic pain, dysesthesia, allodynia, migraine, dental pain and post-surgical pain. (6) Depression, anxiety, diabetic neuropathy and bladder disorders such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemia injury. In an additional aspect, the present invention relates to a compound of general formula 1 for use in the treatment and / or prevention of the diseases and conditions mentioned above. In an additional aspect, the present invention relates to the use of a compound of general formula 1 for the preparation of a medicament for the treatment and / or prevention of the diseases and conditions mentioned above. COMBINATION THERAPY The compounds of the invention may be further combined with one or more, preferably one additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or disorders described above herein, in particular those associated with fibrotic diseases, inflammatory and immunoregulatory disorders, respiratory or gastrointestinal diseases or discomforts, inflammatory diseases of the joints or nasopharynx, eyes and skin, or conditions such as, for example, cough, idiopathic pulmonary fibrosis, other interstitial lung diseases, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, atopic dermatitis, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, or therapeutic agents useful for the treatment of ophthalmic diseases, pain, and depression. Additional therapeutic agents that are suitable for such combinations include in particular those that, for example, enhance the therapeutic effect of one or more active substances with respect to one of the aforementioned indications and / or allow for a reduction in the dosage of one or more active substances. Therefore, a compound of the invention can be combined with one or more additional therapeutic agents selected from the group consisting of antifibrotic agents, antitussive agents, anti-inflammatory agents, anti-atopic dermatitis agents, analgesics, anticonvulsants, anxiolytics, sedatives, skeletal muscle relaxants, or antidepressants. Antifibrotic agents include, for example, nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors such as roflumilast, autotaxin inhibitors such as GLPG-1690 or BBT-877; connective tissue growth factor (CTGF) blocking antibodies such as pamrevlumab; B-cell activating factor receptor (BAFF-R) blocking antibodies such as lanalumab; alpha-V / beta-6 blockade inhibitors such as BG-00011 / STX-100, recombinant pentraxin-2 (PTX-2) such as PRM-151; c-Jun N-terminal kinase (JNK) inhibitors such as CC-90001; galectin-3 inhibitors such as TD-139; and G protein-coupled receptor 84 (GPR84) inhibitors such as GLPG-1205. dual inhibitors of G protein-coupled receptor 84 / G protein-coupled receptor 40 such as PBI-4050; inhibitors of Rho-associated helical helix-containing protein kinase 2 (ROCK2) such as KD-025;small interfering RNA of heat shock protein 47 (HSP47) such as BMS-986263 / ND-L02-s0201; Wnt pathway inhibitor such as SM-04646; LD4 / PDE3 / 4 inhibitors such as Tipelukast; recombinant immunomodulatory domains of histidyl tRNA synthetase (HARS) such as ATYR-1923; prostaglandin synthase inhibitors such as ZL-2102 / SAR-191801; 15-hydroxyeicosapentaenoic acid (15-HEPE, for example, DS-102); lysyl oxidase type 2 (LOXL2) inhibitors such as PAT-1251, PXS-5382 / PXS-5338; dual inhibitors of phosphoinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) such as HEC-68498; calpain inhibitors such as BLD-2660; mitogen-activated protein kinase kinase (MAP3K19) inhibitors such as MG-S-2525; chitinase inhibitors such as OATD-01; mitogen-activated protein kinase 2 (MAPKAPK2) inhibitors such as MMI-0100;small interfering RNA of transforming growth factor beta 1 (TGF-beta1) such as TRK250 / BNC-1021; or lysophosphatidic acid receptor antagonists such as BMS-986278.; Antitussive agents include, for example, purinoceptor 3 (P2X3) receptor antagonists such as gefapixant, S-600918, BAY-1817080, or BLU-5937; neurokinin 1 (NK-1) receptor antagonists such as orvepitant and aprepitant; alpha 7 nicotinic acetylcholine receptor subunit stimulators such as ATA-101 / bradanicline; codeine, gabapentin, pregabline, or azithromycin. Anti-inflammatory agents include, for example, corticosteroids such as prednisolone or dexamethasone; cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; and prostaglandin E2 antagonists. leukotriene B4 antagonists; leukotriene D4 antagonists such as monteleukast; 5-lipoxygenase inhibitors; or other nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, ibuprofen, or indomethacin. Anti-atopic dermatitis agents include, for example, cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, phosphodiesterase inhibitors (e.g., apremilast, crisaborol), Janus-associated kinase (JAK) inhibitors (e.g., tofacitinib), IL-4 / IL-13 neutralizing antibodies (e.g., dupilamab), IL-13 (e.g., lebrikizumab, tralokinumab), and IL-31 (nemolizumab). Analgesics are, for example, of the opioid type, such as morphine, oxymorphine, levopanol, oxycodone, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidin, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butyranolol, nalbuphine, pentazocine; or of the non-opioid type, such as acetophenamine. Antidepressants include, for example, tricyclic antidepressants such as amitriptyline, clomipramine, despramine, doxepin, desipramine, imipramine, nortriptyline; selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine, paroxetine, sertraline, citalopram, escitalopram; norepinephrine reuptake inhibitor (SNRI) antidepressants such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, hydroxybupropion, nomifensine, viloxazine; and dual serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants such as duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran. atypical antidepressants such as trazodone, mirtazapine, vortioxetine, vilazodone, bupropion; or monoamine oxidase inhibitor (MAOI) antidepressants such as tranylcypromine, phenelzine, or isocarboxazid. Ansiolytics are, for example, benzodiazepines such as alprazolam, bromazepam, clordiazepoxide, clonazepam, clorazepato, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam or tofisopam; o those hypnotics different from benzodiazepines such as eszopiclona, ​​zaleplón, zolpidem or zopiclona; o those carbamatoes, for example, meprobamato, carisoprodol, tibamato or lorbamato; or antihistamines such as hydroxyzine, chlorpheniramine or diphenhydramine. Sedantes are, for example, barbituric sedantes, tales like amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metarbital, metohexital, pentobarbital, secobarbital, talbutal, teamilal or tiopental; o those sedantes contain no barbituric tales like gluttimida, meprobamato, metacualona or dicloalphenazona. Skeletal muscle relaxants include, for example, baclofen, meprobamate, carisoprodol, cyclobenzaprine, metaxalone, methocarbamol, tizanidine, chlorzoxazone, or orphenadrine. Other suitable combination pairs include acetylcholinesterase inhibitors such as donepezil; 5-HT3 antagonists such as ondansetron; metabotropic glutamate receptor antagonists; antiarrhythmics such as mexiletine or phenytoin; or NMDA receptor antagonists. Additional suitable combination pairs include incontinence medications, for example, anticholinergics such as oxybutynin, tolterodine, darifenacin, fesoterodine, solifenacin, or trospium; or bladder skeletal muscle relaxants such as mirabegron. or are alpha blockers such as tamsulosin, alfuzosin, silodosin, doxazosin or terazosin. The dosage for the combination couples mentioned above is usually from 1 / 5 of the minimum normally recommended dose to 1 / 1 of the normally recommended dose. 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 above and below in this document for the treatment of diseases or conditions that may be affected by or mediated by TRPA1, in particular diseases or conditions as described above and below in this document. In a further aspect, this invention relates to a method for treating a disease or condition that may be influenced by the inhibition of TRPA1 in a patient, including the step of administering to the patient in need of such treatment an effective therapeutic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents. In an additional aspect, this invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of diseases or conditions that may be influenced by the inhibition of TRPA1 in a patient who needs it. In yet another aspect, the present invention relates to a method for treating a disease or condition mediated by TRPA1 activity in a patient, which includes the step of administering to the patient, preferably a human, who needs such treatment, a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described above and below in this document. The use of the compound according to the invention in combination with the additional therapeutic agent can take place simultaneously or at staggered times. The compound according to the invention and one or more additional therapeutic agents may both be present together in one formulation, for example, a tablet or capsule, or separately in two identical or different formulations, for example, as a so-called kit of parts. Accordingly, in another aspect, this invention relates to a pharmaceutical composition comprising a compound according to the invention and one or more additional therapeutic agents described above and below, optionally together with one or more inert carriers and / or diluents. In yet another aspect, the present invention relates to the use of a compound according to the invention in a cough measuring device. Other features and advantages of the present invention will become evident from the following more detailed examples which illustrate, by way of example, the principles of the invention. PREPARATION The compounds according to the present invention and their intermediate products can be obtained using synthetic methods known to a person skilled in the art and described in the organic synthesis literature. Preferably, the compounds are obtained in a manner analogous to the preparation methods explained more fully below in this document, particularly as described in the experimental section. In some cases, the order in which the reaction steps are carried out may be varied. Variations of the reaction methods known to a person skilled in the art, but not described in detail herein, may also be used. The general processes for preparing the compounds according to the invention will be evident to a person skilled in the art by studying the following schemes. Any functional group in the starting materials or intermediate products can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage within the reaction sequence using methods familiar to a person skilled in the art. The compounds according to the invention are prepared by the synthetic methods described below, in which the substituents in the general formulas have the meanings provided earlier herein. These methods are provided for illustrative purposes only and do not restrict the scope of the claimed compounds to these examples. When the preparation of starting compounds is described, they are commercially available or can be prepared analogously to known compounds or methods described herein. The substances described in the bibliography are prepared according to published synthetic methods. Abbreviations are as defined in the Examples section. Scheme 1 In Scheme 1, chloromethyltetrazole is N-alkylated with a suitable ethanone derivative bearing an alpha "Lg" leaving group (e.g., Cl or Br) relative to the carbonyl group in the presence of a base (e.g., K₂CO₃) to give a mixture of two regioisomers. The unwanted regioisomer (not shown) can be removed by chromatography using an appropriate gradient. The resulting ketone (A) can be reduced in an enantioselective manner using appropriate catalytic systems with a transition metal complex (e.g., Ru or Ir) in combination with a chiral ligand (e.g., ([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido) and a hydrogen source such as a formic acid-triethylamine complex to give alcohol (B). The uracil derivative (D) can be synthesized from a monosubstituted urea and 1,3-diethyl 2-(ethoxymethylidene)propanedioate under pure conditions at elevated temperature to either directly give (D) or give (C), which can be further reacted to give (D) under basic conditions such as NaOEt in EtOH at elevated temperature. The primary amide (E) can be synthesized from ester (D) by stirring with ammonia in a solvent such as water or an alcohol at elevated temperature in a sealed container. The final compounds (I) can be synthesized by alkylation of (E) with the intermediate product (B) in the presence of a base such as K2CO3. Alternatively, alkylation of the intermediate product (D) with (B) in the presence of a base gives (F), which can be hydrolyzed with a suitable reagent such as LiOH to give an acid (G). The acid (G) can then be coupled to an amine in the presence of an amide coupling reagent such as hAtU and in the presence of a base such as DIPEA to provide the final compounds (I). Alternatively, compounds of formula (I) can be prepared as shown in scheme 2 below. In Scheme 2, the intermediate product (H) can be prepared by alkylation of (E) with an acetonitrile derivative bearing an "LG" leaving group (e.g., Cl or Br) in the presence of a base such as DIPEA. The formation of tetrazole (J) can be carried out under typical reaction conditions for tetrazole formation (e.g., using NaN3 in the presence of TEA / TEA hydrochloride in DMF). Alkylation of tetrazole (J) with a suitable ethanone derivative bearing an "LG" leaving group (e.g., Cl or Br) alpha to the carbonyl group is performed in the presence of a base such as DIPEA to provide a mixture of two regioisomers. The unwanted regioisomer (not shown) can be removed by chromatography using an appropriate gradient.Finally, the keto group of (K) can be reduced in an enantioselective manner using appropriate catalytic systems with a transition metal complex (e.g., Ru or Ir) in combination with a chiral ligand (e.g., ([(1S,2SJ-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido) and a hydrogen source such as a formic acid-triethylamine complex to provide the final compounds (I). Alternatively, the final compounds (I) can be prepared by alkylation of the intermediate product (J) with a suitable aromatic or heteroaromatic ethanol derivative bearing an alpha "LG" leaving group (e.g., Cl or Br) relative to the hydroxyl group, in the presence of a base such as DIpEA, and subsequent isolation of the desired regioisomer. EXAMPLES PREPARATION The compounds according to the invention and their intermediate products can be obtained using synthetic methods known to a person skilled in the art and described in the organic synthesis literature, for example, using methods described in "Comprehensive Organic Transformations," 2nd edition, Richard C. Larock, John Wiley & Sons, 2010, and "March's Advanced Organic Chemistry," 7th edition, Michael B. Smith, John Wiley & Sons, 2013. Preferably, the compounds are obtained in a manner analogous to the preparation methods explained more fully below in this document, particularly as described in the experimental section. In some cases, the sequence adopted in carrying out the reaction schemes may be varied. Variations of these reactions known to a person skilled in the art, but not described in detail herein, may also be used.The general processes for preparing the compounds according to the invention will become evident to a person skilled in the art upon studying the following schemes. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared in an analogous or similar manner. Before carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable step within the reaction sequence using methods familiar to a person skilled in the art and described in the literature, for example, in "Protecting Groups," 3rd edition, Philip J. Kocienski, Thieme, 2005, and "Protective Groups in Organic Synthesis," 4th edition, Peter G.M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.The terms "ambient temperature" and "room temperature" are used interchangeably and designate a temperature of approximately 20°C, for example, between 19 and 24°C. Abbreviations: Preparation of intermediate products Intermediate product I Intermediate product I.1 (general procedure) 2-[5-(Chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-dorophenyl)ethan-1-one 1.00 g (8.44 mmol) of 5-(chloromethyl)-2H-1,2,3,4-tetrazol and 2.17 g (9.28 mmol) of 4-chlorophenacyl bromide in 15 mL of DMA are mixed with 1.63 g (11.8 mmol) of K₂CO₃ with stirring at room temperature. The reaction mixture is stirred for 30 min at room temperature and then filtered. The filtrate is diluted with water and saturated aqueous NaCl solution and extracted three times with EtOAc. The combined organic phases are washed with water, dried over Na₂SO₄, filtered through activated carbon, and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; CH₄ / EtOAc, gradient from 80 / 20 to 50 / 50) to yield the product. The following compounds are prepared using procedures analogous to those described for intermediate product I.1 using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate Product II Intermediate product II.1 (general procedure) (1R)-2-[5-(Chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethane-1-ol 1.30 g (4.80 mmol) of 1-(4-chlorophenyl)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]ethan-1-one (intermediate I.1) is dissolved in 20 mL of ACN under an inert atmosphere. 12 mg (0.02 mmol) of chloro([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) (CAS 174813-81-1) is added, followed by the dropwise addition of 0.72 mL (1.73 mmol) of formic acid-triethylamine complex (5:2). After stirring at room temperature for 3 h, the solvent is removed under reduced pressure. Water is added to the remaining crude mixture, and this mixture is extracted with EtOAc. The organic phases are combined, dried over Na2SO4, filtered, treated with activated carbon, filtered again, and the solvent is removed under reduced pressure to provide intermediate product II.1. The following compounds are prepared using procedures analogous to those described for intermediate product II.1 using appropriate starting materials. As those skilled in the art will appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate Product III 3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 10.0 g (50.46 mmol) of ethyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate (CAS: 154942-22-0, intermediate XII.6) in 33% aq ammonia (120 mL) are stirred in a sealed container at 100°C for 10 h. The reaction mixture is cooled to TA and concentrated under reduced pressure. The residue is ground with ACN, separated by filtration, and dried at 50°C to provide intermediate III. Rt (HPLC): 0.48 min (method B) Intermediate Product IV Intermediate product IV.1 (general procedure) 1 - (5, 6-Difluoro-1 -benzofuran-2-yl) ethan-1 -one 5.00 g (31.6 mmol) of 4,5-difluoro-2-hydroxybenzaldehyde in 50 mL of acetone are treated with 6.99 g (50.6 mmol) of potassium carbonate under argon at 0°C. After further stirring for 10 min at 0°C, 3.78 mL (47.4 mmol) of chloroacetone are added dropwise, and the reaction mixture is stirred at 70°C for 3 h. The reaction mixture is cooled to TA and concentrated. The crude product is extracted with EtOAc / water, and the organic phase is concentrated under reduced pressure to provide intermediate IV.1. C10H6F2O2 (M = 196.2 g / mol) 1H NMR (300 MHz, DMSO-de) 5 ppm: 2.56 (s, 3 H), 7.89 (m, 1 H), 7.92 (m, 1 H), 8.01 (m, 1 H) The following compounds are prepared using procedures analogous to those described for intermediate IV.1 using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate product V 5-bromo-1-benzofuran-2-carboxylic acid 6.58 g (24.4 mmol) of ethyl 5-bromo-1-benzofuran-2-carboxylate (IV.4) in 3 mL of EtOH, 66 mL of THF, and 33 mL of water are mixed with 1.23 g (29.3 mmol) of LiOH*H2O at 0°C. The reaction mixture is stirred at room temperature for 2 minutes and then concentrated under reduced pressure. The residue is acidified with 1 M HCl to pH 5, and the resulting precipitate is separated by filtration and dried to provide intermediate product V. CgHeBrOa (M = 241.0 g / mol) 1H NMR (300 MHz, DMSO-de) 5 ppm: 7.59-7.76 (m, 3 H), 8.02 (d, J= 2.0 Hz, 1 H), 13.5 - 14.2 (sa, 1 H). Intermediate product VI 5-Bromo-2-fluoro-1-benzofuran 5.00 g (20.7 mmol) of 5-bromo-1-benzofuran-2-carboxylic acid (V), 14.70 g (41.5 mmol) of Selectflour, and 4.82 g (83.0 mmol) of potassium fluoride in 185 mL of DCE and 95 mL of water are shaken in a sealed tube at 70°C for 20 h. Subsequently, the reaction mixture is extracted with DCM / water. The organic phase is washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, DCM). CsH4BrFO (M = 215.0 g / mol) 1H NMR (300 MHz, from DMSO) at 5 ppm: 6.36 (dd, J= 6, 4, 0.9 Hz, 1 H) , 7.47 (dd, J=8, 7, 2, 1 Hz, 1 H) , 7.58 (d, J= 78, 1 Hz, 1 Hz) (d, J= 2, 1 Hz, 1 H) Intermediate VII 1-(2-Fluoro-1-benzofuran-5-yl) ethane-1-one 218 mg (1.0 mmol) of 5-bromo-2-fluoro-1-benzofuran(VI) in 3 mL of DMF and 0.3 mL of water are mixed with 168 mg (1.2 mmol) of potassium carbonate with stirring at room temperature. The mixture is purged with argon followed by the addition of 25 mg (0.1 mmol) of 1,3-bis(diphenylphosphino)propane, dppp, 7 mg of palladium(II) acetate, and 183 mg (2.5 mmol) of ethyl vinyl ether. The reaction mixture is stirred at 80°C overnight, then cooled to room temperature and treated with 1 M aq HCl (20 mL). After stirring at room temperature for 30 min, the mixture is extracted with EtOAc and the combined organic phases are concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel; EtOAc / hexane, gradient). C10H7FO2 (M = 178.2 g / mol) 1H NMR (300 MHz, DMSO-de) 5 ppm: 2.63 (s, 3H), 6.49 (dd, J= 6, 4, 0.8 Hz, 1H), 7. 70 (dt, J= 8. 7, 0.8 Hz, 1H), 7. 93 (dd, J=8, 7, 1, 9 Hz, 1H), 8, 25 (dd, J= 1, 9, 0, 6 Hz, 1H) Intermediate Product VIII Intermediate product VIII.1 (general procedure) 2-Bromo-1-(2-fluoro-1-benzofuran-5-yl)ethan-1-one 126 mg (0.71 mmol) of 1-(2-fluoro-1-benzofuran-5-yl)ethan-1-one (VII) in 1.5 mL of THF are treated dropwise with 0.34 g (0.71 mmol) of tetrabutylammonium tribromide in 0.08 mL of MeOH and 0.8 mL of THF with stirring at room temperature. After stirring for 2 h, the reaction mixture is concentrated under reduced pressure and the residue is extracted with EtOAc / water. The organic phase is concentrated under reduced pressure and the crude product is purified by column chromatography (silica gel; hexane / EtOAc, gradient). C10H6BrFO2 (M = 257.1 g / mol) 1H NMR (300 MHz, DMSO-de) 5 ppm: 4.99 (s, 2H), 6.53 (dd, J= 6.4, 0.9 Hz, 1H), 7.75 (d, J= 8.7, 1H), 7.88-8.03 (m, 1H), 8.31 (dd, J= 1, 9, 0, 6 Hz, 1H) The following compounds are prepared using procedures analogous to those described for the intermediate product VMM, using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate product IX 1- ({2-[ (2R) -2- (4-Chlorophenyl) -2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl) -3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl 200 mg (1.01 mmol) of ethyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate (CAS: 154942-22-0, intermediate product XII.6) in 8 ml of DMF is mixed with 303 mg (1.11 mmol) of (1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethan-1-ol (intermediate product II.1) and 418 mg (3.03 mmol) of K2CO3 and the mixture is stirred at 50°C for 5 h, then at TA for 17 h. The crude product is purified by reverse-phase HPLC (ACN / H2O gradient, 0.1% TFA) to give the desired product. C18H19ClN6O5 (M = 434.8 g / mol) Intermediate product X 1-({2-[(2R)-2-(4-chlorophenM)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid To 200 mg (0.46 mmol) of intermediate IX in 1 mL of methanol, 1 mL of THF, and 100 µL of water, 44 mg (1.8 mmol) of lithium hydroxide are added. The reaction mixture is stirred for 1 h at 50°C and then cooled to room temperature and diluted with water. The acid phase is washed with DCM three times, acidified with formic acid, and the resulting precipitate is separated by filtration and dried at 50°C to give the desired product. Intermediate product XI Intermediate product XI.1 (general procedure) 1,3-Diethyl 2-{[(Cyclobutylcarbamoyl)amino]methylidene}propanedioate 1.00 g (8.76 mmol) of cyclobutylurea and 3.79 g (17.52 mmol) of 1,3-diethyl 2-(ethoxymethylidene)propanedioate are heated under pure conditions at 100°C for 2.5 h, and then at 130°C for 5 h. The reaction mixture is cooled to TA, diluted with methanol, and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA) to provide intermediate product XI.1. The following compounds are prepared using procedures analogous to those described for intermediate XI.1 using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate product XII Intermediate product XII.1 (general procedure) Ethyl 1-Cyclobutyl-2-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxylate 2.00 g (7.03 mmol) of intermediate product XI.1 in 30 ml of ethanol are mixed with 957 mg (14.1 mmol) of sodium ethoxide and the mixture is stirred at 80°C for 3 h, then diluted with ethanol and purified by reverse-phase HPLC (ACN / H2O gradient, 0.1% TFA). The following compounds are prepared using procedures analogous to those described for intermediate product XII.1 using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate product XII.6 3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate 500 mg (6.75 mmol) of methylurea and 1.36 g (6.75 mmol) of 1,3-diethyl 2-(methoxymethylidene)propanedioate are stirred under pure conditions at 120°C for 2 h, at room temperature for 17 h, at 100°C for 66 h, at 150°C for 17 h, and at 120°C for 17 h. Subsequently, the mixture is diluted with EtOAc and refluxed. The mixture is slowly cooled to room temperature, and the precipitated intermediate product is separated by filtration. Intermediate product XIII Intermediate product XIII.1 (general procedure) 1 -Cyclobutyl-2-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxamide 630 mg (0.03 mmol) of intermediate XII.1 in 10 mL of acetic ammonia (33%) are stirred at 85°C for 17 h in a sealed container. Stirring is continued at 100°C and acetic ammonia is added until the starting material is completely consumed. The reaction mixture is then concentrated under reduced pressure to provide intermediate XIII.1. The following compounds are prepared using procedures analogous to those described for intermediate product XIII.1 using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the overall reaction conditions. Intermediate product XIV.1 (Cyclopropylmethyl)urea 530 mg (4.93 mmol) of 1-cyclopropylmethanamine hydrochloride in 2 ml of water is mixed with 599 mg (7.39 mmol) of potassium cyanate in small portions and the mixture is stirred at 100°C for 3 h. The reaction mixture is left at room temperature for 14 h, then the intermediate product XIV.1 is separated by filtration. Intermediate product XIV.2 (2-Methoxyethyl) urea 2.0 g (26.63 mmol) of 2-methoxyethylamine in 8 ml of water is mixed with 3.24 g (39.94 mmol) of potassium cyanate in small portions and the mixture is stirred at 100°C for 3 h, cooled to TA, diluted with water / methanol and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA). Preparation of the final compounds Example 1 (general procedure) 1-({2-[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 100 mg (0.59 mmol) of 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carboxamide (intermediate III) in 5 mL of DMF is mixed with 178 mg (0.65 mmol) of (1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethan-1-ol (intermediate II.1) and 245 mg (1.77 mmol) of K2CO3, and the mixture is stirred at room temperature overnight. The mixture is purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA) to give the desired product. 1H NMR (400 MHz, DMSO-de) 5 ppm: 3, 21 (s, 3 H) , 4, 7.- 4, 84 (m, 2 H) , 5, 13 (m, 1 H) , 5, 45 (s, 2 H) , 5, 92 (d, J=2, 4 Hz, 1 H) , 7, 35-7, 42 (m, 4 H) , 7, 64 (ad, J=3, 4 Hz, 1 H) , 8, 20 (ad, J=3, 4 Hz, 1 H) , 8, 77 (s, 1 H) The following compounds are prepared using procedures analogous to those described for Example 1, using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the general reaction conditions. Analytical data for the compounds described in the table above: Example 22 (general procedure) 1-({2-[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-N-(2-methoxyethyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide 20 mg (0.05 mmol) of intermediate product X in 1.0 mL of DMF is mixed with 25 µl (0.15 mmol) of DIPEA and 22 mg (0.06 mmol) of HATU with stirring at room temperature. After 30 min, 8 µl (0.10 mmol) of 2-methoxyethan-1-amine is added, and the mixture is stirred at room temperature for 90 min. Subsequent purification by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA) yields the desired product. 1H NMR (400 MHz, DMSO-de) 5 ppm 3, 22 (s, 3 H) , 3, 28 (s, 3 H) , 3, 4.- 3, 51 (m, 4 H) , 4, 7.- 4, 84 (m, 2 H) , 5, 13 (m, 1 H) , 5, 45 (s, 2 H), 5, 5 - 6, 4 (sa, 1 H), 7, 38 (m, 4 H), 8, 77 (s, 1 H), 8, 94 (m, 1 H). The following compounds are prepared using procedures analogous to those described for Example 22, using appropriate starting materials. As those skilled in the art appreciate, these analogous examples may involve variations in the general reaction conditions. Analytical data for the compounds described in the table above: Analytical HPLC methods Method A Method B Method C Method D Method E Method F Method G Method H Method I Method J

Claims

1. A compound according to formula (I) wherein A is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl or benzofuranil, unsubstituted or substituted with one, two or three members of group R3 consisting of halogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 cyclofluoroalkyl, C1-4 O-alkyl, O-cyclopropyl and NC-; or A is selected from the group consisting of and R1 is selected from the group consisting of C1-4 alkyl, C1-4 fluoroalkyl, C3-6 cycloalkyl, R4-(H2C)m- and R5-(H2C)n-; wherein m is 1 or 2; n is 2; R4 is C3-6 cycloalkyl; R5 is C1-4 -O-alkyl or C1-4 -O-fluoroalkyl; R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cyclofluoroalkyl, HO-C1-4 alkyl, C1-4 fluoroalkyl, R6-(H2C)p-, R7-(H2C)q-, R6-(H(R8)C)p- and R7-(H(R9)C)q-; wherein p is 1 or 2; q is 2; R6 is selected from the group consisting of HO-C1-2 alkyl, C3-6 cycloalkyl, C-morpholinyl,C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl are either unsubstituted or substituted with C1-4 alkyl or C1-4 fluoroalkyl; R7 is selected from the group consisting of C1-4-O-alkyl, C1-4-O-fluoroalkyl, C1-4-S(O)2-alkyl, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, N-morpholinyl are either unsubstituted or substituted with C1-4 alkyl or C1-4 fluoroalkyl; R8 and R9 are selected independently of H or C1-4 alkyl.

2. The compound of formula (I) according to claim 1, wherein A is selected from the group consisting of phenyl, thiophenyl, benzothiophenyl, or benzofuranyl, unsubstituted or substituted with one or two members of group R3 consisting of Cl, F, Br, H3C, H3C-O-, and NC-; or A is 3. The compound of formula (I) according to claim 1, wherein A is selected from the group consisting of and unsubstituted or substituted with one or two members of group R3 consisting of Cl, F, Br, H3C,H3C-O- and NC-, A is 4.- The compound of formula (I) according to any one of claims 1 to 3, wherein R1 is selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, R4- (H2C) m- and R5- (H2C) n-; wherein m is 1; n is 2; R4 is C3-6 cycloalkyl; and R5 is -O-C1-4 alkyl. 5.- The compound of formula (I) according to any one of claims 1 to 3, wherein R1 is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, R4- (H2C) m- and R5- (H2C) n-; wherein m is 1; n is 2; R4 is C3-4 cycloalkyl; and R5 is -O-C1-4 alkyl.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl, C1-4 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; wherein p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl,C-imidazolyl and C-morpholinyl are either unsubstituted or substituted with C1-4 alkyl. R7 is selected from the group consisting of -O-C1-4 alkyl, -O-C1-4 fluoroalkyl, C1-4 alkyl-S(O)2-, N-morpholinyl, N-imidazolyl, and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl, and N-morpholinyl are either unsubstituted or substituted with C1-4 alkyl.

7. The compound of formula (I) according to any one of claims 1 to 5, wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl, C1-2 fluoroalkyl, R6-(H2C)p-, and R7-(H2C)q-; wherein p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl; wherein said C-pyrazolyl, C-imidazolyl and C-morpholinyl is unsubstituted or substituted with H3C; R7 is selected from the group consisting of H3C-O, -O-fluoromethyl, H3C-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl; wherein said N-pyrazolyl, N-imidazolyl,N-morpholinyl is unsubstituted or substituted with H3C.

8. The compound of formula (I) according to any one of claims 1 to 5, wherein R2 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl, HO-C1-4 alkyl, C1-2 fluoroalkyl, R6-(H2C)p- and R7-(H2C)q-; wherein p is 1; q is 2; R6 is selected from the group consisting of C3-6 cycloalkyl, and R7 is selected from the group consisting of H3C-O, -O-fluoromethyl, H3C-S (O) 2-, and 9. The compound of formula (I) according to any one of claims 1 to 3, selected from the group consisting of 5 10. The compound of formula (I) according to claim 1, selected from the group consisting of 5 5 5 5 and 11. The compound of formula (I) according to claim 1, having the structure 12. The compound of formula (I) according to claim 1, having the structure 13. The compound of formula (I) according to claim 1,14. The compound of formula (I) according to claim 1, having structure 15. The compound of formula (I) according to claim 1, having structure 16. The compound of formula (I) according to claim 1, having structure 17. The compound of formula (I) according to claim 1, having structure 18. The compound of formula (I) according to claim 1, having structure 19. The compound of formula (I) according to claim 1, having structure 20. The compound of formula (I) according to claim 1, having structure 21. A salt, particularly a pharmaceutically acceptable salt,21. A compound according to any one of claims 1 to 20.

22. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

23. The compound of formula (I) according to one or more of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as a medicament.

24. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of inflammatory diseases of the airways or fibrotic diseases or cough.

25. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of idiopathic pulmonary disease (IPF) or cough.