Tetrazole derivatives as TRPA1 inhibitors

Abstract

In particular, the present invention provides a method for the preparation of a transitory receptor potential ankyrin 1 (transient receptor potential ankyrin 1), and a transitory receptor potential ankyrin 1 (transitory receptor potential ankyrin 1). The present invention relates to certain tetrazole derivatives of inhibitors of TRPA1, and thus are useful in the treatment of diseases that can be treated by inhibition of TRPA1. The invention also provides pharmaceutical compositions containing the same and methods of preparing the compounds.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180045969.9 (Filing Date: June 25, 2021) entitled Tetrazole Derivatives as TRPA1 Inhibitors. TECHNICAL FIELD

[0002] The present application provides certain tetrazole derivatives that are inhibitors of transient receptor potential ankyrin 1 (TRPA1) and are therefore useful in the treatment of diseases that can be treated by inhibition of TRPA1. The present application also provides pharmaceutical compositions containing the same and methods of making the compounds. BACKGROUND

[0003] Transient receptor potential channels (TRP channels) are a group of voltage-gated ion channels that are primarily located on the plasma membrane of numerous mammalian cell types. There are approximately 30 structurally related TRP channels that are divided into the following classes: 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 (about 14 at the N-terminus of human TRPA1), which give rise to the designation of “A” for ankyrin (Montell, 2005).

[0004] TRPA1 is highly expressed in the plasma membrane of sensory neurons of the dorsal root ganglion and nodose ganglion that serve the skin and lungs, as well as in the small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and lymphocytes (https: / / www.proteinatlas.org / ), and in human lung fibroblasts.

[0005] TRPA1 is best known as a sensor of environmental stimuli that generates somatosensory modalities such as pain, cold, and itch. TRPA1 is activated by a number of reactive, electrophilic stimuli (e.g. allyl isothiocyanate, reactive oxygen species), as well as non-reactive compounds (e.g. icilin), which are implicated in cough associated with asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or post-viral cough, or chronic idiopathic cough and cough in hypersensitive patients (Song and Chang, 2015; Grace and Belvisi, 2011). Based on studies showing that cough induces TGF-b elevation (Xie et al., 2009; Froese et al., 2016; Tschumperlin et al., 2003; Yamamoto et al., 2002; Ahamed et al., 2008), TRPA1 inhibitors are indicated for the treatment of IPF, where cough is very prevalent due to the link between cough and lung injury. TRPA1 antagonists inhibit calcium signaling triggered by cough triggers such as cigarette smoke extract (CSE) oxidative stress, inflammatory mediator release, and downregulation of antioxidant gene expression (Lin et al., 2015; Wang et al., 2019). TRPA1 antagonists were effective in studies of atopic dermatitis (Oh et al., 2013; Wilson et al., 2013), contact dermatitis (Liu et al., 2013), psoriasis-related itch (Wilson et al., 2013), and IL-31 -related itch (Cevikbas et al., 2014). Gain-of-function of human TRPA1 is associated with familial episodic pain syndrome (Kremeyer et al., 2010). TRPA1 antagonists were also effective in behavioral models of migraine-associated allodynia (Edelmayer et al., 2012). TRPA1 is selectively increased in trigeminal ganglia innervating damaged teeth when 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), which provides a rationale for TRPA1 inhibitors to relieve postoperative pain. TRPA1 knockout mice and wild-type mice treated with TRPA1 antagonists showed anxiolytic and antidepressant-like phenotypes (de Moura et al., 2014). Based on studies showing mechanistic links between AMPK and TRPA1 exist, TRPA1 inhibitors are expected to be beneficial in the treatment of diabetic neuropathy (Hiyama et al., 2018; Koivisto and Pertovaara, 2013; Wang et al., 2018). TRPA1 knockout mice exhibited smaller myocardial infarct size compared to wild-type mice (Conklin et al., 2019).TRPA1 gene deletion and pharmacological intervention suppress TNBS-induced colitis in mice (Engel et al., 2011). In a mouse model of cerebral ischemia, TRPA1 gene deletion and TRPA1 antagonists reduce myelin damage (Hamilton et al., 2016). In a mouse model of monosodium urate-induced gout, urate crystals and joint inflammation are reduced in TRPA1 gene deletion mice (Moilanen et al., 2015). TRPA1 deletion in rats improves joint inflammation and hyperalgesia in a rat model of acute gout flares (Trevisan et al., 2014). Activation of TRPA1 elicits inflammatory responses in osteoarthritic chondrocytes (Nummenmaa et al., 2016). TRPA1 inhibition and gene deletion reduce inflammatory mediators in osteoarthritic mouse chondrocytes and in murine cartilage (Nummenmaa et al., 2016). Finally, TRPA1 gene deletion mice show improvement in osteoarthritic limb loading in a MIA-induced knee swelling model (Horvath et al., 2016). TRPA1 is expressed in the urothelium of rats (Du et al., 2007) and in patients with bladder outlet obstruction (Du et al., 2008). TRPA1 receptor modulation alleviates bladder hyperactivity in a rat model of spinal cord injury (Andrade et al., 2011) and intrathecal administration of a TRPA1 antagonist alleviates cyclophosphamide-induced cystitis in a rat model of urinary hyperreflexia (Chen et al., 2016).

[0006] Therefore, there is a need to provide potent TRPA1 inhibitors.

[0007] TRPA1 inhibitors of various structural classes are reviewed in S. Skerratt, Progress in Medicinal Chemistry, 2017, Vol. 56, 81-115 and D. Preti, G. Saponaro, A. Szallasi, Pharm. Pat. Anal. (2015) 4(2), 75-94.

[0008] WO 2017 / 060488 discloses compounds as TRPA1 antagonists having the following general structure

[0009]

[0010] Examples 28 and 29, however, which carry a tetrazolyl ring, are not disclosed with respect to their TRPA1 activity.

[0011] L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809 disclose quinazolinone-based TRPA1 antagonists including compounds of the following general structure

[0012]

[0013] Compound 31, wherein R is OH, is disclosed to have an IC 50 of 58 nM antagonizing TRPA1 activity and an intrinsic clearance in human liver microsomes of < 14 μL / min / kg. DETAILED DESCRIPTION

[0014] The present invention discloses novel tetrazole derivatives which are inhibitors of Transient Receptor Potential Ankyrin 1 (TRPA1) with suitable pharmacological and pharmacokinetic properties making them useful as pharmaceutical agents for the treatment of conditions and / or diseases which can be treated by inhibition of TRPA1.

[0015] The compounds of the present invention can provide several advantages such as enhanced potency; high metabolic and / or chemical stability; high selectivity, safety and tolerability; enhanced solubility; enhanced permeability; desired plasma protein binding; enhanced bioavailability; suitable pharmacokinetic profile; and possibility to form stable salts.

[0016] The compounds of the present invention

[0017] The present invention provides novel tetrazole derivatives which are surprisingly potent inhibitors of TRPA1 (assay A) further characterized by

[0018] Improved stability in human liver microsomes (assay B)

[0019] Improved stability in human hepatocytes (assay C).

[0020] The compounds of the present invention differ from examples 28 and 29 in WO 2017 / 060488 in that the compounds of the present invention contain a monocyclic dioxodihydropyrimidine core with an N-substituent, an amide group substituent and a substituent adjacent to a secondary aliphatic alcohol. The compounds of the present invention differ from example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809 in that the compounds of the present invention carry a tetrazolyl ring. These structural differences unexpectedly lead to the advantageous combination of (i) inhibition of TRPA1, (ii) stability in human liver microsomes and (iii) stability in human hepatocytes.

[0021] Thus, the compounds of the present invention are superior to those disclosed in the prior art in the combination of the following parameters:

[0022] - potency as TRPA1 inhibitors

[0023] - stability in human liver microsomes

[0024] -Stability in human liver cells.

[0025] Stability in human liver microsomes refers to the susceptibility of a compound to biotransformation in the selection and / or design of drugs with favorable pharmacokinetic properties as a first screening step. The liver is a major site of metabolism for many drugs. Human liver microsomes contain cytochrome P450 (CYP) and therefore represent a model system for studying phase I drug metabolism in vitro. Enhanced stability in human liver microsomes is associated with several advantages, including increased bioavailability and a suitable half-life, which allows for reduced dosage and frequency of administration to patients. Therefore, enhanced stability in human liver microsomes is an advantageous feature of compounds intended for use as drugs. Thus, in addition to the ability to inhibit TRPA1, the compounds of the present invention are also expected to have favorable in vivo clearance and therefore the desired duration of action in humans.

[0026] Stability in human hepatocytes refers to the susceptibility of a compound to biotransformation in the selection and / or design of drugs with favorable pharmacokinetic properties. The liver is the primary site of metabolism for many drugs. Human hepatocytes contain cytochrome P450 (CYP) and other drug-metabolizing enzymes, and therefore represent a model system for studying in vitro drug metabolism. (Importantly, compared to liver microsomal analysis, hepatocyte analysis also covers phase II biotransformation and processes mediated by liver-specific transporters, and therefore represents a more complete system for drug metabolism studies). Enhanced stability in human hepatocytes is associated with several advantages, including increased bioavailability and an appropriate half-life, allowing for lower doses and frequency of administration to patients. Therefore, enhanced stability in human hepatocytes is a favorable feature for compounds intended for drug use.

[0027] This invention provides novel compounds according to formula (I).

[0028]

[0029] in

[0030] Option A is selected from the group consisting of phenyl, thienyl, benzothienyl, or benzofuranyl groups, which are unsubstituted or derived via halogens, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 Cyclofluoroalkyl, -OC 1-4 R is a group composed of alkyl, -O-cyclopropyl and NC-. 3 One, two, or three members may be replaced;

[0031] or

[0032] A is selected from the group consisting of:

[0033]

[0034] R 1 is selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, R 4 -(H2C) m - and R 5 -(H2C) n -;

[0035] wherein

[0036] m is 1 or 2;

[0037] n is 2;

[0038] R 4 is C 3-6 cycloalkyl;

[0039] R 5 is -O-C 1-4 alkyl or -O-C 1-4 fluoroalkyl;

[0040] R 2 is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cyclofluoroalkyl, HO-C 1-4 alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p -, R 7 -(H2C) q -, R 6 -(H(R 8 )C) p - and R 7 -(H(R 9 )C) q -;

[0041] wherein

[0042] p is 1 or 2;

[0043] q is 2;

[0044] R 6 is selected from the group consisting of HO-C 1-2 alkyl-, C 3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl;

[0045] wherein the C-pyrazolyl, C-imidazolyl and C-morpholinyl groups are unsubstituted or substituted by C 1-4 alkyl or C 1-4 fluoroalkyl;

[0046] R 7 is selected from the group consisting of -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, C 1-4 alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl;

[0047] wherein the N-pyrazolyl, N-imidazolyl, N-morpholinyl groups are unsubstituted or substituted by C 1-4 alkyl or C 1-4 fluoroalkyl;

[0048] R 8 and R 9 are independently selected from H or C 1-4 alkyl.

[0049] Another embodiment of the present application relates to a compound of formula (I), wherein

[0050] A is selected from the group consisting of phenyl, thienyl, benzothienyl or benzofuranyl, which is unsubstituted or substituted by one or two members selected from the group consisting of halogen, C 1-4 alkyl, -O-C 1-4 alkyl and NC-; 3 alkyl.

[0051] or

[0052] A is

[0053]

[0054] R 1 is selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, R 4 -(H2C) m - and R 5 -(H2C) n -;

[0055] wherein

[0056] m is 1 or 2;

[0057] n is 2;

[0058] R 4 is C 3-6 cycloalkyl;

[0059] R 5 is -O-C 1-4alkyl;

[0060] R 2 is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, HO-C 1-4 alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p - and R 7 -(H2C) q - consisting;

[0061] wherein

[0062] p is 1 or 2;

[0063] q is 2;

[0064] R 6 is selected from the group consisting of C 3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl;

[0065] wherein the C-pyrazolyl, C-imidazolyl and C-morpholinyl are unsubstituted or substituted with C 1-4 alkyl;

[0066] R 7 is selected from the group consisting of -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, C 1-4 alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl;

[0067] wherein the N-pyrazolyl, N-imidazolyl, N-morpholinyl are unsubstituted or substituted with C 1-4 alkyl.

[0068] Another embodiment of the present application relates to a compound of formula (I)

[0069] wherein

[0070] A is selected from the group consisting of phenyl, thienyl, benzothienyl or benzofuranyl, which is unsubstituted or substituted by one or two members of the group R 3 consisting of Cl, F, Br, H3C, H3C-O- and NC-;

[0071] or

[0072] A is

[0073]

[0074] and the substituents R 1 and R 2 are as defined in the preceding embodiments.

[0075] Another embodiment of the application relates to a compound of formula (I)

[0076] wherein

[0077] A is selected from the group consisting of:

[0078]

[0079] which is unsubstituted or substituted by one or two members of the group consisting of CI, F, Br, H3C, H3C-O- and NC- 3

[0080] or

[0081] A is

[0082]

[0083] and the substituents R 1 and R 2 are as defined in any of the preceding embodiments. Another embodiment of the application relates to a compound of formula (I), wherein

[0084] A is selected from the group consisting of:

[0085]

[0086]

[0087]

[0088] and the substituents R 1 and R 2 are as defined in any of the preceding embodiments.

[0089] Another embodiment of the application relates to a compound of formula (I), wherein

[0090] R 1 is selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, R 4 -(H2C) m - and R 5 -(H2C) n ; wherein

[0091] m is 1 ;

[0092] n is 2;

[0093] R 4 is C 3-6 cycloalkyl; ​

[0094] R 5 is -O-C 1-4 alkyl;

[0095] and the substituents A and R 2 are as defined in any of the preceding embodiments.

[0096] Another embodiment of the application relates to a compound of formula (I),

[0097] wherein

[0098] R 1 is selected from the group consisting of C 1-4 alkyl, C 3-4 cycloalkyl, R 4 -(H2C) m - and R 5 -(H2C) n -;

[0099] m is 1 ;

[0100] n is 2;

[0101] R 4 is C 3-4 cycloalkyl;

[0102] R 5 is -O-C 1-4 alkyl;

[0103] and the substituents A and R 2 are as defined in any of the preceding embodiments.

[0104] Another embodiment of the application relates to a compound of formula (I),

[0105] wherein

[0106] R 1 is selected from the group consisting of C 1-4 alkyl, C 3-4 cycloalkyl, R 4 -(H2C) m - and R 5 -(H2C) n -;

[0107] wherein

[0108] m is 1 ;

[0109] n is 2;

[0110] R 4 is C 3-4 cycloalkyl;

[0111] R 5H3C-O-;

[0112] and the substituents A and R 2 as defined in any of the preceding embodiments.

[0113] Another embodiment of the application relates to a compound of formula (I), wherein

[0114] R 1 is selected from the group consisting of H3C, H3CH2C, H3COH2CH2C,

[0115]

[0116] and the substituents A and R 2 as defined in any of the preceding embodiments.

[0117] Another embodiment of the application relates to a compound of formula (I), wherein

[0118] R 1 is H3C;

[0119] and the substituents A and R 2 as defined in any of the preceding embodiments.

[0120] Another embodiment of the application relates to a compound of formula (I),

[0121] wherein

[0122] R 2 is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, HO-C 1-4 alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p - and R 7 -(H2C) q - consisting;

[0123] wherein

[0124] p is 1 ;

[0125] q is 2;

[0126] R 6 is selected from the group consisting of C 3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl;

[0127] wherein the C-pyrazolyl, C-imidazolyl and C-morpholinyl are unsubstituted or substituted with C 1-4 alkyl;

[0128] R7 selected from the group consisting of -O-C 1-4 alkyl, -O-C 1-4 fluoroalkyl, C 1-4 alkyl-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl;

[0129] wherein the N-pyrazolyl, N-imidazolyl, N-morpholinyl is unsubstituted or substituted with C 1-4 alkyl;

[0130] and substituents A and R 1 are as defined in any of the preceding embodiments.

[0131] Another embodiment of the present application relates to a compound of formula (I), wherein

[0132] R 2 is selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, HO-C 1-4 alkyl-, C 1-2 fluoroalkyl, R 6 -(H2C) p - and R 7 -(H2C) q - consist;

[0133] wherein

[0134] p is 1 ;

[0135] q is 2;

[0136] R 6 is selected from the group consisting of C 3-6 cycloalkyl, C-morpholinyl, C-imidazolyl and C-pyrazolyl;

[0137] wherein the C-pyrazolyl, C-imidazolyl and C-morpholinyl is unsubstituted or substituted with H3C;

[0138] R 7 is selected from the group consisting of H3C-O-, -O-fluoromethyl, H3C-S(O)2-, N-morpholinyl, N-imidazolyl and N-pyrazolyl;

[0139] wherein the N-pyrazolyl, N-imidazolyl, N-morpholinyl is unsubstituted or substituted with H3C;

[0140] and substituents A and R 1 are as defined in any of the preceding embodiments.

[0141] Another embodiment of the present application relates to a compound of formula (I), wherein

[0142] R2 selected from the group consisting of H, C 1-4 alkyl, C 3-6 cycloalkyl, HO-C 1-4 alkyl-, C 1-2 fluoroalkyl, R 6 -(H2C) p - and R 7 -(H2C) q - consisting;

[0143] wherein

[0144] p is 1 ;

[0145] q is 2;

[0146] R 6 is selected from the group consisting of C 3-6 cycloalkyl,

[0147]

[0148] R 7 is selected from the group consisting of H3C-O, -O-fluoromethyl, H3C-S(O)2-,

[0149]

[0150] and the substituents A and R 1 are as defined in any of the preceding embodiments.

[0151] Another embodiment of the present application relates to a compound of formula (I), wherein

[0152] R 2 is selected from the group consisting of H, H3C, H3CH2C, H3COH2CH2C, F2HCH2C, F3CH2C, FH2CH2C, H3C(O)2SH2CH2C, F3COH2CH2C,

[0153]

[0154] and the substituents A and R 1 are as defined in any of the preceding embodiments.

[0155] Another embodiment of the present application relates to a compound of formula (I), wherein

[0156] R 2 is H;

[0157] and the substituents A and R 1 are as defined in any of the preceding embodiments.

[0158] Preferred are compounds of formula (I) selected from the group consisting of

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] and the substituent A is defined as in any of the preceding embodiments.

[0165] Preferred are compounds according to formula (I) selected from

[0166]

[0167] and the substituent A is defined as in any of the preceding embodiments.

[0168] Especially preferred are compounds according to formula (I) selected from the group consisting of

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Terms and definitions used

[0181] Terms not specifically defined herein have the meanings that would be given to them by a person of ordinary skill in the art in light of the disclosure and context, and are to be used consistent with the teachings and practices of the art. However, unless otherwise defined, the following terms have the specified meanings and are to be construed as follows when used in the specification:

[0182] In groups, radicals or moieties defined below, the number of carbon atoms is often specified before the group, e.g., "C 1-6 "Alkyl" means an alkyl group / alkyl radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or the like, one skilled in the art will see from the group itself the point of attachment of the group to the molecule. For combined groups comprising two or more subgroups, the last named subgroup is the point of attachment of the group to the molecule, e.g., the substituent "aryl-C 1-3 "Alkyl" means an alkyl group / alkyl radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or the like, one skilled in the art will see from the group itself the point of attachment of the group to the molecule. For combined groups comprising two or more subgroups, the last named subgroup is the point of attachment of the group to the molecule, e.g., the substituent "aryl-C 1-3 "Alkyl" means an alkyl group / alkyl radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or the like, one skilled in the art will see from the group itself the point of attachment of the group to the molecule. For combined groups comprising two or more subgroups, the last named subgroup is the point of attachment of the group to the molecule, e.g., the substituent "aryl-C 1-3 "Alkyl" means an alkyl group / alkyl radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, or the like, one skilled in the art will see from the group itself the point of attachment of the group to the molecule. For combined groups comprising two or more subgroups, the last named subgroup is the point of attachment of the group to the molecule, e.g., the substituent "aryl-C

[0183] In the event that a compound of the application is depicted in both chemical name and chemical formula form, in the event of any discrepancy, the chemical formula shall control. An asterisk can be used in sub-formulae to indicate a bond to the core molecule as defined.

[0184] The numbering of substituent atoms begins with the atom closest to the core or to the group to which the substituent is attached.

[0185] For example, the term "3-carboxypropyl" represents the following substituent:

[0186]

[0187] 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:

[0188]

[0189] An asterisk can be used in sub-formulae to indicate a bond to the core molecule as defined.

[0190] The term "C 1-n "Alkyl" (where n is an integer selected from 2, 3, 4, or 5) alone or in combination with another group represents an acyclic saturated branched or straight-chain hydrocarbon having 1 to n C atoms. For example, the term "C 1-5"Alkyl" encompasses the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-.

[0191] The term "fluoro" added to "alkyl," "alkylene," or "cycloalkyl" (saturated or unsaturated) means such alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a fluorine atom. Examples include, but are not limited to: H2FC-, HF2C-, and F3C-.

[0192] The term "C 3-n "Cycloalkyl" (where n is an integer from 4 to n) alone or in combination with another radical means a cyclic saturated unbranched hydrocarbon radical having from 3 to n C atoms. For example, the term "C 3-6 "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0193] The term halogen generally means fluorine, chlorine, bromine, and iodine.

[0194] The term "phenyl" refers to a radical of the following ring:

[0195]

[0196] The term "thienyl" refers to a radical of the following ring:

[0197]

[0198] The term "benzothienyl" refers to a radical of the following ring:

[0199]

[0200] The term "benzofuranyl" refers to a radical of the following ring:

[0201]

[0202] The term "tetrazolyl" refers to a radical of the following ring:

[0203]

[0204] The term "dioxodihydropyrimidinecarboxamide" refers to the following ring of groups:

[0205]

[0206] The term "C-morpholinyl" refers to the following ring of groups:

[0207]

[0208] The term "C-imidazolyl" refers to the following ring of groups:

[0209]

[0210] The term "C-pyrazolyl" refers to the following ring of groups:

[0211]

[0212] The term "N-morpholinyl" refers to the following ring of groups:

[0213]

[0214] The term "N-imidazolyl" refers to the following ring of groups:

[0215]

[0216] The term "N-pyrazolyl" refers to the following ring of groups:

[0217]

[0218] As used herein, the term "substituted" means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.

[0219] Unless specifically indicated otherwise, throughout the specification and the appended claims, a given chemical formula or name is intended to encompass all tautomers and all stereoisomers, optical isomers, and geometric isomers (such as mirror image isomers, non-mirror image isomers, E / Z isomers, etc.) and mixtures of any of these in any proportion, as well as racemates and mixtures of such isomers and mirror image isomers in any of the aforementioned forms, and salts, including pharmaceutically acceptable salts thereof, and solvates thereof (such as hydrates including solvates of free compounds or solvates of salts of compounds).

[0220] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to the person skilled in the art, for example by separation of corresponding mixtures, by use of stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, for example starting from optically active starting materials and / or by use of chiral reagents.

[0221] The enantiomerically pure compounds or intermediates of the application can be prepared via asymmetric synthesis, for example by preparing and subsequent separation of a suitable non-enantiomeric compound or intermediate which can be separated by known methods, for example by chromatographic separation or crystallization, and / or by use of chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0222] Furthermore, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by resolution of the racemic mixture using a suitable resolving agent, for example by formation of non-enantiomeric salts of the racemic compound with an optically active acid or base, followed by separation of the salts and liberation of the desired compound from the salts; or by derivatization of the corresponding racemic compound with an optically active chiral auxiliary, followed by separation of the non-enantiomeric derivatives and removal of the chiral auxiliary group; or by kinetic resolution of the racemate (for example by enzymatic resolution); by enantioselective crystallization from conglomerates of enantiomeric crystals under suitable conditions; or by (fractionated) crystallization from suitable solvents in the presence of an optically active chiral auxiliary.

[0223] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0224] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound forms a salt or complex with an acid or a base. Examples of acids forming pharmaceutically acceptable salts with a parent compound containing a basic moiety include inorganic acids 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.

[0225] Examples of cations and bases forming pharmaceutically acceptable salts with a parent compound containing an acidic moiety include Na + , K + , Ca 2+ , Mg 2+ , NH4 +L-arginine, 2,2'-iminodiethanol, L-lysine, N-methyl-D-glucamine, or tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present application 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 forms of these compounds with a sufficient amount of the appropriate base or acid, respectively, in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0226] In addition to those salts mentioned above, salts of other acids than those implicit to the compounds of this application (e.g. trifluoroacetate) can also be used as a means of further purification or isolation of the compounds of this application.

[0227] Bioassay

[0228] Evaluation of TRPA1 activity

[0229] Assay A: TRPA1 assay

[0230] The following in vitro TRPA1 cell assay can be used to demonstrate the activity of the compounds of the present application:

[0231] Method:

[0232] A human HEK293 cell line overexpressing the human TRPA1 ion channel (Perkin Elmer, product number AX-004-PCL) was used as a test system for compound efficacy and potency. Compound activity was determined by measuring the effect of the compound on intracellular calcium concentration induced by the agonistic effect of allyl isothiocyanate (AITC) in a FLIPRtetra system (Molecular Devices).

[0233] Cell culture:

[0234] Cells were obtained as frozen cells in cryovials and stored at -150°C before use.

[0235] Cells were 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% confluency. For subculturing, cells were detached from the flasks by Versene. One day before the assay, cells were detached, washed twice with culture medium (MEM / EBSS medium with 10% FCS) and 20,000 cells were seeded in 20 μΐ / well into poly-D-lysine (Poly D-Lysin) bio-coated 384-well plates (black clear bottom, Cat. 356697) from Corning. The culture plates were incubated for 24 hours at 37°C / 5% C02 before use in the assay.

[0236] Compound preparation

[0237] Test compounds were dissolved in 100% DMSO at a concentration of 10 mM and diluted in the first step to a concentration of 5 mM in DMSO, followed by consecutive dilution steps in 100% DMSO. The dilution factor and the number of dilution steps can be varied as needed. Typically, 8 different concentrations were prepared by 1 :5 dilutions with further intermediate dilutions (1 :20) of the substances in HBSS / HEPES buffer (1 x HEPES, Cat. 14065 from Gibco; 20 mM HEPES, Cat. 83264 from SIGMA; 0.1% BSA Cat. 11926 from Invitrogen, pH 7.4).

[0238] FLIPR analysis:

[0239] On the day of the assay, cells were washed 3 times with assay buffer, leaving 20 μL buffer remaining in the wells after washing. 10 μL Ca6 kit (Cat. R8191, Molecular Devices) in HBSS / HEPES was added to the cells and the plates were incubated at 37°C / 5% C02, covered, for 120 minutes. 10 μL of compound or control in HBSS / HEPES buffer / 5% DMSO was carefully added to each well from the intermediate dilution plate. Luminescence (indicative of calcium influx or release) was read on a FLIPRtetra instrument for 10 minutes to monitor compound-induced effects (e.g. agonism). Finally, 10 μL of agonist AITC 50 μM (final concentration 10 μM) dissolved in HBSS / HEPES buffer / 0.05% DMSO was added to each well, followed by a further 10 minutes reading on the FLIPRtetra instrument. The area under the curve (AUC) of the signal after AITC addition was used for IC50 / inhibition % calculation.

[0240] Data evaluation and calculation:

[0241] 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 wells with vehicle controls without AITC as a control for non-specific changes in luminescence (0% CTL; low control).

[0242] Data analysis was performed by calculating the area under the curve of the signal of the individual wells. Based on this value, the % of the measured value of each substance concentration was calculated using MegaLab software (in-house development) (AUC(sample) - AUC(low)) * 100 / (AUC(high) - AUC(low)). IC50 values were calculated from the control value % using MegaLab software. Calculation: [y = (a - d) / (1 + (x / c)A + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = hill; y = control %

[0243] Table 1 : Biological data of the compounds of the application as obtained in Assay A

[0244]

[0245]

[0246] Table 2: Biological data of prior art compounds (examples 28 and 29 in WO2017 / 060488) as obtained in Assay A.

[0247]

[0248] Table 3: Biological data of prior art compounds (example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in Assay A.

[0249]

[0250] Evaluation of microsomal clearance

[0251] Assay B: Microsomal clearance:

[0252] Metabolic degradation of the test compounds was analyzed using pooled liver microsomes at 37°C. The final incubation volume of 100 μΐ per time point contained TRIS buffer pH 7.6 (0.1 M) at RT, magnesium chloride (5 mM), microsomal protein (1 mg / ml) and the test compound at a final concentration of 1 μΜ.

[0253] After a short pre-incubation period at 37°C, the reaction was started by addition of beta-nicotinamide adenine dinucleotide phosphate in reduced form (NADPH, 1 mM) and terminated after different time points (0, 5, 15, 30, 60 min) by transferring aliquots into solvents. In addition, NADPH-independent degradation was monitored in incubations without NADPH, 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 were pooled by centrifugation (10000 g, 5 min).

[0254] The amount of parent compound in the supernatant was analyzed by LC-MS / MS in aliquots of the supernatant. The half-life (t1 / 2INVITRO) was determined by the slope of the semi-logarithmic plot of the concentration-time profile.

[0255] The intrinsic clearance (CL_INTRINSIC) was calculated by taking into account the amount of protein in the incubation:

[0256] CL_INTRINSIC [pl / min / mg protein] = (Ln 2 / (half-life [min] * protein content [mg / ml])) * 1000

[0257] CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [pl / min / mg protein] * MPPGL [mg protein / g liver] * liver factor [g / kg body weight]) / 1000

[0258] Qh [%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg]

[0259] Hepatocyte number, human: 120 x 10e6 cells per gram liver

[0260] Liver factor, human: 25.7 g / kg body weight

[0261] Blood flow, human: 21 ml / (min x kg)

[0262] Table 4: Biological data of the compounds of the present application as obtained in analysis B

[0263]

[0264]

[0265] Table 5: Biological data of prior art compounds (example 28 and 29 in WO2017 / 060488) as obtained in analysis B.

[0266]

[0267]

[0268] Table 6: Biological data of a prior art compound (example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in Assay B.

[0269]

[0270] Evaluation of hepatocyte clearance

[0271] Assay C: Hepatocyte clearance

[0272] Test compounds are analyzed for metabolic degradation in hepatocyte suspension. Hepatocytes (cryopreserved) are incubated in Dulbecco's modified eagle medium (supplemented with 3.5 μg insulin / 500 mL, 2.5 mg glucagon / 500 mL and 3.75 mg / 500 mL hydrocortisone) containing 5% or 50% species serum.

[0273] After pre-incubation for 30 min in an incubator (37°C, 10% C02), 5 μl of test compound solution (80 μM; diluted 1 :25 from a 2 mM DMSO stock solution with medium) is added to 395 μl of hepatocyte suspension (cell density in the range of 0.25-5 million cells / mL, depending on the species, typically 1 million cells / mL; final concentration of test compound 1 μM, final DMSO concentration 0.05%).

[0274] Cells are incubated for six hours (incubator, orbital shaker) and samples (25 μl) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples are transferred to acetonitrile and spun down by centrifugation (5 min). Supernatant is transferred to a new 96 deep well plate, evaporated under nitrogen and re-suspended.

[0275] Analysis of parent compound reduction by HPLC-MS / MS

[0276] CLint is calculated as follows: CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD+clast / k) x 1000 / 60. C0: initial concentration in incubate [μΜ], CD: cell density of viable cells [10e6 cells / mL], AUD: area under data [μΜxh], clast: concentration of last data point [μΜ], k: slope of regression line of parent reduction [h1].

[0277] The calculated intrinsic in vitro hepatic clearance can be scaled to intrinsic in vivo hepatic clearance and used to predict in vivo hepatic blood clearance (CL) by using a liver model (well-stirred model).

[0278] CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [pL / min / 10e6 cells] x number of hepatocytes [10e6 cells / gram of liver] x liver factor [g / kg body weight]) / 1000

[0279] CL [ml / min / kg] = CL_INTRINSIC_INVIVO [ml / min / kg] x hepatic blood flow [ml / min / kg] / (CL_INTRINSIC_INVIVO [ml / min / kg] + hepatic blood flow [ml / min / kg])

[0280] Qh [%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg])

[0281] Number of hepatocytes, human: 120 x 10e6 cells / gram of liver

[0282] Liver factor, human: 25.7 g / kg body weight

[0283] Blood flow, human: 21 ml / (min x kg)

[0284] Table 7: Biological data of the compounds of the application as obtained in Assay C

[0285]

[0286]

[0287] Table 8: Biological data of prior art compounds (examples 28 and 29 in WO2017 / 060488) as obtained in Assay C.

[0288]

[0289] Table 9: Biological data of a prior art compound (example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809) as obtained in Assay C.

[0290]

[0291] Evaluation of permeability

[0292] Caco-2 cells (1-2 x 105cells / 1 cm 2Cells (area) seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 pm pore size) and cultured (DMEM) for 10 to 25 days.

[0293] Compounds are dissolved in an appropriate solvent (e.g. DMSO, 1-20 mM stock solutions). Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgS04, 1.8 mM CaCl2, 4.17 mM NaHC03, 1.19 mM Na2HP04x7H20, 0.41 mM NaH2P04xH20, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare transport solutions (0.1-300 mM compound, final DMSO <= 0.5%). Transport solutions (TL) are applied to the apical or basolateral donor side for measuring A-B or B-A permeability, respectively (filters are repeated 3 times). At the beginning and at the end of the experiment samples are collected from the donor and at various time intervals also from the acceptor side, time duration 2 hours, for concentration measurements by HPLC-MS / MS or scintillation counting. The acceptor volume is replaced with fresh acceptor solution after sampling.

[0294] Evaluation of plasma protein binding

[0295] 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 (0.2 ml) are used. Each cell consists of a donor and an acceptor chamber separated by an ultra-thin semi-permeable membrane with a molecular weight cut-off of 5 kDa. Stock solutions for each test compound are prepared in DMSO at 1 mM and diluted to a final concentration of 1.0 mM. Subsequent dialysis solutions are prepared in pooled human or rat plasma (with NaEDTA) from male and female donors. An aliquot of 200 pL dialysis buffer (100 mM potassium phosphate, pH 7.4) is dispensed into the buffer chamber. An aliquot of 200 pL test compound dialysis solution is dispensed into the plasma chamber. Incubate for 2 hours at 37 °C under rotation.

[0296] At the end of the dialysis period, the dialysate is transferred to the reaction tubes. The tubes for the buffer part contain 0.2 mL ACN / water (80 / 20). An aliquot of 25 μL plasma dialysate is transferred to a deep well plate and mixed with 25 μL ACN / water (80 / 20), 25 μL buffer, 25 μL calibration solution and 25 μL internal standard solution. Protein precipitation is performed by adding 200 μL ACN. An aliquot of 50 μL buffer dialysate is transferred to a deep well plate and mixed with 25 μL blank plasma, 25 μL internal standard solution and 200 μL ACN. The samples are measured on a HPLC-MS / MS-system and evaluated by means of the Analyst-Software. The percentage of binding is calculated with the following formula: % binding = (plasma concentration - buffer concentration / plasma 30 concentration) x 100.

[0297] Evaluation of solubility

[0298] Saturated solutions are prepared in well plates (format depending on the robot) by adding the appropriate volume of the selected liquid medium (typically in the range of 0.25-1.5 ml) to the individual wells containing a known amount of the solid drug substance (typically in the range of 0.5-5.0 mg). The individual wells are shaken or stirred for a predetermined period of time (typically in the range of 2-24 h) and then filtered using the appropriate filter membrane (typically a PTFE-filter membrane with a pore size of 0.45 μm). The filter membrane is protected from absorption by discarding the first few drops of the filtrate. The amount of dissolved drug substance is determined by UV spectroscopic analysis. In addition, the pH of the saturated aqueous solution is measured using a glass electrode pH meter.

[0299] Evaluation of pharmacokinetic characteristics in rodents

[0300] The test compound is administered intravenously to fed rats or orally to fasted rats. Blood samples are taken at several time points after administration of the test compound, anticoagulated and centrifuged.

[0301] The concentrations of the administered compound and / or metabolites as analytes in the plasma samples are quantified. The PK parameters are calculated using non-compartmental methods. The AUC and Cmax are normalized to a dose of 1 μmol / kg.

[0302] Evaluation of in vitro human hepatocyte metabolism

[0303] Primary human hepatocytes in suspension are used to investigate the metabolic pathways of the test compound. After recovery from cryopreservation, the human hepatocytes are incubated in Dulbecco's modified Eagle's medium containing 5% human serum and supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml and 3.75 mg / 500 ml hydrocortisone.

[0304] After a pre-incubation of 30 min in a cell culture incubator (37°C, 10% C02), the test compound solution was spiked into the hepatocyte suspension to obtain a final cell density of 1.0*10 6 to 4.0*10 6 cells per milliliter, a final test compound concentration of 10 μΜ and a final DMSO concentration of 0.05%, depending on the metabolic conversion rate of the compound observed with the accompanying primary human hepatocytes.

[0305] The cells were incubated in a cell culture incubator on a horizontal shaker for six hours and samples were removed from the incubation after 0, 0.5, 1, 2, 4 or 6 hours depending on the metabolic conversion rate. The samples were quenched with acetonitrile and pelleted by centrifugation. The supernatant was transferred to a 96-deep well plate, evaporated under nitrogen and re-suspended before bioanalysis by liquid chromatography-high resolution mass spectrometry analysis for the identification of putative metabolites.

[0306] based on Fourier-Transform-MS n Data were tentatively assigned structures. Metabolites were reported in percentage of parent in human hepatocyte incubations with a cut-off of > 4%.

[0307] Therapeutic methods

[0308] The present invention relates to compounds of general formula 1 which 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) the treatment and / or prevention of fibrotic diseases, inflammatory and immunoregulatory disorders, diseases or disorders of the respiratory or gastrointestinal tract, ophthalmic diseases, inflammatory diseases of the joints and inflammatory diseases of the nasopharynx, eye and skin, as well as pain and neurological disorders. The disorders, diseases and conditions include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic, asthma 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, as well as bladder disorders.

[0309] Compounds of general formula 1 are useful for the prevention and / or treatment of:

[0310] (1 ) cough, such as chronic idiopathic cough or chronic intractable cough, cough associated with asthma, COPD, lung cancer, post-viral infection and idiopathic pulmonary fibrosis, as well as other interstitial lung diseases.

[0311] (2) Pulmonary fibrotic diseases (such as pneumonitis or interstitial pneumonitis associated with collagenosis), for example, lupus erythematosus, systemic scleroderma rheumatoid arthritis, polymyositis and dermatomyositis, idiopathic interstitial pneumonia (such as idiopathic pulmonary fibrosis (IPF)), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic fibrosing alveolitis, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhan's cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung disease of known etiology, such as interstitial pneumonitis or granulomatous disease caused by occupational exposure (such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), Pidgeon fanciers lung (birds) or other occupational air-borne triggers (such as metal dust or mycobacteria) or by treatment (such as radiation, methotrexate, amiodarone, nitrofurantoin or chemotherapeutic agents), such as granulomatous polyangiitis, Churg-Strauss syndrome, sarcoidosis, hypersensitivity pneumonitis or interstitial pneumonitis caused by different etiologies (e.g. inhalation of toxic gases, vapors, bronchitis or pneumonia) 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.

[0312] (3) Other fibrotic diseases, such as liver bridging fibrosis, liver cirrhosis, nonalcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scar, arterial stiffness, joint fibrosis, Dupuytren's contracture, keloids, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis.

[0313] (4) inflammatory, autoimmune or allergic diseases and conditions, such as allergic or non-allergic rhinitis or sinusitis, chronic rhinosinusitis or rhinitis, nasal polyps, chronic sinusitis, acute sinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, hyper-responsive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchopulmonary oedema, bronchitis or local pneumonitis, eosinophilic cellulitis (e.g. Well's syndrome), eosinophilic pneumonia (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, emphysema; systemic anaphylaxis or hypersensitivity, drug allergies (e.g. to penicillin, cephalosporins), eosinophilia-myalgia syndrome resulting from ingestion of contaminated tryptophan, insect sting hypersensitivity; autoimmune diseases such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenia (adult ITP / newborn thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug-induced), Evans syndrome (platelet and red cell immune cytopenias), neonatal Rh disease, Goodpasture's syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy juvenile diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; transplant 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; psoriasis (including T cell-mediated psoriasis) and inflammatory dermatoses (such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria); vasculitides (e.g. necrotizing, cutaneous and hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis, cancers with leukocytic infiltration of the skin or organs;Ophthalmic diseases such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema, keratitis, ocular pemphigoid, corneal conjunctivitis, vernal keratoconjunctivitis, scarring, anterior segment scarring, blepharitis, tarsal conjunctivitis, bullous disorders, cicatricial pemphigoid, conjunctival melanoma, papillae conjunctivitis, dry eye, episcleritis, glaucoma, gliomatosis, ring granuloma, Graves' ophthalmopathy, intraocular melanoma, maculae conjunctivales, proliferative vitreoretinopathy, pterygium, scleritis, acute gout flares, gout or osteoarthritis.

[0314] (5) Pain such as chronic idiopathic pain syndrome, neuropathic pain, dysesthesia, allodynia, migraine, dental pain and postoperative pain.

[0315] (6) Depression, anxiety, diabetic neuropathy and bladder disorders such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemic injury.

[0316] The present application thus relates to a compound of general formula 1 for use as a medicament.

[0317] Furthermore, the present application relates to the use of a compound of general formula 1 for the treatment and / or prevention of diseases and / or conditions associated with or modulated by TRPA1 activity.

[0318] Furthermore, the present application relates to the use of a compound of general formula 1 for the treatment and / or prevention of fibrotic diseases, inflammatory and immunoregulatory disorders, diseases or discomforts of the respiratory or gastrointestinal tract, ophthalmic diseases, inflammatory diseases of the joints and of the nasopharynx, eye and skin, pain and neurological disorders. Said disorders, diseases and discomforts include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrosis, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease as well as inflammatory and immunoregulatory disorders such as rheumatoid arthritis and atherosclerosis, and pain and neurological disorders such as acute pain, surgical pain, chronic pain and depression as well as bladder disorders.

[0319] Furthermore, the present application relates to the use of a compound of general formula 1 for the treatment and / or prevention of:

[0320] (1) Cough such as chronic idiopathic cough or chronic intractable cough, cough associated with asthma, COPD, lung cancer, post-viral infection and idiopathic pulmonary fibrosis as well as other interstitial lung diseases.

[0321] (2) Pulmonary fibrotic diseases (such as pneumonitis or interstitial pneumonitis associated with collagenosis), for example, lupus erythematosus, systemic scleroderma rheumatoid arthritis, polymyositis and dermatomyositis, idiopathic interstitial pneumonia (such as idiopathic pulmonary fibrosis (IPF)), nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic fibrosing alveolitis, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans' cell histiocytosis, pleural parenchymal fibroelastosis, interstitial lung disease of known aetiology such as interstitial pneumonitis or granulomatous disease caused by occupational exposure (such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mould), pigeon fancier's lung (birds) or other occupational air-borne aetiological agents such as metal dusts or mycobacteria) or by treatment (such as radiation, methotrexate, amiodarone, furantoin or chemotherapeutic agents), or interstitial pneumonitis or fibrosis caused by different aetiological agents (e.g. inhalation of toxic gases, vapours, bronchitis or pneumonia), or interstitial pneumonitis caused by heart failure, X-rays, radiation, chemotherapy, Buerger's disease or sarcoidosis, granulomatous disease, cystic fibrosis or mucoviscidosis or alpha-1 antitrypsin deficiency.

[0322] (3) Other fibrotic diseases such as liver bridging fibrosis, liver cirrhosis, nonalcoholic steatohepatitis (NASH), atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, glial scars, arterial stiffness, joint fibrosis, Dupuytren's contracture, keloids, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, adhesive capsulitis.

[0323] (4) inflammatory, autoimmune or allergic diseases and conditions, such as allergic or non-allergic rhinitis or sinusitis, chronic rhinosinusitis or rhinitis, nasal polyps, chronic rhinosinusitis, acute rhinosinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, hyper-responsive airways, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary oedema, bronchitis or local pneumonitis, eosinophilic cellulitis (e.g. Wells' syndrome), eosinophilic pneumonia (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, emphysema; systemic anaphylaxis or hypersensitivity, drug allergies (e.g. to penicillin, cephalosporins), eosinophilia-myalgia syndrome resulting from 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 (adult ITP / newborn thrombocytopenia, pediatric ITP), immune hemolytic anemia (autoimmune and drug-induced), Evan's syndrome (platelet and red cell immune cytopenias), neonatal Rh disease, Goodpasture's syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy juvenile diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; transplant rejection (e.g. in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; spondyloarthropathies; 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 oedema, keratitis, eosinophilic keratitis, keratoconjunctivitis, vernal keratoconjunctivitis, scarring, anterior segment scarring, blepharitis, tarsal conjunctivitis, bullous disorders, cicatricial ocular pemphigoid, conjunctival melanoma, papillae conjunctivitis, dry eye, episcleritis, glaucoma, gliomatosis cerebri, granuloma annulare, Graves' ophthalmopathy, intraocular melanoma, macula conjunctiva, proliferative vitreoretinopathy, pterygium, scleritis, acute gout flares, gout or osteoarthritis.

[0324] (5) pain, such as chronic idiopathic pain syndrome, neuralgia, hypesthesia, allodynia, migraine, dental pain and post-operative pain.

[0325] (6) depression, anxiety, diabetic neuropathy and bladder disorders, such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischaemic injury.

[0326] In another aspect, the present application relates to a compound of general formula 1 for use in the treatment and / or prevention of the diseases and conditions mentioned above.

[0327] In another aspect, the present application relates to the use of a compound of general formula 1 for the manufacture of a medicament for the treatment and / or prevention of the diseases and conditions mentioned above.

[0328] In another aspect of the present application, the present application relates to a method for the treatment or prevention of the diseases and conditions mentioned above, which method comprises administering to a human an effective amount of a compound of general formula 1.

[0329] Combination therapy

[0330] The compounds of the present application can further be combined with one or more, preferably one, additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described above, in particular diseases or conditions associated with fibrotic diseases, inflammatory and immune- modulatory disorders, diseases or conditions of the respiratory or gastrointestinal tract, inflammatory diseases or conditions of the joints or nasopharynx, eye and skin (such as cough), idiopathic pulmonary fibrosis, other pulmonary interstitial diseases, asthma or allergic diseases, eosinophilic diseases, chronic obstructive pulmonary disease, atopic dermatitis and autoimmune pathologies (such as rheumatoid arthritis and atherosclerosis); or therapeutic agents useful in the treatment of ophthalmic diseases, pain and depression.

[0331] Additional therapeutic agents suitable for such combinations include in particular those which, for example, enhance the therapeutic effect of the active substance(s) on one of the indications mentioned and / or allow a reduction in the dose of the active substance(s).

[0332] Thus, the compounds of the present application can be combined with one or more additional therapeutic agents selected from the group consisting of anti-fibrotic agents, anti-cough agents, anti-inflammatory agents, anti-atopic dermatitis agents, analgesic agents, anticonvulsant agents, anxiolytic agents, sedative agents, skeletal muscle relaxant agents or antidepressant agents.

[0333] Anti-fibrotic agents are for example nintedanib, pirfenidone, phosphodiesterase type 4 inhibitors (PDE4) 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 blocking inhibitors such as BG-00011 / STX-100, recombinant pentraxin protein-2 (PTX-2) such as PRM-151; c-Jun N-terminal kinase (JNK) inhibitors such as CC-90001; galectin-3 inhibitors such as TD-139; G-protein coupled receptor 84 (GPR84) inhibitors such as GLPG-1205; G-protein coupled receptor 84 / G-protein coupled receptor 40 dual inhibitors such as PBI-4050; Rho-associated coiled-coil protein kinase 2 (ROCK2) such as KD-025; heat shock protein 47 (HSP47) small interfering RNA / ND-L02-s0201 such as BMS-986263; Wnt pathway inhibitors such as SM-04646; LD4 / PDE3 / 4 inhibitors such as Tipelukast; recombinant immunomodulatory domain of histidyl tRNA synthetase (HARS) such as ATYR-1923; prostaglandin synthase inhibitors such as ZL-2102 / SAR-191801; 15-hydroxy-eicosapentaenoic acid (15-HEPE such as DS-102); lysyl oxidase-like 2 (LOXL2) inhibitors such as PAT-1251, PXS-5382 / PXS-5338; phosphoinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) dual inhibitors such as HEC-68498; calpain inhibitors such as BLD-2660; mitogen-activated protein kinase (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-betal) small interfering RNA such as TRK250 / BNC-1021; or lysophosphatidic acid receptor antagonists such as BMS-986278.

[0334] For example, an anti-tussive agent is a purinergic receptor 3 (P2X3) receptor antagonist, such as gefapixant, S-600918, BAY-1817080, or BLU-5937; a neurokinin 1 (NK-1) receptor antagonist, such as Orvepitant, Aprepitant; a nicotinic acetylcholine receptor alpha 7 subunit stimulant, such as ATA-101 / bradanicline, codeine, gabapentin, pregablin, or azithromycin. For example, an anti-inflammatory agent is a corticosteroid, such as prednisolone or dexamethasone; a cyclooxygenase-2 (COX2) inhibitor, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; a prostaglandin E2 antagonist; a leukotriene B4 antagonist; a leukotriene D4 antagonist, such as monteleukast; a 5-lipoxygenase inhibitor; or other non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, ibuprofen, or indomethacin.

[0335] For example, an anti-ectopic dermatitis agent is cyclosporin, methotrexate, mycophenolate mofetil, azathioprine, phosphodiesterase inhibitors (e.g., apremilast, crisaborole), Janus-associated kinase (JAK) inhibitors (e.g., tofacitinib), neutralizing antibodies against IL-4 / IL-13 (e.g., dupilamab), IL-13 (e.g., lebrikizumab, tralokinumab), and IL-31 (nemolizumab).

[0336] For example, the analgesic is an opioid, such as morphine, oxymorphine, levopanol, oxycodone, propoxyphene, nalmefene, fentanyl, hydrocondon, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine; or a non-opioid, such as an acetylenic amine.

[0337] For example, the antidepressant is a tricyclic antidepressant such as amitriptyline, clomipramine, despramine, doxepin, desipramine, imipramine, nortriptyline; a selective serotonin reuptake inhibitor antidepressant (SSRI) such as fluoxetine, paroxetine, sertraline, citalopram, escitalopram; a norepinephrine reuptake inhibitor antidepressant (SNRI) such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, hydroxybuproprion, nomifensine, viloxazine; a dual serotonin-norepinephrine reuptake inhibitor antidepressant (SNRI) such as duloxetine, venlafaxine, desvenlafaxine, levomilnacipran; an atypical antidepressant such as trazodone, mirtazapine, vortioxetine, vilazodone, bupropion; a monoamine oxidase inhibitor antidepressant (MAOI) such as tranylcypromine, phenelzine, or isocarboxazid.

[0338] For example, the anxiolytic agent is a benzodiazepine such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam, or tofisopam; or it is a non-benzodiazepine hypnotic such as eszopiclone, zaleplon, zolpidem, or zopiclone; or it is a carbamate such as meprobamate, carisoprodol, tybamate, or lorbamate; or it is an antihistamine such as hydroxyzine, chlorpheniramine, or diphenhydramine.

[0339] For example, the sedative agent is a barbiturate sedative such as amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, secobarbital, talbutal, theamylal, or thiopental; or it is a non-barbiturate sedative such as glutethimide, meprobamate, methaqualone, or dichloalphenazone.

[0340] For example, the skeletal muscle relaxant is baclofen, meprobamate, carisoprodol, cyclobenzaprine, metaxalone, methocarbamol, tizanidine, chlorzoxazone, or orphenadrine.

[0341] Other suitable combination partners are acetylcholinesterase inhibitors, such as donepezil; 5-HT-3 antagonists, such as ondansetron; metabotropic glutamate receptor antagonists; anti-arrhythmic agents, such as mexiletine or phenytoin; or NMDA receptor antagonists.

[0342] Other suitable combination partners are incontinence drugs, for example anticholinergics, such as oxybutynin, tolterodine, darifenacin, fesoterodine, solifenacin or trospium; or they are bladder muscle relaxants, such as mirabegron; or they are alpha blockers, such as tamsulosin, alfuzosin, silodosin, doxazosin or terazosin.

[0343] The doses of the above-mentioned combination partners are generally 1 / 5 of the normal recommended minimum dose to 1 / 1 of the normal recommended dose.

[0344] Thus, in another aspect, the present application relates to the use of a compound according to the present application in combination with one or more additional therapeutic agents as described hereinabove and hereinbelow for the treatment of a disease or condition which can be affected or mediated by TRPA1, in particular a disease or condition as described hereinabove and hereinbelow.

[0345] In another aspect, the present application relates to a method for the treatment of a disease or condition which can be affected by inhibition of TRPA1 in a patient, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0346] In another aspect, the present application 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 a disease or condition which can be affected by inhibition of TRPA1 in a patient in need thereof.

[0347] In yet another aspect, the present application relates to a method for the treatment of a disease or condition mediated 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 present application in combination with a therapeutically effective amount of one or more additional therapeutic agents as described hereinabove and hereinbelow.

[0348] The use of the compounds according to the application in combination with other therapeutic agents can be performed simultaneously or at staggered times.

[0349] Both the compound according to the application and the additional therapeutic agent(s) can be present together in one formulation (e.g. a tablet or capsule), or separately in two identical or different formulations (e.g. as a so-called kit-of-parts).

[0350] Thus, in another aspect, the present application relates to a pharmaceutical composition comprising a compound according to the application and one or more additional therapeutic agents as described in the context, optionally together with one or more inert carriers and / or diluents.

[0351] In yet another aspect, the present application relates to the use of a compound according to the application in a cough measurement device.

[0352] Other features and advantages of the present application will become apparent from the following more detailed description, which is to be considered in conjunction with the accompanying drawings.

[0353] Preparation

[0354] The compounds of the present application and intermediates thereto can be obtained using the synthetic procedures known to those skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in an analogous manner to the methods of preparation described more fully below, especially as described in the experimental section. In some cases, the order of carrying out the reaction steps can be varied. Variations of reaction procedures known to those skilled in the art but not described in detail herein can also be used.

[0355] General methods of preparing compounds according to the present application will become apparent to those skilled in the art from the following Schemes. Any functional group in a starting material or intermediate can be protected using conventional protecting groups. These protecting groups can be removed again at the appropriate stage within the reaction sequence using methods familiar to those skilled in the art.

[0356] The compounds according to the present application are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to be illustrative of the present application, but not limiting the subject matter and the scope of the compounds claimed by these examples. In cases where the preparation of a starting compound is not described, it is either commercially available or can be prepared in an analogous manner to a known compound or method described herein. The materials described in the literature are prepared according to the published synthesis methods. Abbreviations are defined in the example section.

[0357] Scheme 1:

[0358]

[0359] In Scheme 1, chloromethyltetrazole is N-alkylated with an appropriate ketone derivative bearing a leaving group "LG" (e.g. CI or Br) adjacent to the carbonyl group in the presence of a base (e.g. K2CO3) to give a mixture of two regioisomers. The undesired regioisomer (not shown) can be removed by chromatography using an appropriate gradient. The resulting ketone (A) can be reduced in a mirror image selective manner by using an appropriate catalytic system using 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 triethylamine formate complex to give the alcohol (B).

[0360] The uracil derivative (D) can be synthesized from a monosubstituted urea and 2- (ethoxymethylene)malonic acid 1,3-diethyl ester under neat conditions at elevated temperature to directly give (D), or (C) which can be further reacted under basic conditions such as NaOEt in EtOH solution at elevated temperature to give (D). The primary amide (E) can be synthesized from ester (D) by stirring with ammonia in a solvent such as water or alcohol at elevated temperature in a sealed vessel.

[0361] The final compound (I) can be synthesized by alkylating (E) with intermediate (B) in the presence of a base such as K2CO3. Alternatively, intermediate (D) is alkylated with (B) in the presence of a base to give (F) which can be hydrolyzed with a suitable reagent such as LiOH to give the acid (G). The acid (G) can then be coupled with an amine in the presence of an amide coupling reagent such as HATU and in the presence of a base such as DIPEA to give the final compound (I).

[0362] Alternatively, compounds of formula (I) can be prepared as shown in Scheme 2 below.

[0363] Scheme 2:

[0364]

[0365] In process 2, intermediate (H) can be prepared by alkylation of (E) with an acetonitrile derivative carrying a leaving group "LG" (e.g., Cl or Br) in the presence of a base such as DIPEA. Tetraazole (J) can be formed under typical reaction conditions for tetraazole formation (e.g., using NaN3 in the presence of a DMF solution of TEA / TEA hydrochloride). Alkylation of tetraazole (J) with a suitable acetone derivative carrying a leaving group "LG" (e.g., Cl or Br) adjacent to the carbonyl group, in the presence of a base such as DIPEA, yields a mixture of two regiomeric isomers. Undesired regiomeric isomers (not shown) can be removed by chromatography using an appropriate gradient. Finally, the final compound (I) can be obtained by using a suitable catalytic system to selectively reduce the ketone group of (K) in a mirror-image selective manner using a transition metal complex (e.g., Ru or Ir) with a chiral ligand (e.g., ([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide) and a hydrogen source (e.g., a triethylamine formate complex). Alternatively, the final compound (I) can be prepared by alkylating the intermediate (J) with a suitable aromatic or heteroaromatic ethanol derivative carrying a leaving group “LG” (e.g., Cl or Br) adjacent to a hydroxyl group in the presence of a base such as DIPEA, and subsequently isolating the desired regiomeric isomer.

[0366] Example

[0367] preparation

[0368] The compounds and intermediates according to the invention can be obtained using synthetic methods known to those skilled in the art and described in the literature on organic synthesis, 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 by a preparation method similar to that described more fully below, especially as described in the experimental section. In some cases, the order in which the reaction scheme is carried out may vary. Variations of these reactions known to those skilled in the art but not described in detail herein may also be used. Based on the study of the following procedures, the general method for preparing the compounds according to the invention will become apparent to those skilled in the art. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared in a similar or analogous manner. Prior to the reaction, any corresponding functional groups in the starting compounds may be protected with conventional protecting groups. These protecting groups can be re-cleaved at appropriate stages within the reaction sequence using methods familiar to those skilled in the art and described in, for example, "Protecting Groups," 3rd edition, Philip J. Kocienski, Thieme, 2005 and "Protective Groups in Organic Synthesis," 4th edition, Peter GMWuts, Theodora W. Greene, John Wiley & Sons, 2006. The terms "ambient temperature" and "room temperature" are used interchangeably and represent approximately 20°C, for example, a temperature between 19 and 24°C.

[0369] abbreviation:

[0370]

[0371]

[0372] Preparation of intermediates

[0373] Intermediate I

[0374] Intermediate I.1 (General Program)

[0375] 2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl]-1-(4-chlorophenyl)ethyl-1-one

[0376]

[0377] At RT, 1.63 g (11.8 mmol) of K₂CO₃ was added with stirring to 15 mL of DMA solution containing 1.00 g (8.44 mmol) of 5-(chloromethyl)-2H-1,2,3,4-tetraazole and 2.17 g (9.28 mmol) of 4-chlorobenzoylmethyl bromide. The reaction mixture was stirred at RT for 30 min and then filtered. The filtrate was diluted with water and saturated NaCl aqueous solution and extracted three times with EtOAc. The combined organic phases were washed with water, dried over Na₂SO₄, filtered through activated carbon, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; CH / EtOAc, 80 / 20 to 50 / 50 gradient) to give the product.

[0378] C 10 H8Cl2N4O (M=271.1g / mol)ESI-MS: 271[M+H] +

[0379] R t (HPLC): 1.01 min (Method B)

[0380] The following compounds were prepared using a procedure similar to that described in Intermediate I.1, with appropriate starting materials.

[0381] As those skilled in the art will understand, these similar embodiments may involve variations of general reaction conditions.

[0382]

[0383]

[0384]

[0385] * p-Methoxybenzoylmethyl bromide (1.05 eq.) was slowly added to a stirred solution of chloromethyltetrazole and K2CO3 (1.4 eq) in DMA at 18 °C; the mixture was stirred at RT for 1.5 h; and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA).

[0386] Intermediate II

[0387] Intermediate II.1 (General Program)

[0388] (1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetrazol-2-yl-]-1-(4-chlorophenyl)ethyl-1-ol

[0389]

[0390] 1.30 g (4.80 mmol) of 1-(4-chlorophenyl)-2-[5-(chloromethyl)-2H-1,2,3,4-tetraazol-2-yl]ethyl-1-one (intermediate I.1) was dissolved in 20 mL of ACN under an inert atmosphere. 12 mg (0.02 mmol) of ruthenium(II) chloride ([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)( )ruthenium(II) (CAS174813-81-1) was added, followed by dropwise addition of 0.72 mL (1.73 mmol) of triethylamine formate complex (5:2). After stirring at RT for 3 h, the solvent was removed under reduced pressure. Water was added to the remaining crude mixture, and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, treated with activated carbon, filtered again, and the solvent was removed under reduced pressure to give intermediate II.1.

[0391] C 10 H 10 Cl2N4O (M=273.1g / mol)

[0392] ESI-MS: 273 [M+H] +

[0393] R t (HPLC): 0.96 min (Method B)

[0394] The following compounds were prepared using a procedure similar to that described in Intermediate II.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar examples may involve variations of general reaction conditions.

[0395]

[0396]

[0397]

[0398] Intermediate III

[0399] 3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0400]

[0401] 10.0 g (50.46 mmol) of ethyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (CAS: 154942-22-0, intermediate XII.6) in a 33% ammonia solution (120 mL) was stirred in a sealed container at 100 °C for 10 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was wet-milled with ACN, filtered, and dried at 50 °C to give intermediate III.

[0402] C6H7N3O3 (M=169.1g / mol)ESI-MS: 170[M+H] +

[0403] R t (HPLC): 0.48 min (Method B)

[0404] Intermediate IV

[0405] Intermediate IV.1 (General Program)

[0406] 1-(5,6-Difluoro-1-benzofuran-2-yl)ethyl-1-one

[0407]

[0408] A 50 mL acetone solution of 5.00 g (31.6 mmol) of 4,5-difluoro-2-hydroxybenzaldehyde was treated with 6.99 g (50.6 mmol) of potassium carbonate under argon atmosphere at 0 °C. After stirring at 0 °C for another 10 min, 3.78 mL (47.4 mmol) of chloroacetone was added dropwise, and the reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was cooled to RT and concentrated. The crude product was extracted with EtOAc / water, and the organic phase was concentrated under reduced pressure to give intermediate IV.1.

[0409] C 10 H6F2O2 (M = 196.2 g / mol) 1 H NMR(300MHz,DMSO-d6)δppm:2.56(s,3H),7.89(m,1H),7.92(m,1H),8.01(m,1H)

[0410] The following compounds were prepared using a procedure similar to that described in Intermediate IV.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar examples may involve variations of general reaction conditions.

[0411]

[0412]

[0413] intermediate V

[0414] 5-Bromo-1-benzofuran-2-carboxylic acid

[0415]

[0416] At 0 °C, 1.23 g (29.3 mmol) LiOH*H₂O was added to a solution of 6.58 g (24.4 mmol) ethyl 5-bromo-1-benzofuran-2-carboxylate (IV.4) in 3 mL EtOH, 66 mL THF, and 33 mL water. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was acidified to pH 5 with 1 M HCl, and the resulting precipitate was filtered off and dried to give intermediate V.

[0417] C9H5BrO3 (M = 241.0 g / mol) 1 H NMR (300MHz, DMSO-d6) δppm: 7.59-7.76 (m, 3H), 8.02 (d, J = 2.0Hz, 1H), 13.5-14.2 (br s, 1H).

[0418] Intermediate VI

[0419] 5-Bromo-2-fluoro-1-benzofuran

[0420]

[0421] A solution of 5.00 g (20.7 mmol) 5-bromo-1-benzofuran-2-carboxylic acid (V), 14.70 g (41.5 mmol) Selectflour, and 4.82 g (83.0 mmol) potassium fluoride in 185 mL DCE and 95 mL water was stirred in a sealed tube at 70 °C for 20 h. The reaction mixture was then extracted with DCM / water. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, DCM).

[0422] C8H4BrFO (M = 215.0 g / mol) 1 H NMR (300MHz, DMSO-d6) δppm: 6.36 (dd, J=6.4, 0.9Hz, 1H), 7.47 (dd, J=8.7, 2.1Hz, 1H), 7.58 (d, J=8.7Hz, 1H), 7.82 (d, J=2.1Hz, 1H)

[0423] Intermediate VII

[0424] 1-(2-fluoro-1-benzofuran-5-yl)ethyl-1-one

[0425]

[0426] At RT, 168 mg (1.2 mmol) of potassium carbonate was added with stirring to a solution of 218 mg (1.0 mmol) of 5-bromo-2-fluoro-1-benzofuran (VI) in 3 mL of DMF and 0.3 mL of water. The mixture was purged with argon, followed by the addition of 25 mg (0.1 mmol) of 1,3-bis(diphenylphosphine)propane (dppp), 7 mg of palladium(II) acetate, and 183 mg (2.5 mmol) of ethyl vinyl ether. The reaction mixture was stirred overnight at 80 °C, then cooled to RT and treated with 1 M HCl (20 mL) aqueous solution. After stirring at RT for 30 min, the mixture was extracted with EtOAc, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc / hexane, gradient).

[0427] C 10 H7FO2 (M = 178.2 g / mol) 1 H NMR (300MHz, DMSO-d6) δppm: 2.63 (s, 3H), 6.49 (dd, J=6.4, 0.8Hz, 1H), 7.70 (dt, J=8.7, 0.8Hz, 1H), 7.93 (dd, J=8.7, 1.9Hz, 1H), 8.25 (dd, J=1.9, 0.6Hz, 1H)

[0428] Intermediate VIII

[0429] Intermediate VIII.1 (general procedure)

[0430] 2-Bromo-1-(2-fluoro-1-benzofuran-5-yl)ethyl-1-one

[0431]

[0432] A 1.5 mL THF solution of 126 mg (0.71 mmol) of 1-(2-fluoro-1-benzofuran-5-yl)ethyl-1-one (VII) was treated dropwise with a solution of 0.34 g (0.71 mmol) tetrabutylammonium tribromide in 0.08 mL MeOH and 0.8 mL THF. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc / water. The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel; hexane / EtOAc, gradient).

[0433] C 10 H6BrFO2 (M = 257.1 g / mol) 1H NMR (300MHz, DMSO-d6) δppm: 4.99 (s, 2H), 6.53 (dd, J=6.4, 0.9Hz, 1H), 7.75 (d, J=8.7, 1H), 7.88-8.03 (m, 1H), 8.31 (dd, J=1.9, 0.6Hz, 1H)

[0434] The following compounds were prepared using a procedure similar to that described in Intermediate VIII.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar examples may involve variations of general reaction conditions.

[0435]

[0436] *: The reaction was carried out at RT with bromine (13.6 eq) in dioxane / diethyl ether for 2 h and quenched with sodium thiosulfate solution.

[0437] Intermediate IX

[0438] 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-carboxylic acid ethyl ester

[0439]

[0440] 303 mg (1.11 mmol) of (1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetraazol-2-yl]-1-(4-chlorophenyl)ethyl-1-ol (intermediate II.1) and 418 mg (3.03 mmol) of K2CO3 were added to 8 mL of 200 mg (1.01 mmol) of ethyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (CAS: 154942-22-0, intermediate XII.6) in DMF solution. The mixture was stirred at 50 °C for 5 h, followed by stirring at RT for 17 h. The crude product was purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA) to obtain the desired product.

[0441] C 18 H 19 ClN6O5 (M=434.8g / mol)ESI-MS: 435[M+H] +

[0442] R t (HPLC): 0.48 min (Method A)

[0443] Intermediate X

[0444] 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-carboxylic acid

[0445]

[0446] 44 mg (1.8 mmol) of lithium hydroxide was added to a solution of 200 mg (0.46 mmol) of intermediate IX in 1 mL of methanol, 1 mL of THF, and 100 μL of water. The reaction mixture was stirred at 50 °C for 1 h, then cooled to RT and diluted with water. The aqueous layer was washed three times with DCM, acidified with formic acid, and the resulting precipitate was filtered off and dried at 50 °C to give the desired product.

[0447] C 16 H 15 ClN6O5 (M=406.8g / mol)

[0448] ESI-MS: 407 [M+H] +

[0449] R t (HPLC): 0.46 min (Method A)

[0450] Intermediate XI

[0451] Intermediate XI.1 (general procedure)

[0452] 1,3-Diethyl 2-{[(cyclobutylaminoformyl)amino]methylene}malonate

[0453]

[0454] 1.00 g (8.76 mmol) of cyclobutylurea and 3.79 g (17.52 mmol) of 1,3-diethyl 2-(ethoxymethylene)malonate were heated at 100 °C for 2.5 h under pure conditions, followed by heating at 130 °C for 5 h. The reaction mixture was cooled to RT, diluted with methanol, and purified by reversed-phase HPLC (ACN / H₂O gradient, 0.1% TFA) to give intermediate XI.1.

[0455] C 13 H 20 N2O5 (M=284.3g / mol)ESI-MS: 285[M+H] +

[0456] R t (HPLC): 0.53 min (Method A)

[0457] The following compounds were prepared using a procedure similar to that described in Intermediate XI.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar embodiments may involve variations of general reaction conditions.

[0458]

[0459]

[0460] Intermediate XII

[0461] Intermediate XII.1 (general procedure)

[0462] ethyl 1-cyclobutyl-2-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxylate

[0463]

[0464] 957 mg (14.1 mmol) sodium ethoxide was added to 30 mL of ethanol solution of 2.00 g (7.03 mmol) intermediate XI.1 and the mixture was stirred at 80 °C for 3 h. The mixture was then diluted with ethanol and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA).

[0465] C 11 H 14 N2O4 (M=238.2g / mol)ESI-MS: 239[M+H] +

[0466] R t (HPLC): 0.37 min (Method A)

[0467] The following compounds were prepared using a procedure similar to that described in Intermediate XII.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar examples may involve variations of general reaction conditions.

[0468]

[0469]

[0470] Intermediate XII.6

[0471] ethyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

[0472]

[0473] 500 mg (6.75 mmol) of methylurea and 1.36 g (6.75 mmol) of 1,3-diethyl 2-(methoxymethylene)malonate were stirred at 120 °C for 2 h under pure conditions, then stirred at RT for 17 h, at 100 °C for 66 h, at 150 °C for 17 h, and then at 120 °C for 17 h. The mixture was then diluted with EtOAc and refluxed. The mixture was slowly cooled to RT and the precipitate intermediate was filtered off.

[0474] C8H 10 N2O4 (M=198.2g / mol)ESI-MS: 199[M+H] +

[0475] R t (HPLC): 0.24 min (Method A)

[0476] Intermediate XIII

[0477] Intermediate XIII.1 (general procedure)

[0478] 1-Cyclobutyl-2-hydroxy-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid ammonium

[0479]

[0480] 630 mg (0.03 mmol) of intermediate XII.1 in 10 mL of ammonia solution (33%) was stirred in a sealed container at 85 °C for 17 h. Stirring continued at 100 °C with the addition of ammonia solution until the starting material was completely consumed. The reaction mixture was then concentrated under reduced pressure to give intermediate XIII.1.

[0481] C9H 11 N3O3 (M=209.2g / mol)ESI-MS: 210[M+H] +

[0482] R t (HPLC): 0.31 min (Method A)

[0483] The following compounds were prepared using a procedure similar to that described in Intermediate XIII.1, with appropriate starting materials. As those skilled in the art will appreciate, these similar examples may involve variations of general reaction conditions.

[0484]

[0485] *Treatment: Acidified with aqueous HCl (1M), extracted with DCM, concentrated the organic layer under reduced pressure, and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA).

[0486] Purified by reversed-phase HPLC

[0487] Intermediate XIV.1

[0488] (cyclopropylmethyl)urea

[0489]

[0490] 599 mg (7.39 mmol) of potassium cyanate was added to 2 mL of an aqueous solution of 530 mg (4.93 mmol) of 1-cyclopropylmethylamine hydrochloride, and the mixture was stirred at 100 °C for 3 h. The reaction mixture was allowed to stand at RT for 14 h, and then intermediate XIV.1 was filtered off.

[0491] C5H 10 N2O (M=114.2g / mol)ESI-MS: 115[M+H] +

[0492] R t (HPLC): 0.15 min (Method A)

[0493] Intermediate XIV.2

[0494] (2-Methoxyethyl)urea

[0495]

[0496] 3.24 g (39.94 mmol) of potassium cyanate was added in small amounts to 8 ml of an aqueous solution of 2.0 g (26.63 mmol) of 2-methoxyethylamine, and the mixture was stirred at 100 °C for 3 h. After cooling to RT, the mixture was diluted with water / methanol and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA).

[0497] C4H 10 N2O2 (M=114.2g / mol)ESI-MS: 119[M+H] +

[0498] R t (HPLC): 0.11 min (Method A)

[0499] Preparation of final compounds

[0500] Example 1 (general procedure)

[0501] 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

[0502]

[0503] 178 mg (0.65 mmol) of (1R)-2-[5-(chloromethyl)-2H-1,2,3,4-tetraazol-2-yl]-1-(4-chlorophenyl)ethyl-1-ol (intermediate II.1) and 245 mg (1.77 mmol) of K₂CO₃ were added to 5 mL of a solution of 100 mg (0.59 mmol) of 3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (intermediate III) in DMF, and the mixture was stirred overnight at RT. The mixture was purified by reversed-phase HPLC (ACN / H₂O gradient, 0.1% TFA) to obtain the desired product.

[0504] C 16 H 16 ClN7O4 (M=405.8g / mol)ESI-MS: 406[M+H] +

[0505] R t (HPLC): 1.05 min (Method B)

[0506] 1 H NMR (400MHz, DMSO-d6) δppm: 3.21 (s, 3H), 4.73-4.84 (m, 2H), 5.13 (m, 1H), 5.45 (s, 2H), 5.92 (d, J = 2.4Hz, 1H), 7.35-7.42 (m, 4H), 7.64 (br d,J=3.4Hz,1H),8.20(br d,J=3.4Hz,1H),8.77(s,1H)

[0507] The following compounds were prepared using a procedure similar to that described in Example 1, with appropriate starting materials.

[0508] As those skilled in the art will understand, these similar embodiments may involve variations of general reaction conditions.

[0509]

[0510]

[0511]

[0512]

[0513] The analytical data for the compounds are described in the table above:

[0514]

[0515]

[0516]

[0517]

[0518] Example 22 (general procedure)

[0519] 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

[0520]

[0521] Under stirring at RT, 25 μl (0.15 mmol) of DIPEA and 22 mg (0.06 mmol) of HATU were added to 1.0 mL of DMF solution containing 20 mg (0.05 mmol) of intermediate X. After 30 minutes, 8 μl (0.10 mmol) of 2-methoxyethyl-1-amine was added and the mixture was stirred at RT for 90 min. The product was then purified by reversed-phase HPLC (ACN / H₂O gradient, 0.1% TFA) to obtain the desired product.

[0522] C 19 H 22 ClN7O5 (M=463.9g / mol)ESI-MS: 464[M+H] +

[0523] R t (HPLC): 0.48 min (Method A)

[0524] 1 H NMR(400MHz,DMSO-d6)δppm 3.22(s,3H),3.28(s,3H),3.41-3.51(m,4H),4.73-4.84(m,2H),5.13(m,1H),5.45(s,2H),5.5-6.4(br s,1H),7.38(m,4H),8.77(s,1H),8.94(m,1H).

[0525] The following compounds were prepared using a procedure similar to that described in Example 22, with appropriate starting materials.

[0526] As those skilled in the art will understand, these similar embodiments may involve variations of general reaction conditions.

[0527]

[0528]

[0529]

[0530]

[0531] The analytical data for the compounds are described in the table above:

[0532]

[0533]

[0534]

[0535] Analytical HPLC methods

[0536] Method A

[0537]

[0538] Analytical column: XBridge BEH (Waters) C18 2.1 × 30 mm 1.7 μm; Column temperature: 60℃

[0539] Method B

[0540]

[0541] Analytical column: Stable Bond (Agilent) C18 3.0×30mm 1.8μm; Column temperature: 60℃

[0542] Method C

[0543]

[0544] Analytical column: XBridge (Waters) C18 3.0 × 30 mm 2.5 μm; Column temperature: 60℃

[0545] Method D

[0546]

[0547] Analytical column: XBridge C18 3.0×30mm 2.5μm (Waters); Column temperature: 60℃

[0548] Method E

[0549]

[0550] Analytical column: Sunfire (Waters); C18 3.0 × 30 mm 2.5 μm; column temperature: 60℃

[0551] Method F

[0552]

[0553] Analytical column: XBridge BEH (Waters) C18 2.1 × 30 mm 2.5 μm; Column temperature: 60℃

[0554] Method G

[0555]

[0556] Analytical column: Zorbax StableBond C18 (Agilent) 1.8 μm; 2.1 × 30 mm; column temperature: 60℃

[0557] Method H

[0558] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 × 30 mm; column temperature: 60℃ Method I

[0559] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 × 30 mm; column temperature: 60℃; Method J

[0560] Analytical column: Acquity UPLC BEH; C8 2.1 × 150 mm 1.7 μm; column temperature: 55℃

[0561] This disclosure relates to the following implementation plans.

[0562] 1. A compound according to formula (I)

[0563]

[0564] in

[0565] Option A is selected from the group consisting of phenyl, thienyl, benzothienyl, or benzofuranyl groups, which are unsubstituted or derived via halogens, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 Cyclofluoroalkyl, OC 1-4 Group R consists of alkyl, O-cyclopropyl and NC- 3 One, two, or three members are replaced;

[0566] or

[0567] A. Choose from the following groups:

[0568]

[0569] R 1 Choose C freely 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, R 4 -(H2C) m -and R 5 -(H2C) n -A group;

[0570] in

[0571] m is 1 or 2;

[0572] n is 2;

[0573] R 4 C 3-6 cycloalkyl;

[0574] R 5 -OC 1-4 Alkyl or -OC 1-4 fluoroalkyl;

[0575] R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cyclofluoroalkyl, HO-C 1-4 Alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p -、R 7 -(H2C) q -、R 6 -(H(R 8 C) p -and R 7 -(H(R 9 C) q -A group;

[0576] in

[0577] p is 1 or 2;

[0578] q is 2;

[0579] R 6 Choose HO-C 1-2 Alkyl-, C 3-6 The group consisting of cycloalkyl, C-morpholino, C-imidazolyl and C-pyrazolyl groups;

[0580] Wherein the C-pyrazolyl, C-imidazoyl, and C-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl or C 1-4 Fluoroalkyl substitution;

[0581] R 7 Choose C freely 1-4 Alkyl-O-, C 1-4 Fluoroalkyl-O-, C 1-4 The group consisting of alkyl-S(O)2-, N-morpholino, N-imidazolyl and N-pyrazolyl;

[0582] The N-pyrazolyl, N-imidazolyl, and N-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl or C 1-4 Fluoroalkyl substitution;

[0583] R 8 and R 9 To be independently selected from H or C 1-4 alkyl.

[0584] 2. According to formula (I) of item 1, wherein A is selected from the group consisting of phenyl, thiophene, benzothiophene, or benzofuran, and is unsubstituted or via one or two groups consisting of Cl, F, Br, H3C, H3C-O-, and NC-. 3 Members replaced;

[0585] or

[0586] A is

[0587]

[0588] 3. According to formula (I) of item 1, where A is selected from the group consisting of:

[0589]

[0590] Its unsubstituted or via one or two groups consisting of Cl, F, Br, H3C, H3C-O- and NC- 3 The members were replaced.

[0591] or

[0592] A is

[0593]

[0594] 4. A compound of formula (I) according to any one of items 1 to 3, wherein R 1 Choose C freely 1-4 Alkyl, C 3-6 cycloalkyl, R 4 -(H2C) m-and R 5 -(H2C) n -A group;

[0595] in

[0596] m is 1;

[0597] n is 2;

[0598] R 4 C 3-6 cycloalkyl; and

[0599] R 5 -OC 1-4 alkyl.

[0600] 5. A compound of formula (I) according to any one of items 1 to 3, wherein R 1 Choose C freely 1-4 Alkyl, C 3-4 cycloalkyl, R 4 -(H2C) m -and R 5 -(H2C) n -A group;

[0601] in

[0602] m is 1;

[0603] n is 2;

[0604] R 4 C 3-4 cycloalkyl; and

[0605] R 5 -OC 1-4 alkyl.

[0606] 6. A compound of formula (I) according to any one of items 1 to 5, wherein R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, HO-C 1-4 Alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p -and R 7 -(H2C) q -A group;

[0607] in

[0608] p is 1;

[0609] q is 2;

[0610] R 6 Choose C freely 3-6The group consisting of cycloalkyl, C-morpholino, C-imidazolyl and C-pyrazolyl groups;

[0611] Wherein the C-pyrazolyl, C-imidazoyl, and C-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl substitution;

[0612] R 7 Choose Freedom - OC 1-4 Alkyl, -OC 1-4 fluoroalkyl, C 1-4 The group consisting of alkyl-S(O)2-, N-morpholino, N-imidazolyl and N-pyrazolyl;

[0613] The N-pyrazolyl, N-imidazolyl, and N-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl substitution.

[0614] 7. A compound of formula (I) according to any one of items 1 to 5, wherein R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, HO-C 1-4 Alkyl-, C 1-2 fluoroalkyl, R 6 -(H2C) p -and R 7 -(H2C) q -A group;

[0615] in

[0616] p is 1;

[0617] q is 2;

[0618] R 6 Choose C freely 3-6 The group consisting of cycloalkyl, C-morpholino, C-imidazolyl and C-pyrazolyl groups;

[0619] The C-pyrazolyl, C-imidazoyl, and C-morpholinyl groups are either unsubstituted or substituted with H3C.

[0620] R 7 The group consisting of H3C-O, -O-fluoromethyl, H3C-S(O)2-, N-morpholino, N-imidazolyl and N-pyrazolyl is selected.

[0621] The N-pyrazolyl, N-imidazolyl, and N-morpholinoyl groups are either unsubstituted or substituted with H3C.

[0622] 8. A compound of formula (I) according to any one of items 1 to 5, wherein R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, HO-C1-4 Alkyl-, C 1-2 fluoroalkyl, R 6 -(H2C) p -and R 7 -(H2C) q -A group;

[0623] in

[0624] p is 1;

[0625] q is 2;

[0626] R 6 Choose from the following groups: C 3-6 cycloalkyl,

[0627]

[0628] R 7 Choose from the following groups: H3C-O, -O-fluoromethyl, H3C-S(O)2-,

[0629]

[0630] 9. Compounds of formula (I) according to any one of items 1 to 3, selected from the group consisting of:

[0631]

[0632]

[0633]

[0634]

[0635]

[0636] 10. According to formula (I) of item 1, the compound is selected from the group consisting of:

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] 11. A salt of a compound according to any one of items 1 to 10, particularly a pharmaceutically acceptable salt.

[0649] 12. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0650] 13. A compound of formula (I) according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, used as a medicine.

[0651] 14. Use of a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof for the treatment or prevention of inflammatory tracheal diseases or fibrotic diseases or cough.

[0652] 15. The use of a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof for the treatment or prevention of idiopathic lung disease (IPF) or cough.

Claims

1. A compound according to formula (I) in Option A is selected from the group consisting of phenyl, thienyl, benzothienyl, or benzofuranyl groups, which are unsubstituted or derived via halogens, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 Cyclofluoroalkyl, OC 1-4 Group R consists of alkyl, O-cyclopropyl and NC- 3 One, two, or three members are replaced; or A. Choose from the following groups: R 1 Choose C freely 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, R 4 -(H2C) m -and R 5 -(H2C) n -A group; in m is 1 or 2; n is 2; R 4 C 3-6 cycloalkyl; R 5 -OC 1-4 Alkyl or -OC 1-4 fluoroalkyl; R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cyclofluoroalkyl, HO-C 1-4 Alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p -、R 7 -(H2C) q -、R 6 -(H(R 8 C) p -and R 7 -(H(R 9 C) q -A group; in which p is 1 or 2; q is 2; R 6 Choose HO-C 1-2 Alkyl-, C 3-6 The group consisting of cycloalkyl, C-morpholino, C-imidazolyl and C-pyrazolyl groups; Wherein the C-pyrazolyl, C-imidazoyl, and C-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl or C 1-4 Fluoroalkyl substitution; R 7 Choose C freely 1-4 Alkyl-O-, C 1-4 Fluoroalkyl-O-, C 1-4 The group consisting of alkyl-S(O)2-, N-morpholino, N-imidazolyl and N-pyrazolyl; The N-pyrazolyl, N-imidazolyl, and N-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl or C 1-4 Fluoroalkyl substitution; R 8 and R 9 To be independently selected from H or C 1-4 alkyl.

2. The compound of formula (I) according to claim 1, wherein A is selected from the group consisting of phenyl, thienyl, benzothienyl or benzofuranyl, and is unsubstituted or derived from one or two groups consisting of Cl, F, Br, H3C, H3C-O- and NC-. 3 Members replaced; or A is 3. The compound of formula (I) according to claim 1, wherein A is selected from the group consisting of: Its unsubstituted or via one or two groups consisting of Cl, F, Br, H3C, H3C-O- and NC- 3 Members replaced, or A is 4. The compound of formula (I) according to any one of claims 1 to 3, wherein R 1 Choose C freely 1-4 Alkyl, C 3-6 cycloalkyl, R 4 -(H2C) m -and R 5 -(H2C) n -A group; in m is 1; n is 2; R 4 C 3-6 cycloalkyl; and R 5 -OC 1-4 alkyl.

5. The compound of formula (I) according to any one of claims 1 to 3, wherein R 1 Choose C freely 1-4 Alkyl, C 3-4 cycloalkyl, R 4 -(H2C) m -and R 5 -(H2C) n -A group; in m is 1; n is 2; R 4 C 3-4 cycloalkyl; and R 5 -OC 1-4 alkyl.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, HO-C 1-4 Alkyl-, C 1-4 fluoroalkyl, R 6 -(H2C) p -and R 7 -(H2C) q -A group; in which p is 1; q is 2; R 6 Choose C freely 3-6 The group consisting of cycloalkyl, C-morpholino, C-imidazolyl and C-pyrazolyl groups; Wherein the C-pyrazolyl, C-imidazoyl, and C-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl substitution; R 7 Choose Freedom - OC 1-4 Alkyl, -OC 1-4 fluoroalkyl, C 1-4 The group consisting of alkyl-S(O)2-, N-morpholino, N-imidazolyl and N-pyrazolyl; The N-pyrazolyl, N-imidazolyl, and N-morpholinyl groups are unsubstituted or C-transformed. 1-4 Alkyl substitution.

7. The compound of formula (I) according to any one of claims 1 to 5, wherein R 2 Choose freely from H and C 1-4 Alkyl, C 3-6 cycloalkyl, HO-C 1-4 Alkyl-, C 1-2 fluoroalkyl, R 6 -(H2C) p -and R 7 -(H2C) q -A group; in which p is 1; q is 2; R 6 Choose from the following groups: C 3-6 cycloalkyl, R 7 Choose from the following groups: H3C-O, -O-fluoromethyl, H3C-S(O)2-, 8. A salt of a compound according to any one of claims 1 to 7, particularly a pharmaceutically acceptable salt.

9. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the treatment or prevention of idiopathic lung disease (IPF) or cough.

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