New tetrazoles

Abstract

The present invention relates to tetrazoles, their use as inhibitors of TRPA1 activity, pharmaceutical compositions containing them, and methods of using them as therapeutic and / or preventative agents for fibrotic, inflammatory, autoimmune, and central nervous system-related diseases.

Description

[Technical field]

[0001] The present invention relates to tetrazoles, their use as inhibitors of TRPA1 activity, pharmaceutical compositions containing same, and methods of their use as therapeutic and / or prophylactic agents for fibrotic, inflammatory, autoimmune, and central nervous system-related disorders. [Background technology]

[0002] Transient receptor potential channels (TRP channels) are a group of voltage-gated ion channels located primarily on the plasma membrane in many mammalian cell types. There are approximately 30 structurally related TRP channels, classified as TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Transient receptor potential cation channel subfamily A member 1 (TRPA1), also known as transient receptor potential ankyrin 1, is the only 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), which is the source of the "A" in the ankyrin nomenclature (Montell, 2005).

[0003] TRPA1 is highly expressed in the small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and lymphocytes (https: / / www.proteinatlas.org / ), as well as in the plasma membrane of sensory neurons in dorsal root ganglia and inferior ganglia that serve both the skin and the lungs, and in human lung fibroblasts.

[0004] TRPA1 is best known as a sensor of environmental stimuli that trigger somatosensory modalities such as pain, cold, and itch. TRPA1 is activated by many reactive electrophilic stimuli (e.g., allyl isothiocyanate, reactive oxygen species) as well as non-reactive compounds (e.g., icilin) ​​and is involved in coughing in asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), post-viral cough, chronic idiopathic cough, or coughing in susceptible patients (Song and Chang, 2015; Grace and Belvisi, 2011). Based on studies showing cough-induced TGF-β elevation and the association between cough and lung injury, TRPA1 inhibitors may be useful for treating IPF with high cough (Xie et al., 2009; Froese et al., 2016; Tschumperlin et al., 2003; Yamamoto et al., 2002; Ahamed et al., 2008). TRPA1 antagonists suppress calcium signaling induced by cough triggers such as cigarette smoke extract (CSE) oxidative stress, inflammatory mediator release, and decreased antioxidant gene expression (Lin et al., 2015; Wang et al., 2019). TRPA1 antagonists have been effective in studying atopic dermatitis (Oh et al., 2013; Wilson et al., 2013), contact dermatitis (Liu et al., 2013), psoriasis-associated itch (Wilson et al., 2013), and IL-31-dependent itch (Cevikbas et al., 2014). Gain of function of human TRPA1 has been associated with familial episodic pain syndrome (Kremeyer et al., 2010). A behavioral model of migraine-associated allodynia has been successfully treated with TRPA1 antagonists (Edelmayer et al., 2012). TRPA1 is selectively increased in the trigeminal ganglion of injured teeth compared to stimulation of the trigeminal ganglion of healthy teeth (Haas et al., 2011).Several anesthetics, including isoflurane, are known as TRPA1 antagonists (Matta et al., 2008), providing a rationale for TRPA1 inhibitors for the relief of postoperative pain. TRPA1 knockout and wild-type mice exhibit anxiolytic and antidepressant-like phenotypes after treatment with TRPA1 antagonists (de Moura et al., 2014). TRPA1 antagonists are expected to be advantageous for the treatment of diabetic neuropathy based on studies showing a mechanistic link in the inverse regulation between AMPK and TRPA1 (Hiyama et al., 2018; Koivisto and Pertovaara, 2013; Wang et al., 2018). TRPA1 knockout mice exhibit smaller myocardial infarct size compared to wild-type mice (Conklin et al., 2019). TRPA1 knockout and pharmacological intervention suppressed TNBS-induced colitis in mice (Engel et al., 2011). In a mouse model of cerebral ischemia, TRPA1 knockout and TRPA1 antagonists reduce myelin damage (Hamilton et al., 2016). In a monosodium urate mouse model of gout, TRPA1 knockout mice have reduced urate crystals and arthritis (Moilanen et al., 2015). TRPA1 deletion in rats ameliorates arthritis and hyperalgesia in a rat model of acute gout flare (Trevisan et al., 2014). TRPA1 activation induces an inflammatory response in osteoarthritic chondrocytes (Nummenmaa et al., 2016). Inhibition and genetic deletion of TRPA1 reduces inflammatory mediators in osteoarthritic mouse chondrocytes and mouse cartilage tissue (Nummenmaa et al., 2016). Finally, TRPA1 knockout mice exhibit improved weight bearing on the osteoarthritic limb in an MIA-induced knee swelling model (Horvath et al., 2016).TRPA1 expression is differential in bladder epithelium rats (Du et al., 2007) and patients with bladder outlet obstruction (Du et al., 2008).Modulation of the TRPA1 receptor attenuates bladder overactivity in a rat model of spinal cord injury ( Andrade et al., 2011 ), and intrathecal administration of a TRPA1 antagonist attenuates cyclophosphamide-induced cystitis in rats with hyperreflexia ( Chen et al., 2016 ).

[0005] Therefore, it is expected to provide a potent TRPA1 inhibitor. TRPA1 inhibitors of different 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. WO2017 / 060488 discloses compounds that are TRPA1 antagonists having the general formula: [ka] The TRPA1 activity of Examples 28 and 29, which have a tetrazolyl ring, is not disclosed. L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809, disclose quinazolinone-based TRPA1 antagonists, including compounds of the general formula: [ka] Among them, compound 31 (wherein R is OH) showed antagonistic TRPA1 activity (IC 50 = 58 nM) and has an intrinsic clearance in human liver microsomes of less than 14 μL / min / kg. Summary of the Invention

[0006] The present invention provides novel thienopyrimidinones that are surprisingly potent TRPA1 inhibitors (Assay A), and are further characterized as follows: - Improved stability in human liver microsomes (Assay B) - Improved stability in human hepatocytes (Assay C) The compounds of the present invention differ from the structures of Examples 28 and 29 in WO2017 / 060488 in that they contain a hydroxyl substituent attached to the benzylic carbon adjacent to the p-chlorophenyl group, and in that some compounds also have a different bicyclic moiety attached to the tetrazolyl ring via a methylene linker. The compounds of the present invention also differ from the structure of Compound 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809 in that they have a tetrazolyl ring. These structural differences unexpectedly lead to a favorable combination of (i) inhibition of TRPA1, (ii) stability in human liver microsomes, (iii) stability in human hepatocytes, and (iv) fewer unwanted human metabolites. Thus, the compounds of the present invention are superior to those disclosed in the prior art in terms of the combination of the following parameters: -Efficacy as a TRPA1 inhibitor -Stability in human liver microsomes -Stability in human hepatocytes - Low levels of unwanted human metabolites DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Stability in human liver microsomes refers to the susceptibility of a compound to biotransformation when selecting and / or designing drugs with good pharmacokinetic properties as a first screening step. Many drugs are metabolized mainly in the liver. Human liver microsomes contain cytochrome P450 (CYPs) and therefore represent a model system for phase I studies of drug metabolism in vitro. Improved stability in human liver microsomes entails several advantages, including increased bioavailability and sufficient half-life, allowing for less and less frequent administration to patients. Therefore, improved stability in human liver microsomes is a favorable feature of compounds intended to be used as drugs. Thus, the compounds of the present invention, in addition to being able to inhibit TRPA1, are expected to have a desirable duration of action in humans, since they have favorable clearance in vivo.

[0008] Stability in human hepatocytes refers to the susceptibility of a compound to biotransformation when selecting and / or designing drugs with favorable pharmacokinetic properties. Many drugs are primarily metabolized in the liver. Human hepatocytes represent a model system for studying in vitro drug metabolism, since they contain cytochrome P450 (CYPs) and other drug metabolizing enzymes. (Importantly, in contrast to liver microsomal assays, hepatocyte assays represent a more complete system for studying drug metabolism, since they encompass both phase II biotransformation and processes mediated by liver-specific transporters.) Improved stability in human hepatocytes entails several advantages, including increased bioavailability and sufficient half-life, allowing for less and less frequent dosing to patients. Therefore, improved stability in human hepatocytes is a favorable feature for compounds intended to be used as drugs.

[0009] Terms and Definitions Terms not specifically defined herein should be given the meaning that would be given to those terms by one of ordinary skill in the art in light of this disclosure and the context. However, as used herein, unless otherwise indicated, the following terms have the meanings indicated and follow the following conventions.

[0010] The term "tetrazolyl" refers to the ring radical: [ka] Unless otherwise indicated, throughout this specification and the appended claims, chemical formulas or names are intended to encompass tautomers, and all stereoisomers, optical isomers, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, mixtures of different ratios of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the above-mentioned forms in which such isomers and enantiomers exist, salts (including pharma- ceutically acceptable salts thereof), and solvates, such as hydrates thereof (including, for example, solvates of the free compounds or solvates of a salt of the compounds).

[0011] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of the corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. Methods for preparing optically active forms are known in the art and can be prepared, for example, by resolution of racemic forms or, for example, by synthesis starting from optically active starting materials and / or by using chiral reagents. Enantiomerically pure compounds or intermediates of the present invention may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of suitable diastereomeric compounds or intermediates which may be separated by known methods (e.g. chromatographic separation or crystallization), and / or by the use of chiral reagents, for example chiral starting materials, chiral catalysts or chiral auxiliaries. Methods for preparing enantiomerically pure compounds from the corresponding racemic mixtures are also known to the skilled artisan and can be prepared, for example, by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; by resolution of the racemic mixtures using a suitable resolving agent, for example by means of diastereomeric salt formation of the racemate with an optically active acid or base, followed by resolution of the salt and liberation of the desired compound from the salt; by derivatization of the corresponding racemate with an optically active chiral auxiliary, followed by diastereomeric separation and removal of the chiral auxiliary; by kinetic resolution of the racemates (for example, by enzymatic resolution); by enantioselective crystallization from a consortium of mirror image crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0012] As used herein, the term "pharmaceutical acceptable" means a compound, material, composition, and / or dosage form that is suitable for use without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds by making acid or base salts of the parent compound or acid or base complexes thereof. Examples of acids that form pharma- ceutically acceptable salts with the parent compound that contains 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-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Examples of cations and bases that form pharma- ceutical acceptable salts with parent compounds that contain an acidic moiety include Na + , K + , Ca 2+ , Mg 2+ , N.H. 4 +, L-arginine, 2,2'-iminobisethanol, L-lysine, N-methyl-D-glucamine and tris(hydroxymethyl)-aminomethane. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base 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 are useful, for example, for purifying or isolating the compounds of the invention (eg, trifluoroacetates), also form part of the invention.

[0013] Biological assays Assay A: TRPA1 assay The activity of the compounds of the invention can be demonstrated using the in vitro TRPA1 cell assay described below.

[0014] method: As a test system for compound efficacy and potency, a human HEK293 cell line overexpressing the human TRPA1 ion channel (Perkin Elmer, product number AX-004-PCL) was used. Compound activity was determined by measuring the effect of the compound on intracellular calcium concentration induced by AITC (allyl isothiocyanate) agonism using a FLIPR Tetra system (Molecular Devices).

[0015] Cell culture: Cells were obtained as frozen cells in cryovials and stored at -150°C until use. Cells were grown in culture medium (MEM / EBSS medium with 10% FCS and 0.4 mg / ML geneticin). It is important that the density should not exceed 90% confluence. For subculture, cells were detached from flasks with Versene solution. The day before the assay, cells were detached, washed twice with culture medium (MEM / EBSS medium with 10% FCS) and 20,000 cells (20 μL / well) were seeded in a 384-well plate biocoated with poly-D-lysine (black, clear bottom, catalog number 356697, Corning). Plates were incubated at 37°C / 5% CO before use in the assay. 2 The mixture was incubated at RT for 24 hours.

[0016] Preparation of compounds: Test compounds were dissolved in 100% DMSO to a concentration of 10 mM, and diluted in DMSO to a concentration of 5 mM in a first step, followed by serial dilution steps in 100% DMSO. The dilution factor and number of dilution steps can be changed as required. Typically, 8 different concentrations were prepared by dilution at 1:5, and further intermediate dilutions (1:20) of substances were made in HBSS / HEPES buffer at pH 7.4 (1xHEPES, Cat. No. 14065, Gibco; 20mM HEPES, Cat. No. 83264, SIGMA; 0.1% BSA, Cat. No. 11926, Invitrogen).

[0017] FLIPR Assay: On the day of the assay, cells were washed 3 times with assay buffer, leaving 20 μL buffer in the wells after washing. 10 μL of loading buffer in HBSS / HEPES from the Ca6 kit (catalog no. R8191, Molecular Devices) was added to the cells, the plate was covered and incubated at 37 °C / 5% CO 2The wells were incubated at 4°C for 120 min. 10 μL compound or control in HBSS / HEPES buffer / 5% DMSO from the intermediate dilution plate was carefully added to the cells. Luminescence (indicating calcium influx or release) was read on the FLIPRtetra instrument for 10 min to monitor compounds inducing an effect (e.g., agonism). Finally, 10 μL of the agonist AITC 50 μM (final concentration 10 μM) dissolved in HBSS / HEPES buffer / 0.05% DMSO was added to the wells and read on the FLIPRtetra instrument for another 10 min. The area under the signal curve (AUC) after addition of AITC was used to calculate IC50 / % inhibition.

[0018] Data evaluation and calculations: Each assay microtiter plate contained wells with vehicle (1% DMSO) controls instead of compounds as a control for AITC-induced luminescence (100% CTL; high control) and vehicle controls without AITC as a control for non-specific changes in luminescence (0% CTL; low control). Data analysis was performed by calculation of the area under the signal curve for the individual wells. Based on this value, the % value for the measurement of each substance concentration was calculated with MegaLab software (in-house development) (AUC(sample)-AUC(low) x 100 / AUC(high)-AUC(low)). IC50 values ​​were calculated from the % control values ​​using MegaLab software. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=conc M; c=IC50 M; b=hill; y=% control

[0019] Table 1: Biological data of compounds of the invention obtained in Assay A [Table 1]

[0020] Table 2: Biological data of prior art compounds (Examples 28 and 29 in WO2017 / 060488) obtained in Assay A [Table 2]

[0021] Table 3: Biological data of a prior art compound (Example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) obtained in Assay A [Table 3]

[0022] Assay B: Microsomal Clearance The metabolic degradation of test compounds was assayed using pooled liver microsomes at 37° C. A final incubation volume of 100 μL at each time point contained TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / mL) and test compound at a final concentration of 1 μM at room temperature. After a short preincubation period at 37°C, the reaction was started by the addition of reduced β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated by transferring an aliquot to the solvent after different time points (0, 5, 15, 30, 60 min). In addition, NADPH-independent degradation was monitored during incubation without NADPH and terminated at the last time point. The remaining test compound [%] after NADPH-independent incubation is reflected by the parameter c(control) (metabolic stability). The quenched incubations are pelleted by centrifugation (10000g, 5 min). An aliquot of the supernatant is assayed for the amount of parent compound by LC-MS / MS. The half-life (t1 / 2, in vitro) is determined by the slope of the semi-log plot of the concentration-time profile.

[0023] The intrinsic clearance (CL_INTRINSIC) is calculated considering the amount of protein in the incubation. CL_INTRINSIC [μL / min / mg protein] = (Ln2 / (half-life [min] × protein content [mg / mL])) × 1000 CL_INTRINSIC_in vivo [mL / min / kg] = (CL_INTRINSIC [μL / min / mg protein] × MPPGL [mg protein / g liver] × liver factor [g / kg body weight]) / 1000 Qh [%] = CL [mL / min / kg] / Liver blood flow [mL / min / kg]) Hepatocellularity, human: 120 x 10 6 Cells / g liver Liver factor, human: 25.7 g / kg body weight Blood flow, human: 21 mL / (min x kg)

[0024] Table 4: Biological data of compounds of the invention obtained in assay B [Table 4]

[0025] Table 5: Biological data of prior art compounds (examples 28 and 29 in WO2017 / 060488) obtained in assay B [Table 5]

[0026] Table 6: Biological data of a prior art compound (Example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) obtained in Assay B [Table 6]

[0027] Assay C: Hepatocyte Clearance The metabolic degradation of test compounds was measured in hepatocyte suspensions. Hepatocytes (cryopreserved) were incubated in Dulbecco's modified Eagle's medium (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg / 500 mL hydrocortisone) containing 5% or 50% seed serum. Incubator (37 °C, 10% CO 2 After 30 min of preincubation with 50 mM NaCl, 5 μL of test compound solution (80 μM; 2 mM DMSO stock solution diluted 25-fold with medium) was added to 395 μL hepatocyte suspension (cell density 0.25-5 million (Mio) cells / mL depending on species, typically 1 million cells / mL; final test compound concentration 1 μM, final DMSO concentration 0.05%). Cells are incubated for 6 hours (incubator, orbital shaker) and samples (25 μL) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min). Supernatants are transferred to a new 96-deep well plate, evaporated under nitrogen and resuspended.

[0028] The loss of parent compound is analyzed by HPLC-MS / MS. CLint is calculated as follows: CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD+clast / k) × 1000 / 60. C0: initial concentration of incubation [μM], CD: cell density of viable cells [10 6 cells / mL], AUD: area under the data [μM × h], clast: concentration of the last data point [μM], k: slope of the regression line of the parent compound decrease [h-1]. The calculated in vitro hepatic intrinsic clearance can be scaled up to in vivo intrinsic clearance by use of a liver model (well-stirred model) and used to predict in vitro hepatic blood clearance (CL). CL_INTRINSIC_INVIVO[mL / min / kg]=(CL_INTRINSIC[μL / min / 106 cells] × hepatic cellularity [10 6 cells / g liver x liver factor [g / kg body weight] / 1000 CL[mL / min / kg]=CL_INTRINSIC_INVIVO[mL / min / kg]×Liver blood flow[mL / min / kg] / (CL_INTRINSIC_INVIVO[mL / min / kg]+Liver blood flow[mL / min / kg]) Qh [%] = CL [mL / min / kg] / Liver blood flow [mL / min / kg]) Hepatocyte, human: 120 x 10 6 Cells / g liver Liver factor, human: 25.7 g / kg body weight Blood flow, human: 21 mL / (min x kg)

[0029] Table 7: Biological data of compounds of the invention obtained in Assay C [Table 7]

[0030] Table 8: Biological data of prior art compounds (examples 28 and 29 in WO2017 / 060488) obtained in assay C [Table 8]

[0031] Table 9: Biological data of a prior art compound (Example 31 in L. Schenkel, et al., J. Med. Chem. 2016, 59, 2794-2809) obtained in Assay C [Table 9]

[0032] Assay D: Metabolism in human hepatocytes in vitro The metabolic pathway of the test compound is examined using primary human hepatocytes in suspension. After recovery from cryopreservation, the human hepatocytes were incubated in Dulbecco's modified Eagle's medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg / 500 mL hydrocortisone. Cell culture incubator (37 °C, 10% CO 2 After preincubation for 30 min at 25°C for 1 h, the test compound solution was injected into the hepatocyte suspension to obtain a final cell density of 1.0 × 10 6 ~4.0×10 6 cells / mL (based on compound turnover rates observed in primary human hepatocytes), final compound concentration of 10 μM, and final DMSO concentration of 0.05%. Cells are incubated for 6 hours on a horizontal shaker in a cell culture incubator and samples are removed from incubation at 0, 0.5, 1, 2, 4, or 6 hours depending on turnover rate. Samples are quenched with acetonitrile and pelleted by centrifugation. Supernatants are transferred to 96-deep well plates, evaporated under nitrogen and resuspended prior to bioanalysis by liquid chromatography-high resolution mass spectrometry for identification of putative metabolites.

[0033] Table 10: Major metabolites observed for Example 5 of the present invention obtained in Assay D [Table 10] Interim LC-MS n Based on structural analysis, the integrity of the tetrazole ring was not affected in any of the metabolites mentioned above.

[0034] Treatment method The present invention relates to compounds of general formula 1 that are useful for the prevention and / or treatment of diseases and / or conditions associated with or modulated by TRPA1 activity, including, but not limited to, fibrotic diseases, inflammatory and immunoregulatory disorders, respiratory or digestive diseases or complaints, ophthalmic diseases, inflammatory diseases of the joints, and inflammatory diseases of the nasopharynx, eyes and skin. The above disorders, diseases and complaints include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic diseases, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, as well as autoimmune conditions such as rheumatoid arthritis and atherosclerosis, pain, and neurological disorders such as depression.

[0035] The compounds of general formula 1 are useful for the prevention and / or treatment of: (1) Cough, for example, chronic idiopathic cough or chronic refractory cough, cough associated with asthma, COPD and lung cancer, cough after viral infection; (2) Pulmonary fibrotic diseases, such as pneumonia or interstitial pneumonia associated with collagen fibrosis (e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis), idiopathic interstitial pneumonia such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease (RBID), disease), desquamative interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia or lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, upper lobar pulmonary fibrosis, interstitial lung diseases of known etiology, e.g., interstitial pneumonia resulting from occupational exposures (e.g., asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon breeder's lung (birds), and other occupational airborne triggers (e.g., metal dust, mycobacteria)) and treatment Interstitial pneumonia resulting from (e.g. radiation, methotrexate, amiodarone, nitrofurantoin, chemotherapy drugs), granulomatous diseases such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, interstitial pneumonia of different etiology (e.g. aspiration or inhalation of toxic gases or vapors), bronchitis, pneumonia or interstitial pneumonia due to heart failure, x-rays, radiation, chemotherapy, sarcoidosis (M. boeck, sarcoidosis), granulomatosis, cystic fibrosis, mucoviscidosis or alpha1-antitrypsin deficiency; (3) Other fibrotic diseases, e.g., hepatic bridging fibrosis, liver cirrhosis, nonalcoholic 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 sinusitis, acute sinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial edema and pulmonary edema, bronchitis or pneumonia, eosinophilic cellulitis (e.g., Wells syndrome), eosinophilic pneumonia (e.g., Löffler syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman syndrome), delayed hypersensitivity reactions, non-allergic asthma; exercise-induced bronchoconstriction; chronic obstructive pulmonary disease (COPD), acute tracheal edema, acute bronchitis ... bronchitis, chronic bronchitis, cough, emphysema; systemic anaphylaxis or hypersensitivity reactions, drug allergies (e.g. to penicillins, cephalosporins), eosinophilia-myalgia syndrome due to ingestion of contaminated tryptophan, insect bite allergies; autoimmune diseases, e.g. rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis; immune-mediated thrombocytopenia (adult ITP, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug-induced), Evans' syndrome (immune cytopenia of platelets and red blood cells), neonatal Rh disease, Goodpasture's syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy, juvenile diabetes mellitus; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; transplantation, including allograft rejection or graft-versus-host disease rejection (e.g. during transplantation); inflammatory bowel diseases, e.g. Crohn's disease, ulcerative colitis; spondyloarthropathy; scleroderma; psoriasis (including T cell mediated psoriasis) and inflammatory skin diseases, e.g. dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g. necrotizing vasculitis, cutaneous vasculitis, hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis, cancer with lymphocytic 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 conjunctivitis, scarring, anterior segment scarring, 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 flare, gout or osteoarthritis; (5) Pain, e.g., chronic idiopathic pain syndromes, neuropathic pain, dysesthesias, allodynia, migraine, dental pain, and post-operative pain; (6) depression, anxiety, diabetic neuropathy, and bladder disorders, such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemic injury.

[0036] Thus, the present invention relates to compounds of general formula 1 for use as medicines.

[0037] Furthermore, the present invention relates to the use of compounds of general formula 1 for the treatment and / or prevention of diseases and / or conditions which are associated with TRPA1 activity or which are modulated by said activity.

[0038] Furthermore, the present invention relates to the use of compounds of general formula 1 for the treatment and / or prevention of fibrotic diseases, inflammatory and immunoregulatory disorders, respiratory or digestive diseases or complaints, ophthalmological diseases, inflammatory joint diseases, and inflammatory diseases of the nasopharynx, eyes and skin, including cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic diseases, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, but also autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

[0039] Furthermore, the present invention relates to the use of compounds of general formula 1 for the treatment and / or prevention of: (1) Cough, for example, chronic idiopathic cough or chronic refractory cough, cough associated with asthma, COPD and lung cancer, cough after viral infection; (2) Pulmonary fibrotic diseases, e.g., pneumonia or interstitial pneumonia associated with collagen fibrosis (e.g., lupus erythematosus, systemic sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis), idiopathic interstitial pneumonia such as pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis, upper lobar pulmonary fibrosis, interstitial lung diseases of known etiology, e.g., occupational exposure (e.g., asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon breeding) interstitial pneumonia as a result of occupational airborne triggers (e.g. metal dust, mycobacteria) or as a result of treatment (e.g. radiation, methotrexate, amiodarone, nitrofurantoin, chemotherapy drugs), granulomatous diseases such as granulomatosis with polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis, interstitial pneumonia of different etiology (e.g. aspiration or inhalation of toxic gases, vapors), bronchitis, pneumonia or interstitial pneumonia due to heart failure, x-rays, radiation, chemotherapy, sarcoidosis (M. boeck, sarcoidosis), granulomatosis, cystic fibrosis, mucoviscidosis or alpha1-antitrypsin deficiency; (3) Other fibrotic diseases, e.g., hepatic bridging fibrosis, liver cirrhosis, nonalcoholic 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 nonallergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal polyposis, chronic sinusitis, acute sinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, hyperreactive airway disease, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, eosinophilic cellulitis (e.g., Wells' syndrome), eosinophilic pneumonia (e.g., Refractory pneumonia), eosinophilic pneumonia, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed hypersensitivity reactions, nonallergic asthma; exercise-induced bronchoconstriction; chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, cough, emphysema; systemic anaphylaxis or hypersensitivity reactions, drug allergies (e.g., to penicillin, cephalosporins), eosinophilia myalgia syndrome due to ingestion of contaminated tryptophan, insect bite allergy; autoimmune diseases, e.g., arthritis Eulogy, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenia (adult ITP, neonatal thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug induced), Evans syndrome (immune cytopenia of platelets and red blood cells), neonatal Rh disease, Goodpasture's syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy, juvenile diabetes mellitus; glomerulonephritis, autoimmune thyroiditis, Bethesda syndrome pulmonary tuberculosis; graft rejection (e.g. during transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, e.g., Crohn's disease, ulcerative colitis; spondyloarthropathy; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases, e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing vasculitis, cutaneous vasculitis, hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis, cancer with lymphocytic 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 conjunctivitis, scars, anterior 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 flare, gout or osteoarthritis; (5) Pain, e.g., chronic idiopathic pain syndromes, neuropathic pain, dysesthesias, allodynia, migraine, toothache, postoperative pain; (6) depression, anxiety, diabetic neuropathy, and bladder disorders, such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemic injury.

[0040] In a further aspect, the present invention relates to compounds of general formula 1 for use in the treatment and / or prevention of the aforementioned diseases and conditions.

[0041] In a further aspect, the present invention relates to the use of compounds of general formula 1 for the preparation of a medicament for the treatment and / or prevention of the aforementioned diseases and conditions.

[0042] In a further aspect, the present invention relates to a method for the treatment or prevention of the above mentioned diseases and conditions, said method comprising the administration of an effective amount of a compound of general formula 1 to a human.

[0043] Combination therapy The compounds of the present invention may also be used in combination with one or more, preferably one, additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful for the treatment of the above-mentioned diseases or conditions (particularly fibrotic diseases, inflammatory and immunoregulatory disorders, respiratory or digestive diseases or complaints, arthritis diseases, or nasopharynx, eye and skin inflammatory diseases or conditions, such as cough, idiopathic pulmonary fibrosis, other interstitial lung diseases, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, atopic dermatitis, but also autoimmune pathologies, such as rheumatoid arthritis, atherosclerosis, etc.), or therapeutic agents useful for the treatment of ophthalmological diseases, pain and depression.

[0044] Additional therapeutic agents suitable for such combinations include, inter alia, those that enhance the therapeutic effect of one or more active agents and / or reduce the dosage of one or more active agents, e.g., as described above. Thus, the present invention can be used in combination with one or more additional therapeutic agents selected from the group consisting of antifibrotic agents, antitussives, anti-inflammatory agents, anti-atopic dermatitis agents, analgesics, anticonvulsants, anti-anxiety agents, sedatives, skeletal muscle relaxants, and antidepressants.

[0045] Examples of antifibrotic drugs include phosphodiesterase-IV (PDE4) inhibitors such as nintedanib, pirfenidone, and roflumilast; autotaxin inhibitors such as GLPG-1690 and BBT-877; connective tissue growth factor (CTGF) blocking antibodies such as pamrevlumab; B-cell activating factor receptor (BAFF-R) blocking antibodies such as lanadelumab; α-V / β-6 blocking inhibitors such as BG-00011 / STX-100, recombinant pentraxin-2 (PTX-2) such as PRM-151; and c-Jun N-terminal kinase inhibitors such as CC-90001. JNK inhibitors; galectin-3 inhibitors such as TD-139; G protein-coupled receptor 84 (GPR84) inhibitors such as GLPG-1205; dual G protein-coupled receptor 84 / G protein-coupled receptor 40 inhibitors such as PBI-4050; Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitors such as KD-025; heat shock protein 47 (HSP47) small interfering RNA such as BMS-986263 / ND-L02-s0201; Wnt pathway inhibitors such as SM-04646; LD4 / PDE3 / 4 inhibitors; recombinant immunomodulatory domain of histidyl-tRNA synthetase (HARS) such as ATYR-1923; prostaglandin synthase inhibitors such as ZL-2102 / SAR-191801; 15-hydroxyeicosapentaenoic acid (15-HEPE, e.g., DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors such as PAT-1251, PXS-5382 / PXS-5338; phosphoinositide 3 kinase (PI3K) / mammalian target of rapamycin (mTOR) inhibitors such as HEC-68498 dual inhibitors such as BLD-2660; calpain inhibitors such as BLD-2660; mitogen-activated protein kinase kinase kinase (MAP3K19) inhibitors such as MG-S-2525; chitinase inhibitors such as OATD-01; mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) inhibitors such as MMI-0100; transforming growth factor beta 1 (TGF-β1) small interfering RNAs such as TRK250 / BNC-1021; and lysophosphatidic acid receptor antagonists such as BMS-986278.

[0046] Examples of antitussives include purinergic receptor 3 (P2X3) receptor antagonists such as gefapixant, S-600918, BAY-1817080, and BLU-5937; neurokinin 1 (NK-1) receptor antagonists such as orbepitant and aprepitant; nicotinic acetylcholine receptor α7 subunit agonists such as ATA-101 / bradanicline; codeine, gabapentin, pregabalin, and azithromycin.

[0047] Examples of anti-inflammatory drugs include corticosteroids such as prednisolone and dexamethasone; cyclooxygenase-2 (COX2) inhibitors such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib; prostaglandin E2 antagonists; leukotriene B4 antagonists; leukotriene D4 antagonists such as montelukast; 5-lipoxygenase inhibitors; and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, ibuprofen, and indomethacin.

[0048] Examples of anti-atopic dermatitis drugs include cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, phosphodiesterase inhibitors (e.g., apremilast, crisaborole), Janus kinase (JAK) inhibitors (e.g., tofacitinib), anti-IL-4 / IL-13 neutralizing antibodies (e.g., dupilumab), anti-IL-13 neutralizing antibodies (e.g., lebrikizumab, tralokinumab), and anti-IL-31 neutralizing antibodies (nemolizumab).

[0049] Examples of analgesics include, for opioids, e.g., morphine, oxymorphine, levorphanol, oxycodone, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine; and for non-opioids, e.g., acetophenamine.

[0050] Examples of antidepressants include tricyclic antidepressants such as amitriptyline, clomipramine, desipramine, doxepin, desipramine, imipramine, and nortriptyline; selective serotonin reuptake inhibitor antidepressants (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, and hydroxybupropion. norepinephrine reuptake inhibitor antidepressants (SNRIs) such as nomifensine, viloxazine; dual serotonin-norepinephrine reuptake inhibitor antidepressants (SNRIs) such as duloxetine, venlafaxine, desvenlafaxine, levomilnacipran; atypical antidepressants such as trazodone, mirtazapine, vortioxetine, vilazodone, bupropion; and monoamine oxidase inhibitor antidepressants (monoamine oxidase inhibitors) such as tranylcypromine, phenelzine, and isocarboxazid.

[0051] Examples of anti-anxiety drugs include benzodiazepine drugs such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam, and tofisopam; non-benzodiazepine hypnotics such as eszopiclone, zaleplon, zolpidem, and zopiclone; carbamates such as meprobamate, carisoprodol, tibamate, and lorbamate; and antihistamines such as hydroxyzine, chlorpheniramine, and diphenhydramine.

[0052] Examples of sedatives include barbiturate sedatives such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, secobarbital, talbutal, thiamylal, and thiopental; and non-barbiturate sedatives such as glutethimide, meprobamate, methaqualone, and dichlorphenazone.

[0053] Examples of skeletal muscle relaxants include baclofen, meprobamate, carisoprodol, cyclobenzaprine, metaxalone, methocarbamol, tizanidine, chlorzoxazone, and orphenadrine.

[0054] Other suitable concomitant drugs are acetylcholinesterase inhibitors such as donepezil; 5-HT-3 antagonists such as ondansetron; metabotropic glutamate receptor antagonists; antiarrhythmic drugs such as mexiletine, phenytoin; or antiarrhythmic drug receptor antagonists. More suitable concomitant drugs are urinary incontinence drugs, for example anticholinergic drugs such as oxybutynin, tolterodine, darifenacin, fesoterodine, solifenacin, trospium, etc.; bladder muscle relaxants such as mirabegron, etc.; or alpha blockers such as tamsulosin, alfuzosin, silodosin, doxazosin, terazosin, etc.

[0055] The dosage of the above-mentioned concomitant drugs is generally from 1 / 5 of the normally recommended minimum dose to 1 / 1 of the normally recommended dose. Therefore, in another aspect, the present invention relates to the use of the compounds according to the invention in combination with one or more additional therapeutic agents for the treatment of diseases or conditions that can be affected or modulated by TRPA1 as mentioned above and below (in particular the diseases or conditions as mentioned above and below).

[0056] In a further aspect, the present invention relates to a method of treating a disease or condition that can be affected by TRPA1 inhibition in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0057] In a further aspect, the present invention relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of a disease or condition that can be affected by inhibition of TRPA1 in a patient in need of such treatment.

[0058] In another aspect, the invention relates to a method for the treatment of a disease or condition modulated by TRPA1 activity in a patient, comprising the step of administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of one or more additional therapeutic agents as described above and below.

[0059] The compound of the present invention and the additional therapeutic agent may be administered simultaneously or at staggered times. The compound of the present invention and the additional therapeutic agent may be present together in one formulation, e.g., a tablet or capsule, or may be present separately in two identical or different formulations, e.g., a so-called kit-of-parts.

[0060] Accordingly, in another aspect, the invention relates to pharmaceutical compositions comprising a compound according to the invention and one or more additional therapeutic agents as described above and below, and optionally one or more inert carriers and / or diluents.

[0061] In another aspect the present invention relates to the use of the compounds according to the invention in a cough measuring device. Other features and advantages of the present invention will become apparent from the following more detailed embodiments which illustrate, by way of example, the principles of the invention.

[0062] preparation The compounds according to the invention and intermediates thereof can be obtained by using synthetic methods known to those skilled in the art and described in the literature of organic synthesis, for example by using the methods described in "Comprehensive Organic Transformations", 2nd Edition, Richard C. Larock, John Wiley & Sons, 2010, and "March's Advanced Organic Chemistry", 7th Edition, Michael B. Smith, John Wiley & Sons, 2013. The compounds according to the invention are preferably obtained by methods similar to the preparation methods described more fully below (especially as described in the experimental paragraph). In some cases, the order adopted in carrying out the reaction schemes may be varied. Variants of those reactions known to those skilled in the art but not described in detail herein may also be used. The general process for preparing the compounds according to the invention will become apparent to those skilled in the art upon studying the schemes below. The starting material compounds are commercially available or may be prepared by methods described in the literature or herein, or may be prepared by similar or analogous methods. Before carrying out the reaction, any corresponding functional groups in the starting compounds may be protected by conventional protecting groups. Those protecting groups may be cleaved again at a suitable stage in the reaction sequence using methods well known to those skilled in the art, as described in the literature (e.g., "Protecting Groups", 3rd Edition, Philip J. Kocienski, Thieme, 2005; "Protective Groups in Organic Synthesis", 4th Edition, Peter GM Wuts, Theodora W. Greene, John Wiley & Sons, 2006). The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20° C., e.g., between 19° C. and 24° C.

[0063] Abbreviation: [Table 11] EXAMPLES

[0064] Preparation of starting compounds Intermediate I Intermediate I.1 1-(4-Bromophenyl)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]ethan-1-one [ka] K 2 CO 3 Add 1.63 g (11.8 mmol) of 4-chlorophenacyl bromide (2.17 g (9.28 mmol)) and 1.00 g (8.44 mmol) of 5-(chloromethyl)-2H-1,2,3,4-tetrazole in 15 mL of DMA. Stir the reaction mixture at room temperature for 30 min before filtering the mixture. Dilute the solution with water and saturated aqueous NaCl solution and extract three times with EtOAc. Wash the combined organic phase with water and add Na 2 SO 4 The mixture is dried at 40° C., filtered over activated charcoal and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; CH / EtOAc, 8 / 2→1 / 1). C 10 H 8 Cl 2 N 4 O (M = 271.1 g / mol) ESI-MS: 271 [M+H] + R t (HPLC): 1.01 min (Method B)

[0065] Intermediate II Intermediate II.1 (1R)-1-(4-chlorophenyl)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]ethan-1-ol [ka] 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 added to 20 mL of ACN under an inert atmosphere. 11.9 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 before 0.72 mL (1.73 mmol) of formate triethylamine complex (5:2) is added dropwise. After stirring for 3 h at room temperature, the solvent is removed under vacuum. Water is added to the remaining crude mixture and the mixture is extracted with EtOAc. The organic layers are combined and washed with Na 2 SO 4 Dry at 40° C., filter over activated charcoal and remove the solvent in vacuo. C 10 H 10 Cl- 2 N 4 O (M = 273.1 g / mol) ESI-MS: 273 [M+H] + R t (HPLC): 0.96 min (Method B)

[0066] Intermediate III Intermediate III.1 4-Amino-2-methanesulfonyl-1,3-thiazole-5-carboxylate ethyl [ka] 20.0 g (0.092 mol) of ethyl 4-amino-2-(methylsulfanyl)-1,3-thiazole-5-carboxylate (CAS: 39736-29-3) is added to 500 mL of stirred DCM. The mixture is cooled to 0° C. and 35.0 g (0.142 mol) of 3-chloroperbenzoic acid (70%) is added in portions, maintaining the temperature of the reaction mixture below 24° C. The mixture is stirred overnight at ambient temperature before 10.0 g (0.041 mol) of 3-chloroperbenzoic acid (70%) is added and diluted with 300 mL of DCM and the mixture is stirred at ambient temperature for an additional 2.5 hours. An additional 10 g (0.041 mmol) is added and the reaction mixture is stirred for 2 hours. The mixture is then diluted with saturated Na 2 SO 3 The organic phase is separated and quenched with 2M Na 2 CO 3 The organic extract was washed with aqueous solution (twice) and brine, and then with MgSO 4 Dry at 40° C., filter and concentrate to give the desired product. C 7 H 10 N 2 O 4 S 2 (M = 250.3 g / mol) ESI-MS: 251 [M+H] + R t (HPLC): 0.96 min (Method E)

[0067] Intermediate III.2 Ethyl 4-amino-1,3-thiazole-5-carboxylate [ka] EtOH (100 mL) is added to 7.0 g (28.0 mmol) of ethyl 4-amino-2-methanesulfonyl-1,3-thiazole-5-carboxylate and the mixture is cooled to 0° C. 3.14 g (83.9 mmol) of sodium borohydride are added in portions and the reaction mixture is stirred at ambient temperature for 3 h. The reaction mixture is concentrated and water and EtOAc are added to the residue. The organic phase is separated and washed with saturated NaHCO 3 Wash with aqueous MgSO4 Dry at 40° C., filter and concentrate to give the desired product. C 6 H 8 N 2 O 2 S (M = 172.2 g / mol) ESI-MS: 173 [M+H] + R t (HPLC): 0.77 min (Method B)

[0068] Intermediate III.3 6H,7H-[1,3]thiazolo[4,5-d]pyrimidin-7-one [ka] 650 mg (6.2 mmol) of formamidinium acetate are added to 250 mg (1.45 mmol) of ethyl 4-amino-1,3-thiazole-5-carboxylate in EtOH (5.0 mL). The reaction mixture is heated to 80° C. and stirred at this temperature for 16 h. After cooling to ambient temperature, 605 mg (5.8 mmol) of formamidinium acetate are added and the reaction mixture is heated to 80° C. and stirred at this temperature for 5 h. It is further heated to 110° C. and stirred at this temperature for another 16 h. After cooling to ambient temperature, the mixture is purified by preparative HPLC (X-Bridge C18, ACN / H2O containing 0.1% TFA gradient). 2 O) to give the desired product. C 5 H 3 N 3 OS (M = 153.2 g / mol) ESI-MS: 154 [M+H] + R t (HPLC): 0.12 min (Method A)

[0069] Intermediate IV Intermediate IV.1 1-Methyl-1H,6H,7H-imidazo[4,5-d]pyridazin-7-one hydrobromide [ka] In an autoclave reaction vessel, 200 mg of Pd / C (10%) is added to a mixture of 5.3 g (23.1 mmol) of 2-bromo-1-methyl-1H,6H,7H-imidazo[4,5-d]pyridazin-7-one in 75 mL of MeOH. The space above the reaction mixture is evacuated and charged with 50 psi of hydrogen pressure. The reaction mixture is stirred overnight at ambient temperature under 50 psi of hydrogen pressure. After removing the hydrogen and filling with nitrogen, the reaction mixture is diluted with 300 mL of warm water and filtered. The filtrate is concentrated to dryness to give the desired product. C 6 H 6 N 4 O (M = 231.1 g / mol) ESI-MS: 11 [M-HBr+H] + R t (HPLC): 0.12 min (Method C)

[0070] Intermediate V Intermediate V.1 2-(7-Methyl-6-oxo-6,7-dihydro-1H-purin-1-yl)acetonitrile [ka] K 2 CO 3 2.07 g (15.0 mmol) of 7-methyl-6,7-dihydro-1H-purin-6-one is added to a solution of 0.750 g (4.99 mmol) of 7-methyl-6,7-dihydro-1H-purin-6-one in 15 mL of DMF and the mixture is stirred at ambient temperature for 30 min. Then, 0.418 mL (5.99 mmol) of bromoacetonitrile is added and the reaction mixture is stirred at ambient temperature overnight. The mixture is filtered and the filtrate is concentrated. The precipitate is suspended in diisopropyl ether and the remaining solid is collected by filtration. The collected material is further washed with cold diisopropyl ether and dried under vacuum at 50° C. to give the desired product. C 8 H 7 N 5 O (M = 189.7 g / mol) ESI-MS: 190 [M+H] + R t (HPLC): 0.18 min (Method B)

[0071] Intermediate V.2 7-Methyl-1-[(2H-1,2,3,4-tetrazol-5-yl)methyl]-6,7-dihydro-1H-purin-6-one [ka] 0.480 g (7.39 mmol) of sodium azide and 0.395 g (7.39 mmol) of ammonium chloride are added to a mixture of 1.27 g (6.71 mmol) of 2-(7-methyl-6-oxo-6,7-dihydro-1H-purin-1-yl)acetonitrile in 15 mL of DMF. The reaction mixture is heated to 95° C. and stirred at this temperature overnight. After cooling to ambient temperature, the precipitate is collected by filtration and washed with MeOH. The resulting solid is dried under vacuum at 50° C. to give the desired product. C 8 H 8 N 8 O (M = 232.2 g / mol) ESI-MS: 233 [M+H] + R t (HPLC): 0.17 min (Method B)

[0072] Intermediate V.3 1-({2-[2-(4-chlorophenyl)-2-oxoethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-7-methyl-6,7-dihydro-1H-purin-6-one [ka] 100 mg (0.431 mmol) of 7-methyl-1-[(2H-1,2,3,4-tetrazol-5-yl)methyl]-6,7-dihydro-1H-purin-6-one and K 2 CO 383.3 mg (0.603 mmol) of DMA is added to a solution of 111 mg (0.474 mmol) of 4-chlorophenacyl bromide in 5 mL of ACN. The reaction mixture is stirred at 70° C. overnight. After cooling, 2.5 mL of DMA is added and the mixture is further stirred at 70° C. for 14 h. After cooling to ambient temperature, the reaction mixture is filtered, concentrated and purified by preparative HPLC (ACN / H 2 Purify twice using a 30 mL / TFA gradient to give the desired product. C 16 H 13 ClN 8 O 2 (M = 384.8 g / mol) ESI-MS: 385 [M+H] + R t (HPLC): 0.82 min (Method B)

[0073] Preparation of final compounds Example 1 (General Route) 3-({2-[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-5-methyl-4-oxo-3H,4H-thieno[2,3-d]pyrimidine-6-carboxamide [ka] Add 50.0 mg (0.331 mmol) of 1-methyl-1H,6H,7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one to 1.0 mL of DMF. 2 CO 3 137 mg (0.993 mmol) of intermediate II.1 and 108.4 g (0.397 mmol) of intermediate II.1 are added and the mixture is stirred for 4 h at 50° C. After cooling to room temperature, the mixture is diluted with acetonitrile and methanol, filtered and purified by preparative HPLC (ACN / H 2 Purification by elution with 3H / TFA affords the desired product. C 15 H 14 ClN 9 O 2 (M = 387.8 g / mol) ESI-MS: 388 [M+H] + R t (HPLC): 0.43 min (Method B) 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 4.36(s, 3H), 4.73 - 4.83 (m, 2H), 5.12 (dd, J=7.4, 5.4 Hz, 1H), 5.55 (s, 2H), 5.61 - 6.38 (br s, 1H), 7.31 - 7.43 (m, 4H), 8.61 (s, 1H).

[0074] The following compounds are prepared according to the general procedure above (Example 1). [Table 12] TIFF0007612682000026.tif73151

[0075] Analytical data for the compounds listed in the table above: [Table 13]

[0076] Example 9 1-({2-[(2R)-2-(4-chlorophenyl)-2-hydroxyethyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-7-methyl-6,7-dihydro-1H-purin-6-one [ka] 0.194 mg (0.32 μmol) of chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) (CAS: 174813-81-1) is added to 30 mg (0.078 mmol) of intermediate V3 in MeCN (1.0 mL) under an inert atmosphere, followed by the dropwise addition of 12 μL (0.028 mmol) of formate trimethylamine complex (5:2). The reaction mixture is stirred at ambient temperature for 3 h. The mixture is concentrated and the residue is diluted with water. The mixture is extracted twice with EtOAc. The combined organic extracts are washed with MgSO 4 The mixture is dried at 40° C., filtered and purified by preparative HPLC. C 16 H 15 ClN 8 O 2 (M = 386.8 g / mol) ESI-MS: 387 [M+H]+ R t (HPLC): 0.55 min (Method G) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.96 (s, 3H), 4.75 - 4.82 (m, 2H), 5.12 (dd, J=7.4, 5.4 Hz, 1H), 5.52 (s, 2H), 7.34 - 7.42 (m, 4H), 8.25 (d, J=0.4 Hz, 1H), 8.47 (s, 1H).

[0077] Analytical HPLC method Method A [Table 14] Analytical column: XBridge BEH C18_2.1×30mm, 1.7μm; Column temperature: 60℃

[0078] Method B [Table 15] Analytical column: StableBond (Agilent) 1.8 μm; 3.0 × 30 mm; Column temperature: 60℃

[0079] Method C [Table 16] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 × 30 mm; Column temperature: 60℃

[0080] Method D [Table 17] Analytical column: XBridge C18_3.0×30mm_2.5μm (Waters); Column temperature: 60℃

[0081] Method E [Table 18] Analytical column: XBridge C18_3.0×30mm_2.5μm; Column temperature: 60℃

[0082] Method F [Table 19] Analytical column: XSelect HSS PFP 2.1 × 30 mm, 1.8 μm; Column temperature: 60℃

[0083] Method G [Table 20] Analytical column: Sunfire C18, 3.0 × 30 mm, 2.5 μm; Column temperature: 60℃

Claims

1. A compound selected from the group consisting of: 【Chemistry 1】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 , and 【change】

2. A salt of the compound of claim 1.

3. 10. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

4. 4. The pharmaceutical composition according to claim 3 for the treatment or prevention of inflammatory airway diseases, fibrotic diseases or cough.

5. The pharmaceutical composition according to claim 3 for the treatment or prevention of idiopathic pulmonary disease (IPF) or cough.

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