HETEROARYL ETHER DERIVATIVES AS SODIUM CHANNEL INHIBITORS

Abstract

The present invention generally relates to compounds of formula (I) inhibiting sodium channel (NaV) activity; particularly, the invention relates to compounds that are heteroaryl ester derivatives, including zwitterionic forms and pharmaceutically acceptable salts thereof, methods of preparing such compounds, and therapeutic use thereof. The compounds of the invention may be useful for instance in the treatment of many disorders associated with NaV, such as respiratory diseases.

Description

[0001] HETEROARYL ESTER DERIVATIVES AS SODIUM CHANNEL INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] The present invention generally relates to compounds inhibiting voltage-gated sodium channels (NaV) activity (hereinafter NaV inhibitors); the invention relates to compounds that are heteroaryl ester derivatives, including pharmaceutically acceptable salts thereof, methods of preparing such compounds, and therapeutic use thereof.

[0004] The compounds of the invention may be useful for instance in the treatment of many disorders associated with sodium channel receptors mechanisms, such as respiratory diseases.

[0005] BACKGROUND OF THE INVENTION

[0006] Sensory afferents carry impulses originated by diverse stimuli (thermal, cold, heat, mechanical and chemical) and also mediate the cough reflex.

[0007] Coughing is a defensive reflex designed to protect the airways from foreign bodies and to aid in the removal of luminal debris. Chronic cough is defined as a cough lasting longer than 8 weeks. Hyper- and allo-tussive states are often chronic in nature lasting longer than three months and can be manifested in many airway diseases states including asthma, chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome (ACOS), cough variant asthma, gastroesophageal reflux disease (GERD), idiopathic pulmonary fibrosis (IPF) and lung cancer. In addition, inappropriate cough reflexes can be manifested acutely and chronically following viral infection. Finally, chronic cough can be idiopathic in nature with unknown etiology (Dicpinigaitis, P.V. et al, Pharmacol Rev, 2014, 66, 468- 512; Patil, M.J et al, Pulmonary Pharmacology& Therapeutics, 2019, 56, 15- 19).

[0008] As many therapeutic strategies for cough inhibition have been unsuccessful in clinical practice, increased attention in recent years has been focused on potential inhibitors of voltagegated sodium channels (NaV) which are absolutely required for the conduction of action potentials originated in nerve terminals as a response to a variety of stimuli including many inflammatory mediators. There are currently at least nine known members of the family of voltage-gated sodium channel (NaV) alpha subunits. The NaV family has been phylogenetically divided into two subfamilies NaV 1.x (all but SCN6A) and NaV 2.x (SCN6A). The NaV 1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or TTX-r). Cough is a complex process triggered and regulated by two independent nerve pathways that can interfere with each other: mechanosensitive vagal nodose AS fibres and chemosensitive vagal jugular C-fibres. From the variety of known NaV 1.x subunits, only a few are expressed in airway vagal jugular C-fibres, involving TTX-sensitive NaV 1.7 and TTX- resistant NaV 1.8 and NaV 1.9 (Kollarik, M., et al, JPhysiol, 2018, 596, 1419- 1432). The NaV 1.7 (PN 1 , SCN9A) is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons.

[0009] Cough reflex can be negated by effective sodium channel blockers, wherein Lidocaine is an example. Lidocaine blocks all the sensory inputs (such as in local anesthesia) and mechanoreceptors and motor neurons, leading to numbness and paralysis. A spray of lidocaine is routinely used before bronchoscopies to suppress the cough reflex. Inhalation of lidocaine has been firstly reported to relieve intractable cough in 1977 (C Fletcher et al, BrMedJ, 1977 1(6077), 1645- 8), and then confirmed in a recent clinical trial, formulated as throat spray, on refractory chronic cough (RCC) patients (Abdulqawi, R. et al., The Journal of Allergy and Clinical Immunology: In Practice, 2021, 9, 4, 1640-1647). However, Lidocaine is short-acting, non- selective, weakly potent, with off-target effects (burns when injected) and its use (as antitussive) is limited due to a poor risk / benefit profile (block of cardiac NaV 1.5 channels).

[0010] Sensory neurons express several channels (TRPV1, TRPA1, ASICS, P2X3 etc.) with large pores that, when activated, enable permeation of charged molecules that normally cannot permeate the neuron membrane, differently from the neutral molecules like Lidocaine, that can access to the NaV binding site in the channel pore, penetrating into the lipid membrane surrounding the channel (Frazier et al, JPET, 2015; 171, 1.; Brenneis et al, J Neuroscience, 2013, 33(1):315-26).

[0011] In 1999 Nortran Pharmaceutical filed a patent application (WO99 / 63985) relating to pharmaceutical compositions having anti-tussive activity and a method of treating warm-blooded animals affected by coughs or bronchoconstriction by administering an effective amount of the pharmaceutical compositions of the invention. The exemplified active anti-tussive agent reported therein was a charged quaternary ammonium compound, namely N,N- bis(phenylcarbamoylmethyl)dimethylammonium chloride (aka Carcainium chloride).

[0012] Carcainium chloride had been disclosed for the first time in 1962 by Astra for use in the treatment of arrhythmia (US 3255207). The anti-tussive effects of Carcainium chloride have been investigated in various animal models: in guinea pig model Carcainium chloride was shown to possess higher anti-tussive potency and somewhat a different mechanism of action than Lidocaine (J. J. Adcock, British Journal of Pharmacology, 2003, 138, 407- 416). In 2013 Verona Pharma filed a patent application (WO2013 / 03490) related to Carcainium in the form of a salt having an anion of a pharmaceutically acceptable acid, for use in the treatment and / or suppression of cough, tussive attacks or tussive episodes in patients. The compound was found efficacious in a pilot study conducted in patients with chronic cough and idiopathic interstitial pneumonias (Lavorini et al, Pulmonary Pharmacology & Therapeutics, 2016, 40, 91-94) but never progressed to the market because it failed to reduce frequency and severity of cough in a larger subsequent study (Satia et al, Thorax, 2015;70 (Suppl 3): A1-A254).

[0013] Currently available antitussive drugs have often limited efficacy. The quality of life of patients with cough can be severely affected, with physical (including fatigue, breathlessness, disturbed sleep and incontinence), psychological (including anger, frustration, depression and anxiety) and social consequences. Therefore, a continuous effort in the search for new promising therapies and targets in cough treatment is essential, and chronic cough remains an unmet medical need.

[0014] The state of the art does not describe or suggest the ester derivative compounds of general formula (I) of the present invention which may represent a solution to the afore mentioned unmet medical need.

[0015] SUMMARY OF THE INVENTION

[0016] In a first aspect the invention refers to a compound of formula (I) in zwitterionic or pharmaceutically acceptable salt form, wherein at least one of Y and Z is S, and the other one is CR4;

[0017] Ri and Rz are independently selected from the group consisting of -(Ci-Ce)alkyl and -(Ci- Ce)alkyl-OR6, or are fused together forming a -(C3-Cio)heterocycloalkyl, wherein said -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -C(O)OR6, -(Ci-Ce)alkyl and -(Ci-C6)haloalkyl;

[0018] Rj and R4 are independently H or selected from the group consisting of CN, -(Ci-Ce)alkyl and aryl, or, wherein Y is CR4, R3 and R4 are fused together forming an aryl;

[0019] Rs is selected from the group consisting of -(Ci-Ce)alkyl, -(Ci-Ce)alkyl-NR6R7, -(Ci- Ce)alkyl-OR6, -(Ci-Ce)alkyl-C(O)NR6R7, -(C3-Cio)heterocycloalkyl and -(C3-C7)cycloalkyl;

[0020] Re and R7 are independently H or selected from the group consisting of -(Ci-Ce)alkyl and - (Ci-Ce)alkyl-aryl;

[0021] Li is a bond or selected from the group consisting of -(Ci-Ce)alkylene-,-(Ci- C6)heterocycloalkylene- and -(Ci-C6)cycloalkylene-; and A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-Cio)cycloalkyl and - (C3-Cio)heterocycloalkyl, wherein any of such aryl, heteroaryl, -(C3-Cio)cycloalkyl or -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, - C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-C6)haloalkyl, -(Ci-C6)alkyl-OR6and -(Ci-Ce)alkyl- NReR?; provided that when Li is a bond any of such aryl is not substituted by -(Ci-Ce)alkyl.

[0022] In a second aspect, the invention refers to a pharmaceutical composition comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient.

[0023] In a third aspect, the invention refers to a compound of formula (I) for use as a medicament.

[0024] In a further aspect, the invention refers to a compound of formula (I) for use in treating diseases, disorders or conditions associated with dysregulation of voltage-gated sodium channels (NaV).

[0025] In a further aspect, the invention refers to a compound of formula (I) for use in the prevention and / or treatment of respiratory diseases selected from: cough, sub-acute or chronic cough, treatment-resistant cough, refractory chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] Unless otherwise provided, the term “compound of formula (I)” comprises in its meaning stereoisomers, tautomers, pharmaceutically acceptable salts, zwitterionic forms or solvates thereof.

[0028] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0029] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0030] The term "diastereomer " refers to stereoisomers that are not mirror images.

[0031] The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.

[0032] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s) and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0033] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of an atom or group within the molecule. The compound of formula (I) is a quaternary ammonium compound. The term “pharmaceutically acceptable salt”, as used herein, refers to a compound of formula (I), wherein such compound is provided as an addition salt with any acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of the quaternary ammonium moiety, such as salts of hydrochloric acid, hydrobromic acid, iodic acid, formic acid, benzoic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, 2-naphthoic acid, tartaric acid, 1- hydroxy-2-naphthoic acid, naphthalene-2,7-disulfonic acid and citric acid.

[0034] Alternatively, the compound of formula (I) according to the invention may be provided as a “zwitterionic form”, also referred to as inner salt or dipolar ion, which is a form wherein both a positive electrical charge and a negative electrical charge are present.

[0035] The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate might be isolated by crystallization, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.

[0036] The term “halogen” or “halogen atoms” or “halo” as used herein includes fluorine, chlorine, bromine and iodine atom.

[0037] The term "-(Cx-Cy)alkyl" wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term "-(Ci-Ce)alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl and n-hexyl. When x is 1 and y is 4, the term "-(Ci-C4)alkyl includes methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0038] The term "-(Cx-Cy)alkylene-" wherein x and y are integers, refers to a (Cx-Cy)alkyl radical having in total two unsatisfied valences. Example of such "-(Cx-Cy)alkylene-" groups may include for example a divalent methylene radical -CEE- and -CH(CH3)-.

[0039] The term “-(Cx-Cy)haloalkyl” wherein x and y are integers, refers to the above defined “(Cx-Cy)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different. Examples of said “-(Cx-Cy)haloalkyl” groups include “(Ci-C6)haloalkyl” and “(Ci-C4)haloalkyl”. “-(Cx-Cy)haloalkyl” groups may include halogenated, poly-halogenated and fully halogenated alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl.

[0040] The term "-(Cx-Cy)aminoalkyl” wherein x and y are integers, refers to the above defined “- (Cx-Cy)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more amino group, which can be the same or different. Examples of "-(Cx-Cy)aminoalkyl” include, for instance, aminomethyl.

[0041] The term “-(Cx-Cy)hydroxy alkyl” wherein x and y are integers, refers to the above defined “-(Cx-Cy)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more one or more hydroxy (OH). Examples of said “-(Cx-Cy)hydroxyalkyl” include, for instance, hydroxymethyl.

[0042] The term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0043] The term “-(Cx-Cy)cycloalkyl” wherein x and y are integers, refers to saturated or partially unsaturated mono- or poly-cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0044] The term "-(Cx-Cy)cycloalkylene-” wherein x and y are integers, refers to saturated or partially unsaturated mono- or poly- (Cx-Cy)cycloalkyl groups containing the indicated number of ring carbon atoms, having in total two unsatisfied valences on the same carbon atom. Examples of “-(Cx-Cy)cycloalkylene-“ include “-(Ci-C4)cycloalkylene-“ and “-(Ci-C6)cycloalkylene-“, for instance cyclopropylene.

[0045] The term “(C3-Cio)heterocycloalkyl” refers to saturated or partially unsaturated monocyclic or polycyclic or polycyclic spiro groups, containing the indicated number of ring carbon atoms, in which at least one ring carbon atom is replaced by at least one heteroatom or hetero-group (e.g. N, NH, S or O) or bears an oxo (=0) substituent group. The said heterocycloalkyl (i.e. heterocyclic radical or group) might be further optionally substituted on the available positions in the ring, namely on carbon atoms, or on heteroatoms or hetero-groups available for substitution, by one or more specific groups. When more than one substituent are present, these may involve the same or adjacent positions in the ring, e.g. the “(C3-Cio)heterocycloalkyl” may be 1,1- or 1,2- or 1,3- di substituted. Substitution on a carbon atom includes spiro di -substitution, wherein an additional spiro condensed 3- to 6-membered ring is formed. Such spiro di-substitution is included in the meaning of “(C3-Cio)heterocycloalkyl” as polycyclic spiro group. Non limiting examples of “(C3- Cio)heterocycloalkyl” are represented by pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, oxetanyl, tetrahydropyranyl, isoindolyl, pyranyl, dihydro- or tetrahydrofuranyl, 7-azaspirononyl and 7-azaspirooctyl.

[0046] The term “-(Cx-Cy)heterocycloalkylene-“, wherein x and y are integers, refers to saturated or partially unsaturated mono- or poly- (Cx-Cy)heterocycloalkyl groups containing the indicated number of ring carbon atoms, having in total two unsatisfied valences on the same carbon atom.

[0047] Examples include divalent oxetane or oxetanyl group, like for instance: Examples of “-(Cx-Cy)heterocycloalkylene-“ include “-(Ci-

[0048] C4)heterocycloalkylene-“ and “-(Ci-C6)heterocycloalkylene-“.

[0049] A group may be optionally substituted, wherein the term “optionally substituted” refers to being substituted or unsubstituted. When the term "one or more " refers to any atoms or groups as substituents of the groups of the compound of formula (I), it is intended that from 1 to 3, preferably 1 to 2, more preferably 1 of such substituents may replace hydrogens on such variables.

[0050] The term “aryl” refers to mono- or bi-cyclic unsaturated or partially unsaturated carbon ring systems wherein at least one ring is aromatic. Examples of suitable aryl ring systems include, for instance, phenyl, dihydro- IH-indenyl and naphthyl.

[0051] The term “heteroaryl” refers to mono- or bi- or tri-cyclic ring systems with 5 to 20, preferably from 5 to 15 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, NH, S or O). Examples of “heteroaryl” include thiophenyl, benzothiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl.

[0052] A bond pointing to a wavy or squiggly line, such as as used in structural formulas herein, depicts the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0053] The term "bond" used to define a substituent refers to the situation where the two functional groups which the substituent is connected to are directly linked to each other with no additional atoms in between.

[0054] A dash (“-”) that is not between two letters or symbols is meant to represent the point of attachment for a substituent.

[0055] The terms “sodium channel receptors” or “voltage-gated sodium channels receptors” or “NaV receptors” used to refer to the inhibitory activity of the compounds of the present invention, are meant to include the members of the family of voltage-gated sodium channel (NaV) alpha subunits which are expressed in airway vagal jugular C-fibres, i.e. NaV 1.7, NaV 1.8 and NaV 1.9.

[0056] The term “NaV inhibitor” refers to the compounds of present invention as inhibitors of NaV receptors, in particular, but not limited, NaV 1.7 receptor.

[0057] The term “ICso” refers to the half maximal inhibitory concentration as a measure of the potency of a substance in inhibiting a specific biological or biochemical function.

[0058] The term “pICso” refers to the negative logarithm of the ICso value expressed as molar concentration.

[0059] Whenever other basic amino or quaternary ammonium groups are present in the compounds of formula (I), pharmaceutically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, emipamoate, xinafoate and naphthalene disulfonate. Likewise, in the presence of acidic groups, such as for instance COOH groups, corresponding pharmaceutically acceptable cations may be present, for instance including alkaline or alkaline earth metal ions, including sodium, potassium, calcium and the like.

[0060] As above indicated, the present invention refers to a series of compounds represented by the general formula (I), as herein below described in detail, which are endowed with an inhibitory activity versus voltage-gated sodium channels receptors.

[0061] Inhibitory activity of the compounds of formula (I) was tested on CHO cells stably expressing human NaV 1.7 channel in an Automated Patch Clamp assay, as described in the experimental part.

[0062] For some compounds of the invention, pICso values were calculated, demonstrating the intracellular inhibition of the NaV 1.7 receptor by the tested compounds (see Qian, Binbin et al, Current protocols in pharmacology, 2020, 89, 1).

[0063] Indeed, the compounds of formula (I) of the present invention are able to act as inhibitors of NaV 1.7 in a substantive and effective way. In particular, as indicated in the experimental part, the compounds of formula (I) of the invention show intracellular inhibition of NaV 1.7, as reported in Table 2.

[0064] The compounds of formula (I) are heteroaryl quaternary ammonium ester derivatives in salt or zwitterionic form, having a good inhibitory activity in particular on NaV 1.7.

[0065] As indicated in the experimental part, comparative compounds section, in particular in Table 3, conversely to Carcainium chloride, which is considered as comparative Compound Ci, the presence of an ester-substituted tiophene or benzothiophene ring in the compounds of the present invention unexpectedly and remarkably determines a relevant increase in the intracellular inhibitory activity on NaV 1.7 receptor.

[0066] Furthermore, as indicated in the same experimental part section, the reported data demonstrate that, conversely to comparative Compound C2, characterized by a different heteroaryl ring, the presence of the ester-substituted thiophene or benzothiophene ring in the compounds of the present invention unexpectedly and noteworthy determines a relevant increase in the inhibitory activity on NaV receptors.

[0067] Compounds of formula (I) in pharmaceutically acceptable salt or zwitterionic form, hereinafter alternatively referred to as compounds of the invention, are useful as medicaments. Accordingly, the invention also provides a compound of formula (I) in pharmaceutically acceptable salt or zwitterionic form for use as a medicament.

[0068] The compounds of formula (I) of the present invention are able to act as inhibitors of NaV 1.7 receptor in a substantive and effective way, particularly appreciated by the skilled person when looking for compounds for the potential treatment of respiratory diseases such as: cough, asthma, IPF and COPD, and in particular chronic cough.

[0069] Accordingly, the compounds of formula (I) can be used in the treatment of respiratory diseases selected from cough, asthma, IPF and COPD, and in particular chronic cough, whenever NaV receptors are involved.

[0070] As it can be appreciated, the compounds of the present invention according to Table 2 show a potency with respect to their intracellular inhibitory activity on NaV 1.7 receptor, expressed as pICso values, equal to or higher than 5, preferably between 5 and 5.5, more preferably equal to or higher than 5.5.

[0071] More advantageously, the compounds represented by the general formula (I) are able of inhibiting one or more voltage-gated ion channels when exposed or applied into the cell but show little or no inhibition when applied outside the cell.

[0072] The compounds of formula (I) were also tested in Automated Patch Clamp assay with a similar protocol for extracellular inhibition, i.e. after exchange of the external solution with a solution containing the test compound: the obtained experimental values were used to calculate pICso values representing the extracellular inhibition of NaV 1.7 receptor.

[0073] As indicated in the experimental part, the compounds of formula (I) of the present invention have a NaV 1.7 extracellular inhibition lower than the intracellular inhibition, as shown in Table 2.

[0074] Accordingly, the compounds of the present invention according to Table 2 show a difference between intracellular and extracellular potency with respect to NaV 1.7 inhibition, defined as DELTA, which is equal to or higher than 0,5, preferably between 0,5 and 1, more preferably equal to or higher than 1.

[0075] This difference between intracellular and extracellular inhibition could result in a greater safety of the compounds on sensory neurons.

[0076] The compounds of the invention were tested also in safety pharmacological assays, in particular in human Ether-a-go-go Related Gene (hERG) channel in vitro assay. Safety pharmacological studies are non-clinical studies to test the safety of novel drugs on human from pharmacological viewpoints. Guideline on Safety Pharmacology Studies which aims at examining the safety of test substances on human and predicting adverse effects thereof has been set in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) between Europe, Japan and the United States. According to the Guideline, examination of the arrhythmogenic effect, in particular, the presence or absence of electrocardiographic QT interval prolongation effect, of test substances is required as a part of safety pharmacological studies. The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart, and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. In order to protect patients from ventricular tachycardia, torsades de pointes and lethal arrhythmia associated with QT interval prolongation induced by drug administration, it is very important in the development of drugs to detect QT interval prolongation effect which may induce such serious adverse effects.

[0077] To date, it has been known that a large number of drugs having QT interval prolongation effect inhibit delayed rectifier potassium channels in cardiomyocytes. It is believed that hERG channel is functioning as a major constituent protein in the delayed rectifier potassium channel. Therefore, in the draft guideline for non-clinical evaluation of the potential for delayed ventricular repolarization (QT Interval Prolongation) by human pharmaceuticals, ion channel assay using hERG channel-transferred cells is recommended as a non-clinical study.

[0078] In addition to being notably potent with respect to their inhibitory activity on NaV receptors, the compounds of formula (I) of the present invention were tested for in vitro inhibition of the hERG channel and showed low toxicity profile for hERG, thus reducing the possibility to observe adverse events during clinical studies.

[0079] Thus, in one aspect the present invention relates to a compound of general formula (I) in zwitterionic or pharmaceutically acceptable salt form, wherein at least one of Y and Z is S, and the other one is CR4; Ri and Rz are independently selected from the group consisting of -(Ci-Ce)alkyl and -(Ci- Ce)alkyl-OR6, or are fused together forming a -(C3-Cio)heterocycloalkyl, wherein said -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -C(O)OR6, -(Ci-Ce)alkyl and -(Ci-Ce)haloalkyl;

[0080] Rj and R4 are independently H or selected from the group consisting of CN, -(Ci-Ce)alkyl and aryl, or, wherein Y is CR4, R3 and R4 are fused together forming an aryl, preferably phenyl;

[0081] Rs is selected from the group consisting of -(Ci-Ce)alkyl, -(Ci-Ce)alkyl-NReR7, -(Ci- Ce)alkyl-ORe, -(Ci-Ce)alkyl-C(O)NReR7, -(C3-Cio)heterocycloalkyl and -(C3-C7)cycloalkyl;

[0082] Re and R7 are independently H or selected from the group consisting of -(Ci-Ce)alkyl and - (Ci-Ce)alkyl-aryl;

[0083] Li is a bond or selected from the group consisting of -(Ci-Ce)alkylene-,-(Ci- C6)heterocycloalkylene- and -(Ci-C6)cycloalkylene-; and

[0084] A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-Cio)cycloalkyl and - (C3-Cio)heterocycloalkyl, wherein any of such aryl, heteroaryl, -(C3-Cio)cycloalkyl or -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, - C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-Ce)haloalkyl, -(Ci-C6)alkyl-OR6and -(Ci-Ce)alkyl- NReR?; provided that when Li is a bond any of such aryl is not substituted by -(Ci-Ce)alkyl.

[0085] All the listed groups for each of the variable moieties Y, Z, Ri, R2, R3, R>, Rs, Re, R7, Li and A of the compounds of the invention have to be intended as alternatives and may be combined with each other in embodiments which are included in the scope of the invention.

[0086] The 5-membered ring comprising Y and Z is an aromatic ring, namely a thiophene ring, substituted by a COORs group.

[0087] In a preferred embodiment Z is S and Y is CR4. In a more preferred embodiment, Z is S and Y is CH.

[0088] In another embodiment, Y is S and Z is CR4, wherein R4 is preferably hydrogen.

[0089] In one embodiment, Ri and Rz are independently selected from the group consisting of -(Ci- Ce)alkyl and -(Ci-Ce)alkyl-ORe, or are fused together forming a -(C3-Cio)heterocycloalkyl, wherein said -(C3-Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -C(O)ORe, -(Ci-Ce)alkyl and -(Ci-Ce)haloalkyl. In a preferred embodiment Ri and Rz are independently -(Ci-Ce)alkyl, -(Ci-Ce)alkyl-ORe, or are fused together forming a - (C3-Cio)heterocycloalkyl, wherein said -(C3-Cio)heterocycloalkyl is optionally substituted by one or more groups selected from -ORe, -(Ci-Ce)alkyl and -C(O)ORe.

[0090] In another preferred embodiment, Ri and Rz are independently -(Ci-Ce)alkyl. In a more preferred embodiment, Ri and Rz are independently -(Ci-C4)alkyl. In an even more preferred embodiment, Ri and Rz are methyl. In another preferred embodiment, Ri and Rz are fused together forming a -(C3-Cio)heterocycloalkyl wherein said -(C3-Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -C(O)ORe, -(Ci-Ce)alkyl and - (Ci-Ce)haloalkyl. In a more preferred embodiment, Ri and Rz are fused together forming a -(C3- Cio)heterocycloalkyl, wherein said -(C3-Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -C(O)ORe, -(Ci-C4)alkyl and -(Ci-C4)haloalkyl. In a most preferred embodiment, Ri and R2 are fused together forming a piperidinyl or azepanyl ring optionally substituted by one or more groups selected from halogen, -ORe, -C(O)ORe, -(Ci- C4)alkyl and -(Ci-C4)haloalkyl.

[0091] In one embodiment, Rj and R4 are independently H or selected from the group consisting of CN, -(Ci-Ce)alkyl and aryl, or, wherein Y is CR4, R3 and R4 are fused together forming an aryl.

[0092] In a preferred embodiment, Rj and R4 are independently selected from the group consisting of H and -(Ci-Ce)alkyl, or, wherein Y is CR4, Rj and R4 are fused together forming an aryl. In another embodiment, Rj and R4 are independently -(Ci-Ce)alkyl. In a preferred embodiment, Rj and R4 are independently -(Ci-C4)alkyl. In another embodiment R3 and R4 are H. In a more preferred embodiment, Rj and R4 are independently H or methyl, most preferably Rj is methyl and R4 is H. In another preferred embodiment, Rj and R4 are fused together forming an optionally substituted phenyl ring, which is condensed with the 5-membered ring thus forming an optionally substituted benzothiophene ring system.

[0093] In one embodiment, R5 is selected from the group consisting of -(Ci-Ce)alkyl, -(Ci-Ce)alkyl- NReR?, -(Ci-Ce)alkyl-ORe, -(Ci-Ce)alkyl-C(O)NReR7, -(C3-Cio)heterocycloalkyl and -(C3- C7)cycloalkyl. In a preferred embodiment, R5 is selected from the group consisting of -(Ci- C4)alkyl, -(Ci-C4)alkyl-NReR7, -(Ci-C4)alkyl-ORe, -(Ci-C4)alkyl-C(O)NReR7. In another embodiment, R5 is -(Ci-Ce)alkyl-NReR7. In a preferred embodiment, R5 is -(Ci-C4)alkyl-NReR7. In another embodiment, R5 is -(Ci-Ce)alkyl. In a preferred embodiment, R5 is -(Ci-C4)alkyl. In more preferred embodiment, R5 is methyl, ethyl, isopropyl or tert-butyl. In another embodiment, Rs is -(C3-C7)cycloalkyl. In a preferred embodiment, R5 is cyclopropyl. In another embodiment, Rs is -(C3-Cio)heterocycloalkyl. In another preferred embodiment, R5 is selected from piperidine and oxetane. In another preferred embodiment R5 is selected from the group consisting of -(Ci- Ce)alkyl and -(C3-C6)cycloalkyl.

[0094] In one embodiment Re and R7 are independently H or selected from the group consisting of -(Ci-Ce)alkyl and -(Ci-Ce)alkyl-aryl. In a preferred embodiment, Re and R7 are independently H or -(Ci-C4)alkyl. In another embodiment, Re and R7 are -(Ci-C4)alkyl. In a preferred embodiment, Re and R7 are independently H or methyl. In a preferred embodiment, Re and R7 are H. In a more preferred embodiment, Re and R7 are methyl. In another embodiment, Re and R7 are independently H or -(Ci-C6)alkyl-aryl. In a preferred embodiment, Re and R? are independently -(Ci-C4)alkyl- aryl. In a more preferred embodiment, Re and R? are independently H or benzyl.

[0095] In one embodiment, Li is a bond or selected from the group consisting of -(Ci-Ce)alkylene- ,-(Ci-Ce)heterocycloalkylene- and -(Ci-Ce)cycloalkylene-. In a preferred embodiment, Li is a bond or selected from the group consisting of -(Ci-C4)alkylene-, -(Ci-C4)heterocycloalkylene- and -(Ci-C4)cycloalkylene-. In a more preferred embodiment, Li is a bond. In another more preferred embodiment, Li is selected from the group consisting of methylene, cyclopropylene, oxetane and -CH(CH3)-.

[0096] In one embodiment, A is a ring selected from the group consisting of aryl, heteroaryl, -(C3- Cio)cycloalkyl and -(C3-Cio)heterocycloalkyl, wherein any of such aryl, heteroaryl, -(C3- Cio)cycloalkyl or -(C3-Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -C(O)ORe, -(Ci-Ce)alkyl, -C(O)NReR7, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl- ORe and -(Ci-Ce)alkyl-NR6R7; provided that when Li is a bond any of such aryl is not substituted by -(Ci-Ce)alkyl. In another embodiment, A is a ring selected from aryl and heteroaryl, wherein any of such aryl and heteroaryl is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-C6)haloalkyl, -(Ci-C6)alkyl-OR6 and -(Ci- Ce)alkyl-NR6R7; provided that when Li is a bond any of such aryl is not substituted by -(Ci- Ce)alkyl. In a preferred embodiment, A is heteroaryl, optionally substituted by one or more groups selected from halogen, -ORe, -C(O)ORe, -(Ci-Ce)alkyl, -C(O)NReR7, -(Ci-Ce)haloalkyl, -(Ci- Ce)alkyl-ORe, -(Ci-Ce)alkyl-NReR7 and -(Ci-Ce)alkyl-C(O)NReR7. In another preferred embodiment, A is heteroaryl selected from the group consisting of optionally substituted thiophenyl, benzothiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl. In another preferred embodiment, A is an aryl, optionally substituted by one or more groups selected from halogen, -C(O)ORe, -(Ci- Ce)alkyl, -C(O)NReR7, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl-ORe and -(Ci-Ce)alkyl-NReR7. In another preferred embodiment, A is an aryl, optionally substituted by one or more groups selected from - ORe, -C(O)ORe and -C(O)NReR7. In a more preferred embodiment, A is phenyl, optionally substituted by one or more groups selected from -ORe, -C(O)ORe and -C(O)NReR7.

[0097] All the preferred groups listed above for each of the variable moieties Y, Z, Ri, Rz, Rj, Rt, Rs, Re, R7, Li and A of the compounds of the invention may be combined with each other in embodiments which are included in the scope of the invention.

[0098] Preferred halogens, as such and in -(Cx-Cy)haloalkyl substituents, are fluorine and bromine, wherein fluorine is more preferred.

[0099] In another preferred embodiment, the invention refers to a compound of formula (I) as defined above wherein

[0100] Z, Y, Ri, Rz, Rj, t, Rs, Re and R7 are defined as above;

[0101] Li is selected from the group consisting of -(Ci-Ce)alkylene-, -(Ci-C6)heterocycloalkylene- and -(Ci-C6)cycloalkylene-; and

[0102] A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-Cio)cycloalkyl and - (C3-Cio)heterocycloalkyl, wherein any of such aryl, heteroaryl, -(C3-Cio)cycloalkyl or -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, - C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-C6)haloalkyl, -(Ci-C6)alkyl-OR6and -(Ci-Ce)alkyl- NReR7.

[0103] In a preferred embodiment, Li is selected from the group consisting of -(Ci-C4)alkylene-,- (Ci-C4)heterocycloalkylene- and -(Ci-C4)cycloalkylene-. In an even more preferred embodiment, Li is selected from the group consisting of methylene, cyclopropylene, oxetane and -CH(CH )-.

[0104] In another preferred embodiment, A is a ring selected from aryl and heteroaryl, wherein any of such aryl and heteroaryl is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-C6)haloalkyl, -(Ci-C6)alkyl-OR6and -(Ci-Ce)alkyl- NReR7. In a more preferred embodiment, A is heteroaryl, wherein any of such heteroaryl is optionally substituted by one or more groups selected from halogen, -C(O)ORe, -(Ci-Ce)alkyl, - C(O)NReR7, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl-OR6 and -(Ci-Ce)alkyl-NR6R7. In another more preferred embodiment, A is an aryl, wherein any of such aryl is optionally substituted by one or more groups selected from halogen, -C(O)ORe, -(Ci-Ce)alkyl, -C(O)NReR7, -(Ci-Ce)haloalkyl, - (Ci-Ce)alkyl-OR6 and -(Ci-Ce)alkyl-NR6R7. In an even more preferred embodiment, A is an aryl, wherein any of such aryl is optionally substituted by one or more groups selected from -ORe, - C(O)OR6and -C(O)NR6R7.

[0105] In another embodiment, the invention refers to a compound of formula (I) wherein Li is a bond, represented by formula (la): in zwitterionic or pharmaceutically acceptable salt form, wherein

[0106] Z, Y, Ri, R2, R3, R4, Rs, Re and R7 are defined as above; and

[0107] A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-Cio)cycloalkyl and - (C3-Cio)heterocycloalkyl, wherein any of such heteroaryl, -(C3-Cio)cycloalkyl or -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, - C(O)OR6, -(Ci-Ce)alkyl, -C(O)NR6R7, -(Ci-C6)haloalkyl, -(Ci-C6)alkyl-OR6and -(Ci-Ce)alkyl- NReR?; and wherein any of such aryl is optionally substituted by one or more groups selected from halogen, -C(O)ORe, -C(0)NReR7, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl-OR6 and -(Ci-Ce)alkyl- NReR?.

[0108] In a preferred embodiment, A is heteroaryl, optionally substituted by one or more groups selected from halogen, -C(O)ORe, -(Ci-Ce)alkyl, -C(0)NReR7, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl- ORe and -(Ci-Ce)alkyl-NR6R7. In a more preferred embodiment, A is heteroaryl, optionally substituted by one or more halogen, -C(O)ORe, -C(0)NReR7, -(Ci-C4)alkyl, and -(Ci-C4)alkyl- ORe. In an even more preferred embodiment, A is heteroaryl, selected from the group consisting of optionally substituted thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl, and is optionally substituted by one or more methyl, ethyl, isopropyl or tert-butyl.

[0109] In another preferred embodiment, the invention refers to a compound of formula (I) as defined above, wherein at least one of Y and Z is S, and the other one is CR4;

[0110] Ri and R2 are independently selected from the group consisting of -(Ci-Ce)alkyl and -(Ci- C4)alkyl-OR6, or are fused together forming a -(C3-Cio)heterocycloalkyl, wherein said -(C3- Cio)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -ORe, -(Ci-Ce)alkyl and -C(O)OR6-;

[0111] Rj and R4 are independently H or -(Ci-Ce)alkyl, or, wherein Y is CR4, Rj and R4 are fused together forming an aryl;

[0112] Rs is selected from the group consisting of -(Ci-Ce)alkyl and -(C3-C6)cycloalkyl;

[0113] Re and R7 are independently H or selected from the group consisting of -(Ci-C4)alkyl and - (Ci-C4)alkyl-aryl;

[0114] Li is a bond or selected from the group consisting of -(Ci-Ce)alkylene-,-(Ci- C6)heterocycloalkylene- and -(Ci-C6)cycloalkylene-; and

[0115] A is a ring selected from the group consisting of aryl, heteroaryl and -(C3-Cio)cycloalkyl, wherein any of such aryl, heteroaryl or -(C3-Cio)cycloalkyl is optionally substituted by one or more groups selected from -ORe, -C(O)ORe, -C(O)NReR7, -(Ci-Ce)alkyl and -(Ci-Ce)haloalkyl; provided that when Li is a bond any of such aryl is not substituted by -(Ci-Ce)alkyl.

[0116] In another preferred embodiment, the invention refers to a compound of formula (I) as defined above, wherein Z is S and Y is CH or Z is CH and Y is S;

[0117] Rj is H or methyl and

[0118] Ri, Rz, R4, Rs, Re, R7, Li and A are defined as above.

[0119] In a preferred embodiment, the invention refers to at least one of the compounds listed in Table 1 below in zwitterionic form or as pharmaceutically acceptable salts thereof.

[0120] Table 1 - List of preferred compounds

[0121] It is to be understood that all the single enantiomers, diastereoisomers and mixtures thereof, in any proportion, of the compounds of formula (I) of the invention are encompassed within the scope of the present invention.

[0122] In a preferred embodiment, the invention refers to a compound of formula (I) as NaV inhibitor. In this respect, it has been found that the compounds of formula (I) of the present invention have an inhibitor drug potency expressed as pICso on NaV 1.7 receptor equal or higher than 5.

[0123] Preferably, the compounds of the present invention have a pICso on NaV 1.7 between 5 and 5.5. More preferably, the compounds of the present invention have a pICso on NaV 1.7 equal or higher than 5.5. Even more preferably the compounds of the present invention have a pICso on NaV 1.7 between 5.5 and 6.

[0124] The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) in zwitterionic or pharmaceutically acceptable salt form, in admixture with at least one or more pharmaceutically acceptable carrier and / or excipient.

[0125] As used herein, "effective amount" in reference to a compound of formula (I), in zwitterionic or pharmaceutically acceptable salt form, or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan.

[0126] The compounds of formula (I) may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen. In one embodiment, the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

[0127] In therapeutic use, the compound of formula (I) may be administered by any convenient, suitable, or effective route. Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastemally and by infusion) and by inhalation.

[0128] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0129] In a more preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered by inhalation.

[0130] In another preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered orally.

[0131] In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) in zwitterionic or pharmaceutically acceptable salt form is a solid oral dosage form such as tablets, gel caps, capsules, caplets, granules, lozenges and bulk powders.

[0132] The compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.

[0133] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solution, emulsion, suspension, syrup. Such liquid dosage form can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and / or suspending the compounds of the invention.

[0134] In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. Inhalable preparations may be administered through a suitable inhalation device which may be selected from dry powder inhalers, pressurized metered dosed inhalers or nebulizers.

[0135] In another embodiment the invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in zwitterionic or pharmaceutically acceptable salt form, obtained as described above according to the invention, in form of a single- or multi-dose dry powder inhaler or a metered dose inhaler. For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges, or blister packs or in a reservoir.

[0136] A diluent or carrier, chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0137] Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers, and optionally other excipients.

[0138] The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by j et or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.

[0139] The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.

[0140] The dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.

[0141] In a further aspect, the invention refers to the use of the compounds of formula (I) for the preparation of a medicament. In another aspect, the present invention refers to a compound of formula (I) for use as a medicament.

[0142] Thus, the invention refers to a compound of formula (I) in the preparation of a medicament, preferably for use in the treatment of disorders associated with voltage-gated sodium channels (NaV) receptors mechanism.

[0143] In another embodiment, the present invention refers to a compound of formula (I) for use in the prevention and / or treatment of diseases, disorders or conditions associated with dysregulation of voltage-gated sodium channels (NaV).

[0144] In one aspect, the invention also refers to a method for the prevention and / or treatment of disorders associated with NaV receptors mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

[0145] Preferably, the compounds of the present invention are useful for the treatment and / or prevention of respiratory diseases.

[0146] In a preferred embodiment, the present invention provides a method for preventing and / or treating respiratory diseases, the method comprising administering a compound of formula (I). In another aspect, the present invention is directed to a pharmaceutical composition comprising the compounds of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients, for use in the prevention and / or treatment of respiratory diseases.

[0147] In another embodiment, the present invention provides a method for preventing and / or treating respiratory diseases, the method comprising administering a pharmaceutical composition comprising the compounds of formula (I).

[0148] In a further aspect, the respiratory diseases mentioned above are selected from cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, refractory chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0149] In one embodiment, the invention refers to the use of the compound of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and / or prevention of cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, refractory chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0150] In another embodiment, the invention refers to a compound of formula (I) or a pharmaceutical composition for use in the prevention and / or treatment of a respiratory disease, wherein the respiratory disease is selected from: cough, sub-acute or chronic cough, treatmentresistant cough, idiopathic chronic cough, refractory chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0151] In another embodiment, the invention refers to a method for the treatment and / or prevention of respiratory diseases selected from the group consisting of cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, refractory chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD and cough associated with respiratory diseases such as COPD, asthma and bronchospasm, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0152] In a preferred embodiment, the respiratory disease mentioned above is chronic cough.

[0153] In another preferred embodiment, the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and / or treatment of chronic cough.

[0154] In another preferred embodiment, the invention refers to the use of a compound of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and / or prevention of chronic cough. In another preferred embodiment, the invention refers to a method for the treatment and / or prevention of chronic cough, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0155] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of the compound of formula (I).

[0156] The magnitude of prophylactic or therapeutic dose of the compound of formula (I) will, of course, vary with the nature of the severity of the condition to be treated and with its route of administration, and will generally be determined by clinical trial as required in the pharmaceutical art. It will also vary according to the age, weight and response of the individual patient.

[0157] All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and apply as well mutatis mutandis.

[0158] The compounds of the present invention can be prepared in a number of ways known to the one skilled in the art of organic synthesis. It will be understood that the functionality present on the molecule should be consistent with the transformation proposed. This will sometimes require a modification of the order of synthetic steps in order to obtain a desired compound of the invention. While the optimal reaction conditions may vary depending on the particular reactants or solvent used, such conditions can be readily determined by those skilled in the art by routine optimization procedures. Thus, processes described below should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention. In some cases, generally known protective groups (PG) may be employed when needed to mask or protect sensitive or reactive moieties, in accordance to general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts).

[0159] The compounds of formula (I), including all the compounds here above listed, can be generally prepared according to the procedures outlined in Schemes 1 to 4 shown below, wherein at least one non-limiting synthetic route is provided for the preparation of the exemplified compounds (i.e. the Examples). Scheme 1

[0160] In one embodiment of the present invention, intermediate compounds for the preparation of the compounds of the invention may be prepared according to Scheme 1. Compound (III) may be prepared from compound (II) and compound (VII) from compound

[0161] (IV). Compound (III) may be prepared from compound (II) by acylation reaction with a suitable haloacetyl halide (IX), wherein Xi and X2 are halogens, preferably and independently chlorine or bromine.

[0162] Analogously, compound (V) may be prepared from compound (IV) by acylation reaction with a suitable haloacetyl halide (IX), wherein Xi and X2 are halogens, preferably and independently chlorine or bromine. Compound (VII) may be prepared from compound (V) by alkylation reaction with a suitable amine NHR1R2 (VI). Alternatively, compound (VII) may be prepared directly from compound (IV) by acylation with a suitable amino acid (VIII), by using coupling reagents like TCFH or similar. Scheme 2

[0163] According to Scheme 2, intermediate compound (X) may be prepared from compound (II) or compound (III). Compound (X) may be prepared from compound (III) by alkylation reaction with a suitable amine NHR1R2 (VI). Alternatively, Compound (X) may be prepared from compound (II) by acylation reaction with a suitable amino acid (VIII), by using coupling reagents like TCFH or similar.

[0164] Scheme 3 In one embodiment of the present invention, according to Scheme 3, compounds (Xa), wherein Rs is other than methyl, may be prepared from compounds (Xb), obtained as described in Scheme 2 for compounds (X) wherein Rs is methyl. Compound (XI) may be prepared from compound (Xb) by methyl ester hydrolysis reaction in the presence of a base, like for instance NaOH or KOH, or an acid, like for instance HC1 or H2SO4. Compound (XII) may be prepared from compound (XI) by cyclization reaction mediated by reagents like TCFH or similar. Compound (Xa) may be then prepared from compound (XII) by ring opening reaction in the presence of a suitable alcohol Rs-OH (XIII).

[0165] Scheme 4

[0166] Compounds of formula (I) according to the invention may be prepared by coupling of compounds (III) and (VII) or compounds (V) and (X), respectively, according to Scheme 4, wherein compounds (X) may be compounds of formula (Xa) or (Xb).

[0167] Compounds of formula (I) may be prepared from compound (III) and compound (VII) by a nitrogen quatemarization reaction (Menshutkin reaction). Alternatively, a Menshutkin reaction may involve compound (V) and compound (X), thus obtaining a compound of formula (I).

[0168] Accordingly, the present invention provides intermediate compounds (III), (V), (VII), (VIII), (X), (XI) and (XII), as defined above, and their use in the preparation of compounds of formula (I).

[0169] In another aspect, the invention provides the use of an intermediate compound selected from the group consisting of compound (III), (V), (VII) and (X) as defined above, in particular in Scheme 4, for the preparation of the compounds of formula (I), as defined above.

[0170] When compounds of formula (I) were isolated by precipitation from the reaction mixture and then triturated or crystallized, they were generally obtained as salt forms, with the anion being chloride or bromide, depending on the meaning of X2 in the alkylating agent, i.e. the compound (III) or (V), used in the formation of the quaternary ammonium salt (see Scheme 4). Compounds of formula (I) in salt form can be obtained in zwitterionic form by subsequent treatment in basic conditions, such as by purification on amino-functionalized silica gel chromatography. Zwitterionic forms of compounds of formula (I) may be treated with acids, such as hydrochloric acid or the like, to obtain the corresponding compounds of formula (I) in salt form.

[0171] Exemplified preparation processes are given in the following experimental part.

[0172] PREPARATIONS OF INTERMEDIATES AND EXAMPLES

[0173] Chemical Names of the compounds were generated with Structure-To-Name tool of PerkinElmer ChemDraw® Professional application (v. 20.0.0.41.) or are common chemical names. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0174] In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step number. This is provided merely for assistance to the skilled chemist.

[0175] When reference is made to the use of a “similar” or “analogous” procedure, as it will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent / solvent amount, reaction time, work-up conditions or chromatographic purification conditions, that will be appreciated by those skilled in the art. All final compounds were obtained as pharmaceutically acceptable salts, unless stated otherwise.

[0176] All the Intermediates and the Examples reported were analytically characterized by LC-MS and / orJH-NMR as described therein, the optimal proton frequency and solvent conditions may vary and can be readily determined by those skilled in the art by routine optimization procedures.

[0177] Abbreviations

[0178] ACN = acetonitrile; AMU = Atomic Mass Unit; CDCh = deuterated chloroform; CyHex = cyclohexane; DCM = dichloromethane; DIPEA = Diisopropylethylamine; DMF = dimethylformamide; diastereomeric excess = d.e.; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; EGTA = ethylene glycol-bis(P-aminoethyl ether)-N,N,N',N'- tetraacetic acid; Et2O = diethyl ether; EtOAc = Ethyl acetate; eq. = equivalents; FCC = flash column chromatography; h = hour / s; HATU = l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HEPES = N-2-hydroxyethylpiperazine- N'-2-ethanesulfonic acid; HCOOH = formic acid; HPLC = high performance liquid chromatography; MeOH = methyl alcohol; min = minute / s; NMR = nuclear magnetic resonance; RT / rt = room temperature; s.s .= saturated solution; U? = retention time; TCFH = chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; T3P = (2s,4s,6s)-2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; LC-MS = Liquid Chromatography / Mass Spectrometry; v / v = volume / volume; w / w = weight / weight; XPhos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2- (2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate; NMDG = N-methyl-D-glucamine.

[0179] Analytical Methods

[0180] NMR characterization:

[0181] JH-NMR spectra were performed on 400 Agilent INOVA, 500 Agilent VNMRS, 600 Agilent INOVA spectrometers operating at 400, 500, 600 MHz (proton frequency), or on a Bruker Avance III 400 or Avance III HD 600 spectrometer.

[0182] Chemical shifts are reported as 5 values in ppm relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation (s=singlet, d=doublet, t=triplet, quin=quintet, m=multiplet, br=broad).

[0183] Information on the zwitterionic or salt form for compounds of formula (I) was obtained by 'H-NMR spectroscopy: zwitterionic forms generally showed one missing amide NH signal. HBr or HC1 salts generally showed all amide NH signals. Formic acid salts (i.e. formates) were checked and quantified by 'H-NMR signal of formic acid.

[0184] LC-MS:

[0185] LC-MS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on Waters LC / PDA / MS Acquity™ system coupled with Micromass ZQ™ or Waters SQD single quadrupole mass spectrometer operated in positive and / or negative electron spray ES ionization mode.

[0186] LC / UV / MS characterization:

[0187] LC / MS retention times (tz?) are estimated to be affected by an experimental error of ± 0.5 min.

[0188] LC-MS Method 1: Column Acquity CSH C18 2.1 x 50mm 1.7pm, the column temperature was 40 °C; mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B ACN + 0.1% HCOOH. The flow rate was 1 mL / min.

[0189] The gradient table was t=0 min 97% A 3% B, t=1.5 min 0.1% A 99.9% B, t=1.9 min 0.1% A 99.9% B and t=2 min 97% A 3% B. The UV detection range was 210-350 nm and ES+ZES- range was 100 to 1000 AMU.

[0190] LC-MS Method 2: Column Kinetex EVO Cl 8 2.1 x 50mm 1.7pm, the column temperature was 40 °C; mobile phase solvent A was 10 mM aqueous solution of NH4HCO3 adjusted to pH=10 with ammonia, mobile phase solvent B ACN. The flow rate was 1 mL / min. The gradient table was t=0 min 97% A 3% B, t=l .5 min 0.1% A 99.9% B, t=l .9 min 0.1% A 99.9% B and t=2 min 97% A 3% B. The UV detection range was 210-350 nm and ES+ZES- range was 100 to 1200 AMU.

[0191] LC-MS Method 3: Column Acquity CSH C18 2.1 x 50mm 1.7pm, the column temperature was 40 °C; mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B ACN + 0.1% HCOOH. The flow rate was 1 mL / min. The gradient table was t=0 min 97% A 3% B, t=3.5 min 0.1% A 99.9% B, t=3.9 min 0.1% A 99.9% B and t=4.0 min 97% A 3% B. The UV detection range was 210-350 nm and ES+ZES- range was 100 to 1000 AMU.

[0192] Purification Methods

[0193] The purification of some compounds was achieved by semipreparative HPLC (HPLC Semiprep Method) by using a MDAP Waters apparatus with mass spectrometry detection (MS:ZQ2000) and DAD detection 220, equipped with CSH C18 (30 x 100 mm, 5pm) column and 1 mL injection loop. A gradient of ACN in H2O + 0.1 % HCOOH (flow= 40.00 mL / min.) was used as mobile phase: gradient conditions are specified in each example. Other compounds were purified by FCC using Biotage® columns and conditions specified in each Example. Biotage® columns used are herein described with their abbreviations used in the synthetic procedures:

[0194] Sfar silica: Silica column Biotage® Sfar silica D Duo 60 pM

[0195] Sfar amino: amino-functionalized silica column Biotage® Sfar KP-amino D Duo 50 pM

[0196] Sfar Cl 8: C18 derivatized silica column Biotage® Sfar C18 D Duo 100 A 30 pM

[0197] The separation of some diastereoisomeric mixtures was achieved by semipreparative chiral HPLC using the following methods.

[0198] Method Chiral HPLC 1: Column Chiralcel OD-H (25 x 2.0 cm), 5 p Mobile phase n- Hexane / (Ethanol + 0.1% isopropylamine) 60 / 40 % v / v. Flow rate (mL / min) 17 mL / min. DAD detection 220 nm. Loop 1000 pL.

[0199] Method Chiral HPLC 2: Column Chiralcel OD-H (25 x 3.0 cm), 5 p Mobile phase n- Hexane / (Ethanol / Methanol 1 / 1 + 0.1 % isopropylamine) 75 / 25 % v / v. Flow rate (mL / min) 40 mL / min. DAD detection 220 nm. Loop 500 pL.

[0200] General Synthetic procedures

[0201] Intermediate 1: Methyl 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2- carboxylate A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (500 mg, 2.92 mmol), N,N- dimethyl-4-pyridinamine (570 mg, 4.67 mmol), di-tert-butyl dicarbonate (1.91 g, 8.76 mmol) and TEA (0.85 mL, 6.13 mmol) in DCM (12 mL) was stirred overnight at RT. The mixture was diluted with DCM, washed with HC1 0.1M and the separated organic layers were washed with water, brine, dried over a phase separator and concentrated under high vacuo. The crude was purified by FCC on Sfar silica (CyHex 100% to CyHexZEtOAc 9: 1) affording the title compound (Intermediate 1 , 720 mg, 1.94 mmol, 66% yield) as white oil.

[0202] LC-MS Method 1 : tz? = 1.23 min, m / z =394.1[M+Na]+

[0203] Intermediate 2: 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2-carboxylic acid

[0204] A solution of Intermediate 1 (700 mg, 1.88 mmol) in MeOH (25 mL) was treated with aqueous sodium hydroxide solution (2.19 mL, 1.31 mmol) then the reaction mixture was heated to 50 °C and left under vigorous stirring overnight. The mixture was diluted with water and MeOH was evaporated under reduced pressure. The aqueous layer was washed with EtOAc then acidified to pH=3 with sulfuric acid (10%v / v). The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over a phase separator and concentrated under vacuo affording the title compound (Intermediate 2, 510 mg, 1.427 mmol, 76% yield) as an off-white solid used for the following step without further purification.

[0205] LC-MS Method 1: tz? = 1.09 min, m / z =356.3[M-H]-

[0206] Intermediate 3: isopropyl 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2- carboxylate

[0207] A solution of Intermediate 2 (180 mg, 0.50 mmol) in acetone (5 mL) was treated with potassium carbonate (83 mg, 0.60 mmol). 2-iodopropane (94 mg, 0.55 mmol) was added at RT and the mixture was stirred for 30 h at 70 °C. The reaction mixture was cooled to RT and concentrated under vacuum. The residue was dissolved with EtOAc and washed with water. The aqueous layer was separated and extracted with EtOAc, the organic layers was washed with brine, dried over phase separator and concentrated under high vacuum affording the title compound (Intermediate 3, 202 mg, 0.506 mmol, crude) as yellow oil used for the following step without further purification.

[0208] LC-MS Method 1 : tz? = 1.38 min, m / z =422.4[M+Na]+

[0209] Intermediate 4: (propyl 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2- carboxylate)

[0210] Following the same procedure as for Intermediate 3, Intermediate 4 was prepared starting from Intermediate 2 by using 1 -iodopropane. The title compound was used for the next step without further purification (Intermediate 4, 210 mg, 0.526 mmol).

[0211] LC-MS Method 1 : t« = 1.39 min, m / z =422.4[M+Na]+

[0212] Intermediate 5: Isopropyl 3-amino-4-methylthiophene-2-carboxylate

[0213] TFA (0.39 mL, 5.10 mmol) was slowly added to an ice-cooled solution of Intermediate 3 (202 mg, 0.51 mmol) dissolved in DCM (5.0mL) The reaction mixture was allowed to reach RT and stirred for 4h, diluted with DCM and washed with NaHCCh s.s. The aqueous layer was separated and extracted with DCM, the organic layers were dried over phase separator and concentrated under vacuum affording the title compound (Intermediate 5, 108 mg, 0.542 mmol, quantitative yield) as yellow oil used for the following step without further purification.

[0214] LC-MS Method 1 : tz? = 1.07 min, m / z = 200.3 [M+H]+

[0215] Intermediate 6: (Propyl 3-amino-4-methylthiophene-2-carboxylate)

[0216] Following the same procedure as for Intermediate 5, Intermediate 6 was prepared starting from Intermediate 4 and used for the next step without further purification. (Intermediate 6, 108 mg, 0.526 mmol, quantitative yield). LC-MS Method 1 : t« = 1.09 min, m / z =200.3 [M+H]+

[0217] Intermediate 7 : Isopropyl 2-aminobenzoate

[0218] Tripotassium phosphate (351 mg, 1.65 mmol) and triethyl-(phenylmethyl) ammonium chloride (75 mg, 0.33 mmol) were added to a solution of 2-aminobenzoic acid methyl ester (0.43 mL, 3.31 mmol) in anhydrous propan-2-ol (7 mL, 86.64 mmol) in a microwave vial. The vial was sealed and the reaction mixture was shaken at 90 °C overnight. After cooling to RT, the solvent was removed under reduced pressure and the crude was purified by FCC on Sfar silica (CyHex / EtOAc from 100:0 to 85: 15) to afford the title compound (Intermediate 7, 460 mg, 2.57 mmol, 78% yield).

[0219] LC-MS Method 1 : t« = 1.10 min, m / z =180.3[M+H]+

[0220] Intermediate 8: Methyl 3-cyano-4-methylthiophene-2-carboxylate

[0221] Potassium hexacyanoferrate (II), 0.1N solution (64.1 mL, 6.41 mmol) and tert-butanol (85.1 mL) were added to methyl 3-iodo-4-methyl-thiophene-2-carboxylate (3.1 g, 11.0 mmol), potassium acetate (215.7 mg, 2.2 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphine (1.05 g, 2.2 mmol) and XPhos PD G3 (930.2 mg, 1.1 mmol). Three N2-vacuum cycles were performed and the mixture was stirred for 3 h at 100 °C. Further XPhos PD G3 (460 mg, 0.55 mmol) and potassium hexacyanoferrate (II), 0.1N solution (27 mL, 2.7 mmol) were added at RT under N2 and the reaction mixture was further stirred 5 h at 100 °C. EtOAc was added to the cooled reaction mixture and the organic layer was concentrated under vacuo. The crude was purified by FCC, Sfar silica (CyHex 100% to CyHex / EtOAc 9: 1) to obtain the title compound (Intermediate 8, 850 mg, 4.7 mmol, 43% yield).

[0222] LC-MS Method 1 : ta = 0.82 min, m / z =182.1[M+H]+

[0223] Intermediate 9: Methyl 3-(aminomethyl)-4-methylthiophene-2-carboxylate

[0224] A suspension of Intermediate 8 (850.0 mg, 4.69 mmol), Nickel Raney (50% slurry in water) (27.5 mg, 0.47 mmol) and ammonia (7N in MeOH, 2.0 mL, 14.0 mmol) in MeOH (47 mL) was stirred at RT under hydrogen atmosphere for 36 h at 1 atm. Catalyst was filtered and washed with MeOH, DCM then DCM / MeOH 8:2. The organic phase was evaporated under reduced pressure and the crude was purified by FCC, Sfar silica (DCM 100 % to DCM / MEOH 9: 1) to give the title compound (Intermediate 9, 150 mg, 0.810 mmol, 17% yield).

[0225] LC-MS Method 2: ta = 0.66 min, m / z =186.4[M+H]+

[0226] Intermediate 80 : (3-amino-4-methylthiophen-2-yl)methanol

[0227] To a flask containing a solution of lithium aluminium hydride 2 M in THF (20 mL, 40 mmol) at -15 °C, a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (6.8 g, 40 mmol) in THF (48 mL) was added dropwise over 30 min keeping the temperature between - 15 °C and -10 °C. After 2 h further lithium aluminium hydride 2 M in THF (10 mL, 20 mmol) was added dropwise and the reaction mixture stirred for further 2 h keeping the temperature between - 15 °C and -10 °C. Reaction was quenched at -10 °C by adding 18 mL of water dropwise, then after 5 min, 9 mL of aq. NaOH 15% (w / w). The cooling bath was removed and after 30 min of stirring at RT the suspension was filtered over a celite pad that was washed with THF. The organic layer was evaporated under reduced pressure to afford a solid which was triturated with Et2O to obtain the title compound (Intermediate 80, 4.0 g, 28 mmol, 70% yield).

[0228] LC-MS Method 1: ta = 0.44 min, MS (ESI) m / z = 126.0 [M-H20+H]+

[0229] Intermediate 81: 2-bromo-N-(2-(hydroxymethyl)-4-methylthiophen-3-yl)acetamide

[0230] To a solution of Intermediate 80 (200.0 mg, 1.4 mmol) in DCM (7 mL) at 0°C, TEA (0.48 mL, 3.49 mmol) was added, followed by 2-bromoacetyl bromide (0.26 mL, 2.79 mmol). After 1 hour of stirring at 0°C, the reaction was concentrated to half of its volume, then it was purified by FCC, Sfar silica (from 80:20 to 50:50 CyHex / EtOAc) affording the title compound (Intermediate 81, 142 mg, 0.54 mmol, 38% yield).

[0231] LC-MS Method 1 : tz? = 0.57 min, MS (ESI) m / z = 246.3 / 248.3 [M-H20]+

[0232] 'HNMR (400 MHz, DMSO-d6) 5 ppm 9.67 (br s, 1H), 7.02 (s, 1H), 5.34 (br s, 1H), 4.43 (s, 2H), 4.01 (s, 2H), 2.00 (br s, 3H)

[0233] Intermediate 82: 2-(methoxymethyl)-4-methylthiophen-3-amine

[0234] To a solution of Intermediate 80 (1.96 g, 14 mmol) in THF (91 mL), sodium hydride (60% suspension, 602 mg, 15 mmol) was added at 0 °C. The mixture was stirred at the same temperature for 15 min, then iodomethane (0.94 mL, 16 mmol) was added. The mixture was stirred at 0 °C for 2 h. Water was added and the mixture was extracted with EtOAc (3x). The combined organic fractions were washed with water and brine and concentrated under reduced pressure. The crude was purified by FCC, Sfar silica (from 100% of CyHex to 40:60 CyHex / EtOAc) to obtain the title compound (Intermediate 82, 365 mg, 3.32 mmol, 17% yield).

[0235] LC-MS Method 2: tz? = 0.50 min, MS (ESI) m / z = 158.0 [M+H]+

[0236] Intermediate 83: 2-bromo-N-(2-(methoxymethyl)-4-methylthiophen-3-yl)acetamide

[0237] To a suspension of potassium carbonate (641 mg, 4.63 mmol) and Intermediate 82 (365 mg, 2.32 mmol) in ACN (13 mL), 2-bromoacetyl bromide (0.224 mL, 2.55 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 2 h at RT then it was filtered and concentrated under reduced pressure. The residue was stored at -5°C for one week then it was purified by FCC, Sfar silica (from 100% of CyHex to 40:60 CyHex / EtOAc) affording the title compound (Intermediate 83, 375 mg, 1.35 mmol, 58% yield).

[0238] LC-MS Method 1 : tz? = 0.74 min, MS (ESI) m / z = 246.0 / 248.0 [M-31]+

[0239] 'HNMR (400 MHz, CDCh) 5 7.88 (s, 1H), 6.90 (q, J = 1.10 Hz, 1H), 4.48 (s, 2H), 4.04 (s, 2H), 3.39 (s, 3H), 2.12 (d, J = 1.09 Hz, 3H)

[0240] Intermediate 84: 2-((tert-butyldimethylsilyl)oxy)ethyl 3-amino-4-methylthiophene-2- carboxylate

[0241] To a stirring suspension of 2-((tert-butyldimethylsilyl)oxy)ethan-l-ol (10.5 mL, 52.5 mmol) and sodium hydride (60% suspension, 2.10 g, 52.6 mmol) in THF (35 mL), methyl 3-amino-4- methylthiophene-2-carboxylate (3.00 g, 17.5 mmol) was slowly added at 0°C. The reaction mixture was stirred at RT for 2h. The reaction mixture was neutralized by dropwise addition of glacial acetic acid. The resulting mixture was filtered over a Gooch funnel and the solid was washed with EtOAc. The liquid organic phase was concentrated under reduced pressure to afford a crude that was purified by FCC, Sfar silica (from CyHex 100% to 6:4 CyHex / EtOAc) to obtain the title compound (Intermediate 84, 1.80 g, 5.70 mmol, 33% yield).

[0242] LC-MS Method 1 : tz? = 1.43 min, MS (ESI) m / z = 316.2 [M+H]+

[0243] Intermediate 85: tert-butyl 4-((3-amino-4-methylthiophene-2-carbonyl)oxy) piperidine-l-carboxylate

[0244] To a stirring suspension of tert-butyl 4-hydroxypiperidine-l -carboxylate (6.11 g, 30.4 mmol) and sodium hydride (60% suspension, 1.17 g, 29.2 mmol) in THF (44 mL), methyl 3-amino-4- methylthiophene-2-carboxylate (2.00 g, 11.7 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 5h. The resulting mixture was filtered over a Gooch funnel and the solid was washed with EtOAc. The liquid organic phase was concentrated under reduced pressure to afford a crude that was purified by FCC, Sfar silica (from DCM 100% to 75:25 DCM:ACN) to obtain the title compound (Intermediate 85, 500 mg, 1.46 mmol, 13% yield).

[0245] LC-MS Method 1: ta = 1.19 min, MS (ESI) m / z = 285.1 [M -57]+

[0246] Intermediate 86: 2-methoxyethyl 3-amino-4-methylthiophene-2-carboxylate To a solution of 3-amino-4-methylthiophene-2-carboxylic acid (900 mg, 5.73 mmol) in DMF (20 mL), potassium carbonate (1.58 mg, 11.5 mmol) was added followed by l-bromo-2- methoxyethane (0.54 mL, 5.7 mmol) at RT. After 4 h water was added and the mixture extracted with EtOAc (3x). The collected organic layers were washed with BRINE, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC, Sfar silica (from 100% CyHex to CyHexZEtOAc 90: 10) to obtain the title compound (Intermediate 86, 824 mg, 3.83 mmol, 67% yield).

[0247] LC-MS method 1 : ty? = 0.85 min, MS (m / z) = 216.0 [M+H]+

[0248] Intermediate 10: Methyl 3-(2-bromoacetamido)-4-methylthiophene-2-carboxylate

[0249] 2-bromoacetyl bromide (6.1 mL, 70.90 mmol) was added dropwise to a stirred suspension of methyl 3-amino-4-methylthiophehene-2-carboxylate (10.0 g, 58.4 mmol) in water (235 mL) cooled to 0 °C then the reaction was allowed to warm to rt and stirred overnight. Further 2- bromoacetyl bromide (5.08 mL, 58.40 mmol) was added at 0 °C and the reaction mixture was stirred for 5 h at rt. The solid formed was filtered, washed with water and dried under high vacuum to obtain the title compound (Intermediate 10, 15 g, 51.34 mmol, 88% yield) as an off-white powder.

[0250] LC-MS Method 1 : ty? = 0.82 min, m / z =292.1-294.1[M+H]+

[0251] The following intermediates have been prepared analogously to the procedure described for Intermediate 10, starting from the suitable starting materials.

[0252]

[0253] Intermediate 27: methyl 2-(2-chloroacetamido)4,5,6,7 tetrahydrobenzo[b]thiophene3- carboxylate

[0254] 2-chloroacetyl chloride (0.17 mL, 2.19 mmol) was added dropwise to a solution of 2-amino- 4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid methyl ester (420 mg, 1.99 mmol) and TEA (0.31 mL, 2.19 mmol) in DCM (15.78 mL) cooled to 0 °C, then the reaction was allowed to warm to rt. After 1 h stirring at rt, the reaction mixture was washed with water, the layers were separated and the combined aqueous phases were washed with DCM. The organic phases were combined, dried over a phase separator, concentrated under high vacuum affording the crude title compound (Intermediate 27, 585 mg, 2.03 mmol, quantitative yield) as a yellow powder. The product was used in the next step without further purification.

[0255] LC-MS Method 2: tR = 1.13 min, m / z =288.03 [M+H]+

[0256] The following intermediates have been prepared analogously to the procedure described for Intermediate 27, starting from the suitable starting materials.

[0257] Intermediate 95: methyl 4-(2-chloroacetamido)-5-cyanothiophene-3-carboxylate

[0258] To a suspension of methyl 4-amino-5-cyanothiophene-3-carboxylate (300 mg, 1.65 mmol) in 1,4-dioxane (3 mL), 2-chloroacetyl chloride (0.13 mL, 1.65 mmol) was added. The reaction was stirred at 100 °C for 16 h. The resulting solution was diluted with water and extracted with EtOAc (3x). The organic phase was dried using a phase separator and concentrated under reduced pressure to afford a crude that was purified by FCC on Sfar amino (CyHex 100% to CyHex / EtOAc 70:30) affording the title compound (Intermediate 95, 322 mg, 1.24 mmol, 76 % yield).

[0259] LC-MS Method 1 : tz? = 0.75 min, m / z = 259.4 [M+H]+

[0260] Intermediate 39: methyl 3-(2-(azepan-l-yl)acetamido)-4-methylthiophene-2- carboxylate

[0261] Homopiperidine (3.5 mL, 30.8 mmol) was added to a stirred solution of Intermediate 10 (3.03 g, 10.3 mmol) in ACN (34 mL) and the mixture was stirred 2 h. The solvent was concentrated under high vacuum and the crude mixture was purified by FCC on Sfar amino (CyHex 100% to CyHex / EtOAc 1 :9) affording the title compound (Intermediate 39, 2.6 g, 8.38 mmol, 82 % yield) as colorless oil.

[0262] LC-MS Method 1 : ta = 0.48 min, m / z = 311.3 [M+H]+

[0263] The following intermediates have been prepared analogously to the procedure described for Intermediate 39, starting from the suitable starting materials.

[0264]

[0265]

[0266]

[0267]

[0268] Intermediate 66: 2-(dimethylamino)-N-(2-(methoxymethyl)benzyl)acetamide

[0269] To a solution of 2-(dimethylamino) acetic acid (273 mg, 2.65 mmol) in DMF (4 mL), 3- (ethyliminomethylideneamino)-N,N-dimethyl-l-propanamine hydrochloride (761 mg, 3.97 mmol) and 1 -hydroxybenzotriazole hydrate (405 mg, 2.65 mmol) were added. The mixture was stirred for 15 min then [2-(Methoxymethyl)phenyl]methanamine (400 mg, 2.65 mmol) was added and the reaction was stirred overnight at RT. The reaction mixture was diluted with NaHCCh s.s. and extracted with EtOAc. The organic layer was separated, dried over a phase separator and concentrated under reduced pressure. The crude was purified by FCC, Sfar amino (EtOAc 100% to EtOAc:MeOH 90: 10 ) then by FCC reverse phase, Sfar C18 (water / NFUOH 0.1%) 100% to (water / NFUOH 0.1%) / ACN 7:3) to afford the title compound (Intermediate 66, 176 mg, 0.745 mmol, 28% yield).

[0270] LC-MS Method 2: tz? = 0.69 min, m / z = 237.3 [M+H]+

[0271] Intermediate 67: methyl 3-(2-(azepan-l-yl)acetamido)thiophene-2-carboxylate

[0272] To a suspension of methyl 3-Amino-2-thiophenecarboxylate (1.5 g, 9.54 mmol) and potassium carbonate (3.9 g, 28.63 mmol) in ACN (29 mL), 2-bromoacetyl bromide (0.83 mL, 9.54 mmol) was slowly added at 0°C .The reaction was allowed to stir at RT for 2h then homopiperidine (1.1 mL, 9.54 mmol) was added and the reaction mixture was further stirred at RT for 45 min. Volatiles were removed under reduced pressure and the crude was purified by FCC, Sfar amino (CyHex 100% to CyHex / EtOAc 1 : 1) to obtain the title compound (Intermediate 67, 1.8 g, 6.07 mmol, 64% yield).

[0273] LC-MS Method 1 : tz? = 0.54 min, m / z = 297.2 [M+H]+ Intermediate 113: tert-butyl 4-((3-(2-(azepan-l-yl)acetamido)-4-methylthiophene-2- carbonyl)oxy)piperidine-l-carboxylate

[0274] 2-bromoacetyl bromide (0.14 mL, 1.62 mmol) was added dropwise at 0 °C to a stirred suspension of Intermediate 85 (515 mg, 1.47 mmol) and potassium carbonate (405 mg, 2.94 mmol) in ACN (8 mL). Then the reaction was allowed to warm to RT and stirred for 2 h. Then azepane (0.17 mL, 1.47 mmol) was added and, after 2 h of stirring at RT, the solid was removed by filtration and the liquid phase concentrated to afford title compound (Intermediate 113, 600 mg, 1.25 mmol, 85% yield).

[0275] LC-MS Method 1 : tz? = 0.75 min, m / z = 480.2 [M+H]+

[0276] Intermediate 68: methyl 3-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-l- yl)acetamido)-4-methylthiophene-2-carboxylate

[0277] To a stirred solution of Intermediate 54 (825 mg, 2.64 mmol) in DCM (21 mL), tert-butyl- chloro-dimethylsilane (597 mg, 3.96 mmol) was added at 0°C and the mixture was stirred overnight at rt. Water and EtOAc were added to the reaction mixture, the organic layer was separated and the aqueous was extracted with EtOAc. The solvent was removed under reduced pressure and the crude was purified by FCC Sfar amino (100% of CyHex to CyHex / EtOAc 2:8) to afford the title compound (Intermediate 68, 470 mg, 1.10 mmol, 42 % yield) as a colorless oil.

[0278] LC-MS Method 1 : tz? = 0.85 min, m / z = 427.2 [M+H]+

[0279] Intermediate 69: methyl 4-methyl-3-(2-(piperazin-l-yl)acetamido)thiophene-2- carboxylate hydrochloride

[0280] To a stirred solution of Intermediate 64 (490 mg, 1.23 mmol) in 1,4-dioxane (3 mL) HC1 4 M in 1,4-dioxane (3.1 mL, 12.4 mmol) was added dropwise at rt. After 6 h further HC1 4 M in 1,4- dioxane (1.2 mL, 4.8 mmol) was added. The reaction mixture was stirred overnight, volatiles were removed under reduced pressure and the crude was triturated with DCM to afford the title compound (Intermediate 69, 241 mg, 0.722 mmol, 58 % yield).

[0281] LC-MS Method 1 : tz? = 0.42 min, m / z = 298.2 [M+H]+

[0282] Intermediate 70: ethyl 4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2- oxoethyl)piperazine-l-carboxylate

[0283] To a stirred solution of Intermediate 69 (241.0 mg, 0.72 mmol) in ethanol (6.0 mL), sodium carbonate (267.8 mg, 2.53 mmol) and ethyl chloroformate (0.08 mL, 0.80 mmol) were added and the reaction mixture was stirred 4 h at rt. Volatiles were removed under reduced pressure and the residue was partitioned between water and EtOAc. The collected organic layers were dried over Na2SO4, filtered and concentrated to obtain the crude title compound (Intermediate 70, 200 mg, 0.54 mmol, 75 % yield), used for the following step without further purification.

[0284] LC-MS Method 1: ta = 0.64 min, m / z = 370.3 [M+H]+

[0285] Intermediate 71: 3-(2-(azepan-l-yl)acetamido)-4-methylthiophene-2-carboxylic acid

[0286] Intermediate 39 (4.5 g, 14.5 mmol) was dissolved in THF (50 mL), water (9 mL) and sodium hydroxide 2 M in water (8.7 mL, 17.4 mmol) were added and the reaction mixture was heated at 50°C overnight. The pH was adjusted adding aq HC1 2M at 0°C until pH = 7, and volatiles were removed under reduced pressure to afford the title compound (Intermediate 71, 5.0 g, 14.1 mmol, 97 % yield) as an orange solid.

[0287] LC-MS Method 1 : tz? = 0.43 min, m / z = 297.1 [M+H]+

[0288] Intermediate 72: 2-(azepan-l-ylmethyl)-7-methyl-4H-thieno[3,2-d] [l,3]oxazin-4-one

[0289] To a suspension of Intermediate 71 (500.0 mg, 1.41 mmol) in anhydrous ACN (13 mL), 1- methylimidazole (0.34 mL, 4.23 mmol) was added. The suspension was cooled to 0°C, TCFH (435 mg, 1.55 mmol) was added and the reaction mixture was allowed to reach RT and stirred 1 h. The solid was filtered and washed with ACN to afford the title compound (Intermediate 72, 450 mg, 1.617 mmol) as a white solid used for the following step without further purification.

[0290] LC-MS Method 1 : tz? = 0.49 min, m / z = 279.1 [M+H]+

[0291] Intermediate 73: tert-butyl 3-(2-(azepan-l-yl)acetamido)-4-methylthiophene-2- carboxylate

[0292] A stirred suspension of Intermediate 71 (6.30 g, 16.0 mmol) in toluene (113 mL), was refluxed for 15 min. To the resulting solution, l,l-di-tert-butoxy-N,N-dimethylmethanamine (7.66 mL, 32.0 mmol) was added dropwise. The reaction was stirred at reflux for 24 h. The solvent was evaporated to yield a crude mixture that was purified by FCC, Sfar amino(100% CyHex to CyHex / (DCM / EtOAc 1 : 1) 8:2) to afford the title compound (Intermediate 73, 3.15 g, 8.9 mmol, 56 % yield).

[0293] LC-MS Method 1 : tz? = 0.65 min, MS (ESI) m / z = 353.2 [M+H]+

[0294] Intermediate 74: cyclopropyl 3-(2-(azepan-l-yl)acetamido)-4-methylthiophene-2- carboxylate

[0295] To a solution of cyclopropanol (27 mg, 0.47 mmol) in THF (2 mL) under nitrogen atmosphere at 0°C, sodium hydride (60% suspension, 19 mg, 0.47 mmol) was added. After 2 min Intermediate 72 (100 mg, 0.36 mmol) was added and the reaction mixture was stirred at 0°C for 1 h. Water (5 mL) was added and the reaction mixture was extracted with EtOAc. The collected organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by FCC, Sfar amino (CyHex:EtOAc from 8:2 to 100% EtOAc) to afford the title compound (Intermediate 74, 50 mg, 0.15 mmol, 41% yield).

[0296] LC-MS Method 1 : tz? = 0.55 min, m / z = 337.3 [M+H]+

[0297] Intermediate 114: 4-((tert-butoxycarbonyl)amino)butyl 3-(2-(azepan-l-yl)acetamido)- 4-methylthiophene-2-carboxylate

[0298] To a solution of tert-butyl (4-hydroxybutyl)carbamate (0.40 mL, 2.16 mmol) in ACN (7 mL) under nitrogen atmosphere at 0°C, sodium hydride (60% suspension, 86 mg, 2.16 mmol) was added. After 5 min, Intermediate 72 (606 mg, 2.16 mmol) was added at 0°C, then the reaction mixture was stirred at RT for 12 h. Volatiles were removed under reduced pressure and the residue was purified by FCC, Sfar silica (CyHex:(EtOAc / EtOH 3: 1 v / v) from 100:0 to 40:60) to afford the title compound (Intermediate 114, 530 mg, 1.13 mmol, 53% yield).

[0299] LC-MS Method 1 : tz? = 0.69 min, m / z = 468.4 [M+H]+

[0300] Intermediate 115: 3-(2-(4,4-dimethylpiperidin-l-yl)acetamido)-4-methylthiophene-2- carboxylic acid

[0301] Following the procedure described as for Intermediate 71 and starting from Intermediate 52 (2.20 g, 6.30 mmol), the title compound was obtained (Intermediate 115, 2.40 g, quant. Yield).

[0302] LC-MS Method 1 : tz? = 0.52 min, MS (ESI) m / z = 311.2 [M+H]+

[0303] Intermediate 116: 2-((4,4-dimethylpiperidin-l-yl)methyl)-7-methyl-4H-thieno[3,2- d] [l,3]oxazin-4-one

[0304] Following the procedure described as for Intermediate 72 and starting from Intermediate 115 (2.20 g, 7.09 mmol), the title compound was obtained (Intermediate 116, 1.70 g, 8.65 mmol, 82 % yield).

[0305] LC-MS Method 1 : t« = 0.51 min, MS (ESI) m / z = 293.3 [M+H]+ Intermediate 117: oxetan-3-yl 3-(2-(4,4-dimethylpipendin-l-yl)acetamido)-4- methylthiophene-2-carboxylate

[0306] To a solution of oxetan-3-ol (84 mg, 1.13 mmol) in ACN (1 mL) under nitrogen atmosphere at 0°C, sodium hydride (60% suspension, 45 mg, 1.13 mmol) was added. After 5 min, Intermediate 116 (300 mg, 1.03 mmol) was added and the reaction mixture was stirred at 0°C for 15 min then it was allowed to reach RT. After 4 h, aqueous phosphate buffer pH = 7 (10 mL) was added and the reaction mixture was extracted with EtOAc. The collected organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by FCC, Sfar amino (CyHex:EtOAc from 9: 1 to 7:3) to afford the title compound (Intermediate 117, 120 mg, 0.33 mmol, 32% yield).

[0307] LC-MS Method 1: ta = 0.51 min, m / z = 367.2 [M+H]+

[0308] Intermediate 118: tetrahydro-2H-pyran-4-yl 3-(2-(4,4-dimethylpiperidin-l- yl)acetamido)-4-methylthiophene-2-carboxylate

[0309] Following the procedure followed as for Intermediate 117 and starting from Intermediate 116 (300 mg, 1.03 mmol) and tetrahydro-2H-pyran-4-ol (115 mg, 1.13 mmol) the title compound was obtained (Intermediate 118, 191 mg, 0.48 mmol, 47 % yield).

[0310] LC-MS Method 1 : tz? = 0.58 min, MS (ESI) m / z = 395.4 [M+H]+

[0311] Intermediate 75: 4-((tert-butyldimethylsilyl)oxy)-l-(2-(isoxazol-3-ylamino)-2- oxoethyl)-l-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidin- 1 -in m To a stirred solution of Intermediate 68 (240 mg, 0.56 mmol) in ACN (4 mL), Intermediate 18 (123 mg, 0.56 mmol) was added. The mixture was stirred at 55 °C for 24h. The reaction mixture was concentrated under reduced pressure and the crude was purified through FCC, Sfar amino, (from 0% to 5% of MeOH in DCM) affording the title compound (Intermediate 75, zwitterion, mixture of diastereoisomers, 90 mg, 0.163 mmol, 29 % yield) as a colorless oil.

[0312] LC-MS Method 2: tz? = 1.10 min, m / z = 551.3 [M+H]+

[0313] Intermediate 76: 4-((tert-butyldimethylsilyl)oxy)-l-(2-((2-(methoxycarbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)-l-(2-((4-methylisoxazol-3-yl)amino)-2- oxoethyl)piperidin-l-ium formate

[0314] To a stirred solution of Intermediate 68 (200 mg, 0.47 mmol) in ACN (3 mL), Intermediate 16 (120.2 mg, 0.52 mmol) was added. The mixture was stirred at 80 °C overnight then it was concentrated under reduced pressure. The residue was purified by FCC, Sfar amino (100% DCM to DCM:MeOH 96:4). The resulting impure compound was further purified by FCC, Sfar C18 (water + 0.1% HCOOH / ACN 95:5 to water + 0.1% HCOOH / ACN 6:4) affording the title compound (Intermediate 76, formate salt, mixture of diastereoisomers, 51 mg, 0.082 mmol, 17% yield).

[0315] LC-MS Method 1 : tz? = 0.88 min, m / z = 565.4 [M+H]+

[0316] Intermediate 77: methyl 3-((2-(azepan-l-yl)acetamido)methyl)-4-methylthiophene-2- carboxylate

[0317] To a suspension of Intermediate 9 (150 mg, 0.81 mmol) and TEA (0.12 mL, 0.89 mmol) in ACN (4.5 mL), 2-bromoacetyl bromide (0.07 mL, 0.81 mmol) was added dropwise at 0 °C. Then the reaction was allowed to warm to RT and stirred for 20 min. Homopiperidine (0.46 mL, 4.05 mmol) was added at RT to the reaction mixture and after stirring for 3 h volatiles were removed under reduced pressure. The crude was purified by FCC, Sfar silica (100% DCM to DCM / MeOH 95:5) to obtain the title compound (Intermediate 77, 170 mg, 0.52 mmol, 65% yield).

[0318] LC-MS Method 2: tz? = 1.05 min, m / z = 325.5 [M+H]+

[0319] Intermediate 119: tert-butyl 2-(4,4-dimethylpiperidin-l-yl)acetate

[0320] In a two-neck round bottom flask, to a stirred solution of 4,4-dimethylpiperidine hydrochloride (0.77 g, 5.13 mmol) in anhydrous DCM (25 mL), potassium carbonate (1.42 g, 10.3 mmol) was added followed by tert-butyl 2-bromoacetate (0.76 mL, 5.1 mmol) and the mixture was stirred at RT overnight. After this time, NaHCCh aq. Sat. sol. was added and the mixture was extracted DCM (3x). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to obtain the title compound (Intermediate 119, 1.0 g, 4.40 mmol, 86% yield).

[0321] 'H NMR (400 MHz, DMSO) 5 3.09 (s, 2H), 2.46 (dd, J = 6.6, 4.7 Hz, 4H), 1.41 (s, 9H), 1.34 - 1.26 (m, 4H), 0.89 (s, 6H)

[0322] Intermediate 120 : 2-(4,4-dimethylpiperidin-l-yl)acetic acid hydrochloride

[0323] Intermediate! 19 (1.0 g, 4.4 mmol) was dissolved in HC1 (4 M in 1,4-dioxane, 22 mL, 88 mmol) and the resulting solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the title compound (Intermediate 120, 913 mg, 4.39 mmol, 99% yield).

[0324] XH NMR (400 MHz, DMSO) 5 4.11 (s, 2H), 3.26 (s, 4H), 1.79 - 1.43 (m, 4H), 0.98 (s, 6H)

[0325] Intermediate 121: 2-(4,4-dimethylpiperidin-l-yl)-N-(l-(pyrimidin-2- yl)cyclopropyl)acetamide

[0326] To a suspension of Intermediate 120 (100 mg, 0.48 mmol) in EtOAc (5 mL), TEA (0.27 mL, 1.93 mmol) and T3P (50% solution in EtOAc, 0.290 mL, 0.48 mmol) were added. After 5 minutes of stirring l-(pyrimidin-2-yl)cyclopropan-l -amine hydrochloride (99 mg, 0.58 mmol) was added and the mixture was stirred at RT for 3 hours. Then T3P (50% solution in EtOAc, 0.290 mL, 0.48 mmol) was added and the mixture was stirred at RT overnight. Then T3P (50% solution in EtOAc, 0.29 mL, 0.48 mmol) was added. After 3 hours of stirring at RT the mixture was heated at 50°C for 2 hours. The mixture was cooled down to RT and diluted with EtOAc and water. The two phases were separated and the organic phase was washed with BRINE. The water phase was extracted with DCM:iPrOH (2 / 1 v / v) (x3). Collected organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by FCC Sfar amino (CyHex from 100% to CyHex / EtOAc 40:60) to obtain the title compound (Intermediate 121, 76 mg, 0.26 mmol, 55% yield) as a white solid.

[0327] LC-MS Method 2: tz? = 0.75 min, MS (ESI) m / z =289.2 [M+H]+

[0328] Intermediate 122: 2-(azepan-l-yl)-N-(3-phenyloxetan-3-yl)acetamide

[0329] To a suspension of 2-(azepan-l-yl)acetic acid hydrochloride (573 mg, 2.96 mmol) and TEA (1.31 mL, 9.43 mmol) in EtOAc (25 mL) at RT, T3P (50% solution in EtOAc, 1.92 mL, 3.23 mmol) was added drop-wise, followed by 3-phenyloxetan-3-amine hydrochloride (500 mg, 2.69 mmol) and the reaction mixture was stirred at RT for 22 h. Then the reaction mixture was partitioned between EtOAc and NaHCOi aq. Sat. sol. Phases were separated and the organic one was washed with NaHCOi aq. sat. sol. and concentrated under reduced pressure. The residue was purified by FCC, Sfar silica (from CyHex 100% to 3 :7 CyHex / EtOAc) to obtain the title compound (Intermediate 122, 277 mg, 0.96 mmol, 36% yield).

[0330] LC-MS Method 1 : tz? = 0.40 min, MS (ESI) (m / z) = 289.6 [M+H]+

[0331] Intermediate 123: 2-(4,4-dimethylpiperidin-l-yl)-N-(l-(pyridin-2- yl)cyclopropyl)acetamide

[0332] To a solution of Intermediate 120 (511 mg, 2.46 mmol) in DMF (9 mL), HATU (1.10 g, 2.91 mmol) was added. After 5 minutes a solution of l-(pyridin-2-yl)cyclopropan-l -amine (300 mg, 2.24 mmol) in DMF (2 mL) was added followed by DIPEA (0.233 mL, 1.34 mmol) and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and water, phases were separated and the organic one was washed with NaHCO3 aq. Sat. sol. then with water. The organic layer was dried over Na2SO4 filtered and concentrated under reduced pressure. The residue purified by FCC, Sfar amino (from CyHex 100% to 60:40 CyHex / EtOAc) affording the title compound (Intermediate 123, 487 mg, 1.69 mmol, 76% yield). LC-MS method 2: tR= 0.82 min, MS (ESI) m / z = 288.1 [M+H]+

[0333] Intermediate 124: N-(3-phenyloxetan-3-yl)-2-(piperidin-l-yl)acetamide

[0334] To a suspension of 2-(piperidin-l-yl)acetic acid hydrochloride (145 mg, 0.81 mmol) in ACN (7 mL), 1 -methylimidazole (0.20 mL, 2.5 mmol) and DIPEA (0.28 mL, 1.62 mmol) were added. The suspension turned into a homogeneous solution. Then TCFH (249 mg, 0.89 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 15 min. After that time 3-phenyloxetan-3- amine hydrochloride (150 mg, 0.81 mmol) was added and the reaction mixture was stirred at RT overnight. Volatiles were evaporated, then the water was added and the mixture was extracted with DCM. Collected organic phases were filtered through a phase separator and concentrated under reduced pressure. The residue was purified through FCC Sfar silica (from 100% of CyHex60 4:6 CyHex / EtOAc) to obtain the title compound (Intermediate 124, 163 mg, 0.59 mmol, 74% yield).

[0335] ‘H NMR (400 MHz, DMSO-d6) 5 1.34 - 1.47 (m, 2H), 1.57 (p, J = 5.6 Hz, 4H), 2.42 (t, J = 5.4 Hz, 4H), 2.94 (s, 2H), 4.69 (d, J = 6.8 Hz, 2H), 4.89 (d, J = 6.8 Hz, 2H), 7.24 - 7.33 (m, 1H), 7.34 - 7.44 (m, 2H), 7.48 - 7.57 (m, 2H), 8.77 (s, 1H)

[0336] Intermediate 125: (3-(2-chloroacetamido)-4-methylthiophen-2-yl)methyl 2- chloroacetate

[0337] To a solution of Intermediate 80 (1.0 g, 7.0 mmol) in DCM (28 mL) at 0°C, TEA (2.14 mL, 15.4 mmol) was added, followed by 2-chloroacetyl chloride (1.17 mL, 14.7 mmol) and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM and water, the two phases were separated and the organic one was washed with a NaHCO3 aq. sat. sol. and concentrated. The residue was purified by FCC, Sfar silica (from CyHex 100% to 60:40 CyHex / EtOAc) affording the title compound (Intermediate 125, 1.54 g, 5.2 mmol, 75% yield).

[0338] LC-MS Method 1 : tz? = 0.88 min, MS (ESI) m / z = 294.1 / 296.1 [M-H]-

[0339] Intermediate 126: 2-(4,4-dimethylpiperidin-l-yl)-N-(2-(hydroxymethyl)-4- methylthiophen-3-yl)acetamide

[0340] To a suspension of Intermediate 125 (770 mg, 2.60 mmol) in ACN (25 mL) atRT, potassium carbonate (1.44 g, 10.4 mmol) and 4,4-dimethylpiperidine hydrochloride (856 mg, 5.72 mmol) were added. The reaction mixture was stirred at RT overnight. The mixture was evaporated to dryness and the residue was dissolved with MeOH (25 mL), then potassium carbonate (1.44 mg, 10.4 mmol) was added and the mixture was stirred at RT overnight. Then the solid was filtered off and the organic phase was concentrated affording a crude that was purified by FCC, Sfar amino (from CyHex 100% to 60:40 CyHex / EtOAc), to obtain the title compound (Intermediate 126, 423 mg, 1.43 mmol, 55% yield).

[0341] LC-MS Method 2: ty? = 0.92 min, MS (ESI) m / z = 297.4 [M+H]+

[0342] Intermediate 127 : 2-(4,4-dimethylpiperidin-l-yl)-N-(2-formyl-4-methylthiophen-3- yl)acetamide

[0343] To a stirred solution of Intermediate 126 (820 mg, 2.77 mmol) in DCM (16 mL), manganese(IV)oxide (1.20 g, 13.8 mmol) was added at 0°C. The mixture was stirred at RT for 8 h. Further manganese(IV)oxide (721 mg, 8.30 mmol) was added and the mixture was stirred at RT overnight. Then it was filtered on a celite pad that was washed with DCM. The filtered organic phase was concentrated affording the title compound (Intermediate 127, 700 mg, 2.38 mmol, 88% yield).

[0344] LC-MS Method 2: tz? = 1.01 min, MS (ESI) m / z = 295.1 [M+H]+

[0345] Intermediate 128: 2-(4,4-dimethylpiperidin-l-yl)-N-(4-methyl-2-

[0346] ((methylamino)methyl)thiophen-3-yl)acetamide

[0347] To a stirred solution of Intermediate 127 (300 mg, 1.02 mmol) in MeOH (3.0 mL), TEA (0.21 mL, 1.53 mmol) and methanamine hydrochloride (103 mg, 1.53 mmol) were added and the mixture was stirred at RT overnight. After this time the reaction mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4.0 mL). Then sodium borohydride (51 mg, 1.35 mmol) was added at 0°C and the reaction mixture was stirred at RT for 2 h. After this time water and DCM were added. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure affording the title compound (Intermediate 128, 180 mg, 0.58 mmol, 43% yield).

[0348] LC-MS method 2: ta = 0.92 min, MS (ESI) m / z = 310.2 [M+H]+

[0349] Intermediate 129: tert-butyl ((3-(2-(4,4-dimethylpiperidin-l-yl)acetamido)-4- methylthiophen-2-yl)methyl)(methyl)carbamate

[0350] To a stirred solution of Intermediate 128 (180 mg, 0.582 mmol) in MeOH (3.0 mL), triethylamine (0.162 mL, 1.16 mmol), N,N-dimethyl-4-pyridinamine (7 mg, 0.06 mmol) and di- tert-butyl dicarbonate (152 mg, 0.67 mmol) were added. The mixture was stirred at RT for 3h. After this time water was added and the reaction was extracted with DCM. The collected organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified through column by FCC, Sfar amino (from CyHex 100% to 60:40 CyHex / EtOAc) affording the title compound (Intermediate 129, 118 mg, 0.044 mmol, 50% yield).

[0351] LC-MS Method 1 ta = 0.75 min, MS (ESI) m / z = 410.3 [M+H]+

[0352] Intermediate 130: l-(2-((2-((4-((tert-butoxycarbonyl)amino)butoxy)carbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)-l-(2-(isoxazol-3-ylamino)-2-oxoethyl)azepan-l- mm

[0353] To a stirred solution of Intermediate 114 (265 mg, 0.57 mmol) in ACN (1.4 mL), Intermediate 18 (117 mg, 0.57 mmol) was added. The mixture was stirred at 70 °C for 24h in a sealed vial. The reaction mixture was concentrated under reduced pressure and the residue was purified through FFC, Sfar-amino (from 0% to 40% of EtOAc / EtOH (3: 1 v / v) in DCM) affording the title compound (Intermediate 130, zwitterion, 117 mg, 0.20 mmol, 35% yield) as a off-white solid.

[0354] LC-MS Method 1 : tz? = 0.70 min, m / z = 592.8 [M]+

[0355] The following intermediates have been prepared analogously to the procedure described for Intermediate 130, starting from the suitable starting materials.

[0356] Example 1 : l,l-bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2- oxoethyl)azepan-l-ium bromide

[0357] To a stirred solution of Intermediate 10 (190.14 mg, 0.640 mmol) in ACN (2 mL), Intermediate 39 (200.0 mg, 0.640 mmol) was added. The mixture was stirred at 80 °C for 24h in a sealed vial. The reaction mixture was concentrated under reduced pressure and the residue was purified through FFC, Sfar Cl 8 (from 0% to 100% of ACN in H2O) affording the title compound (Example 1, 131 mg, 0.217 mmol, 34% yield) as a off-white solid.

[0358] LC-MS Method 2: ty? = 1.06 min, m / z = 522.3 [M]+

[0359] 'HNMR (400 MHz, DMSO-d6) 5 ppm 13.01 - 15.38 (m, 2 H), 7.38 (s, 2 H), 4.47 (s, 4 H), 3.71 - 3.90 (m, 4 H), 3.68 (s, 6 H), 1.92 - 2.11 (m, 4 H), 1.89 (s, 6 H), 1.57 - 1.76 (m, 4 H).

[0360] The following examples have been prepared analogously to the procedure described for

[0361] Example 1, starting from the suitable starting materials.

[0362]

[0363]

[0364] Example 67 as zwitterion: (lr,4r)-4-fluoro-l-(2-((2-(methoxycarbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)-4-methyl-l-(2-((4-methylisoxazol-3-yl)amino)-2- oxoethyl)piperidin-l-ium (diastereoisomer 1 trans) and Example 98 as zwitterion: (ls,4s)-4-fluoro-l-(2-((2-(methoxycarbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)-4-methyl-l-(2-((4-methylisoxazol-3-yl)amino)-2- oxoethyl)piperidin-l-ium

[0365] Example 65 (mixture of diastereoisomers, 43 mg, 0.092 mmol) was separated by chiral preparative HPLC (Method Chiral HPLC 1) to afford diastereoisomer 1 and diastereosomer 2. Example 67, diastereoisomer 1, trans, as zwitterion: 23 mg, 0.049 mmol, 54% yield, 100% d.e., as a off-white solid.

[0366] LC-MS Method 1 : tz? = 0.56 min, m / z = 467.4 [M]+

[0367] 'H NMR (500 MHz, DMSO-d6) 5 ppm 12.47 (br s, 1 H), 8.25 (s, 1 H), 7.50 (s, 1 H), 4.61 (s, 2 H), 4.42 (s, 2 H), 3.84 - 3.98 (m, 3 H), 3.74 (s, 3 H), 3.64 - 3.79 (m, 1 H), 2.25 - 2.41 (m, 2 H), 2.04 (s, 3 H), 1.98 - 2.09 (m, 2 H), 1.78 (d, J=1.0 Hz, 3 H), 1.46 (d, J=21.6 Hz, 3 H) Example 98, diastereoisomer 2, cis, as zwitterion: 7 mg, 0.015 mmol, 16% yield, 100% d.e., as a off-white solid.

[0368] LC-MS Method 1 : tz? = 0.59 min, m / z = 467.3 [M]+

[0369] 'H NMR (400 MHz, DMSO-d6) 5 12.12 (br s, 1H), 8.21 (s, 1H), 7.54 (s, 1H), 4.68 (s, 2H), 4.34 (s, 2H), 3.97 (br d, J = 12.2 Hz, 2H), 3.78 - 3.64 (m, 5H), 2.47 - 2.23 (m, 2H), 2.05 (s, 3H), 2.11 - 1.96 (m, 2H), 1.79 (s, 3H), 1.45 (d, J = 21.7 Hz, 3H)

[0370] Example 75 as zwitterion: (ls,4s)-l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((2- (methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4- (trifluoromethyl)piperidin-l-ium and

[0371] Example 99 as zwitterion: (lr,4r)-l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((2- (methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4- (trifluoromethyl)piperidin-l-ium

[0372] To a stirred solution of Intermediate 98 (1.30 g, 4.69 mmol) in ACN (23 mL), Intermediate 10 (1.37 g, 4.69 mmol) was added. The mixture was stirred at 80 °C for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was purified through FFC, Sfar amino (from 0% to 5% of MeOH in DCM) affording the desired product as mixture of diastereoisomers (299 mg, 0.61 mmol). The mixture was separated by chiral preparative HPLC (Method Chiral HPLC 2) to afford diastereoisomer 1 and diastereosomer 2.

[0373] Diastereoisomer 1 was purified through FFC, Sfar amino (from 0% to 5% of MeOH in DCM) affording the title compound as zwitterion (Example 75, diastereoisomer 1, cis, as zwitterion, 85 mg, 0.17 mmol, 4% yield, 100% d.e.) as a off-white solid.

[0374] LC-MS Method 1 : tz? = 0.61 min, m / z = 489.2 [M]+

[0375] 'H NMR (500 MHz, CDCh) 5 ppm 8.20 (d, J=1.6 Hz, 1 H), 7.15 (d, J=1.0 Hz, 1 H), 6.85 (d, J=1.6 Hz, 1 H), 4.63 (br s, 2 H), 4.53 (br s, 2 H), 4.21 (br d, J=13.2 Hz, 2 H), 3.80 (s, 3 H), 3.65 - 3.76 (m, 2 H), 2.52 - 2.64 (m, 1 H), 2.14 - 2.30 (m, 7 H)

[0376] Diastereoisomer 2 was purified by crystallization from DCM affording the title compound as zwitterion (Example 99, diastereoisomer 2, trans, as zwitterion, 75 mg, 0.15 mmol, 3% yield, 100% d.e.) as a off-white solid.

[0377] LC-MS Method 1 : tz? = 0.58 min, m / z = 489.2 [M]+

[0378] 'H NMR (500 MHz, CDCh) 5 ppm 8.20 (d, J=1.6 Hz, 1 H), 7.13 (d, J=1.0 Hz, 1 H), 6.85 (d, J=1.5 Hz, 1 H), 4.58 (s, 2 H), 4.47 (s, 2 H), 4.34 (br d, J=12.9 Hz, 2 H), 3.79 (s, 3 H), 3.45 - 3.56 (m, 2 H), 2.48 (d, J=11.4 Hz, 1 H), 2.30 - 2.42 (m, 2 H), 2.22 (s, 3 H), 2.15 - 2.24 (m, 2 H) Example 94: l-(2-((2-(hydroxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-l- (2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-l-ium chloride

[0379] To a stirred solution of Intermediate 81 (100 mg, 0.38 mmol) in ACN (1.9 mL), Intermediate 39 (130 mg, 0.38 mmol) was added. The mixture was stirred at 80 °C for 18 h in a sealed vial. The reaction mixture was concentrated under reduced pressure and the residue was purified through FFC, Sfar amino (from 0% to 3% of MeOH in DCM) affording the desired product as zwitterion. This was dissolved in DCM (1.0 mL) and HC1 2 M in Et2O (0.5 mL, 1 mmol) was added at RT under stirring. After 5 min, volatiles were removed under reduced prssure to afford title compound as chloride salt (Example 94, 146 mg, 0.28 mmol, 73% yield) as a off-white solid. LC-MS Method 1 : tz? = 0.85 min, m / z = 494.4 [M]+

[0380] 'H NMR (500 MHz, DMSO-d6) 5 ppm 10.58 (br s, 1H), 10.14 (br s, 1H), 7.58 (br s, 1H), 7.04 (d, J = 0.8 Hz, 1H), 5.39 (br t, J = 5.3 Hz, 1H), 4.67 (br s, 4H), 4.46 (d, J = 4.9 Hz, 2H), 4.00 - 3.82 (m, 4H), 3.75 (s, 3H), 2.07 (br s, 3H), 2.04 - 1.98 (m, 7H), 1.77 - 1.60 (m, 4H)

[0381] The following examples have been prepared analogously to the procedure described for Example 94, starting from the suitable starting materials, and have been isolated as chloride salts.

[0382]

[0383] Example 3: 2-((3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)- N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2- oxoethan-l-aminium formate

[0384] To a stirred solution of potassium iodide (5 mg, 0.03 mmol) and Intermediate 40 (80 mg, 0.27 mmol) in ACN (1 mL), Intermediate 10 (79 mg, 0.27 mmol) was added. The resulting solution was stirred at 55 °C overnight in a sealed vial. The reaction mixture was concentrated at residue was purified by FCC on Sfar C18 (from (H2O+0.1% HCOOH) 100% to (H2O+0.1% HCOOH) / ACN 6:4). Pure fractions were combined and concentrated under reduced pressure at 30°C. The residue dissolved in H2O+ACN 1 : 1 and was freeze-dried overnight affording the title compound (Example 3: 53 mg, 0.09 mmol, 35 % yield) as pale yellow powder.

[0385] LC-MS Method 3 : tz? = 2.62 min, m / z = 508.4 [M]+

[0386] 'H NMR (500 MHz, DMSO-d6) 5 ppm 10.71 (br s, 1 H), 8.32 (s, 1 H), 7.58 (s, 1 H), 4.84 (br s, 2 H), 4.45 (br s, 2 H), 3.74 (s, 3 H), 3.69 (s, 3 H), 3.46 (s, 6 H), 2.51 - 2.70 (m, 4 H), 2.03 (s, 3 H), 1.60 - 1.80 (m, 4 H). The following examples wereprepared analogously to the procedure described for Example

[0387] 3, starting from the suitable starting materials.

[0388] Example 42: 4-hydroxy-l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((2-

[0389] (methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidin-l-ium chloride

[0390] Intermediate 75 (36 mg, 0.065 mmol) was dissolved in DCM (1 mL) and HC1 2 M in Et20 (0.7 mL, 1.4 mmol) was added dropwise at RT. After stirring 24 h at rt, volatiles were evaporated to afford the title compound (Example 42, mixture of diastereoisomers, 19 mg, 0.04 mmol, 62% yield).

[0391] LC-MS Method 1 : ty? = 0.52 min, m / z = 437.1 [M]+

[0392] JH NMR (500 MHz, DMSO-d6) 5 ppm 11.76 (br s, 1H), 10.84 - 10.31 (m, 1H), 8.88 (d, J = 1.6 Hz, 1H), 7.58 (s, 1H), 6.92 (d, J = 1.5 Hz, 1H), 5.28 - 5.20 (m, 1H), 4.81 - 4.67 (m, 4H), 4.03 - 3.91 (m, 2H), 3.88 (br s, 3H), 3.76 - 3.68 (m, 3H), 2.26 - 2.06 (m, 2H), 2.01 (s, 3H), 1.94 - 1.78 (m, 2H).

[0393] Example 63: 4-hydroxy-l-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2- oxoethyl)-l-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidin-l-ium chloride

[0394] Intermediate 76 (51 mg, 0.08 mmol) was dissolved in DCM (1.5 mL) and HC1 2 M in Et2O (1.8 mL, 1.8 mmol) was added dropwise at RT. After 24 h at volatiles were evaporated and the solid was residue redissolved in DCM / MeOH then the solvents were removed under reduced pressure affording the title compound (Example 63, mixture of diastereoisomers, 24 mg, 0.05 mmol, 60% yield) as a pale yellow solid.

[0395] LC-MS Method 1 : tz? = 0.51 min, m / z = 451.3 [M]+

[0396] ‘HNMR (400 MHz, DMSO-d6) 5 ppm 11.00 (brd, J=4.4 Hz, 1 H), 10.50 (s, 1 H), 8.68 (s, 1 H), 7.60 (s, 1 H), 5.24 (dd, J=12.8, 3.0 Hz, 1 H), 4.65 - 4.89 (m, 4 H), 3.79 - 4.09 (m, 5 H), 3.75 (d, J=1.0 Hz, 3 H), 2.05 (s, 3 H), 1.91 (s, 3 H), 1.77 - 2.28 (m, 4 H).

[0397] Example 44: 4-(2-(isoxazol-3-ylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)morpholin-4-ium formate

[0398] Activated molecular sieves were added to a mixture of Intermediate 55 (100 mg, 0.34 mmol), Intermediate 18 (78.8 mg, 0.34 mmol), 2,6-bis(l,l-dimethylethyl)pyridine (26 mg, 0.15 mmol) in ACN (2 mL) and the reaction mixture was stirred at 60 °C for 24h. After this time the mixture was concentrated under reduced pressure and the residue was purified by FCC, Sfar amino (from 100% DCM to DCM / (DCM / MeOH 9: 1) 5:95) then by FCC, Sfar C18 (H2O + HCOOH 0.1% / ACN 95:5 to H2O + HCOOH 0.1% / ACN 60:30) to afford the title compound (Example 44, 8 mg, 0.016 mmol, 10% yield) as a white solid.

[0399] LC-MS Method 1: ta = 0.49 min, m / z = 423.2 [M]+

[0400] 'HNMR (500 MHz, DMSO-d6) 5 ppm 8.75 (s, 1 H), 8.40 (s, 1 H), 7.56 (s, 1 H), 6.90 (s, 1 H), 4.88 (br s, 2 H), 4.80 (br s, 2 H), 4.01 - 4.15 (m, 4 H), 3.90 - 3.99 (m, 4 H), 3.70 (s, 3 H), 2.03 (s, 3 H).

[0401] Example 60: l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((2-(methoxycarbonyl)-4- methylthiophen-3-yl)amino)-2-oxoethyl)piperazin-l-ium chloride hydrochloride

[0402] Example 58 (35 mg, 0.067 mmol) was dissolved in 1,4-dioxane (0.116 mL) and HC1 4 M in 1,4-dioxane (0.145 mL, 0.581 mmol) was added dropwise at rt. After 24 h at rt volatiles were evaporated, the solid residue was dissolved in DCM / MeOH then dried to afford the title compound (Example 60, 20 mg, 0.04 mmol, 60% yield) as a pale yellow solid.

[0403] LC-MS Method 2: tR = 0.63 min, m / z = 422.2 [M]+

[0404] 1HNMR (400 MHz, DMSO-d6) 5 ppm 11.89 (s, 1 H), 10.80 (s, 1 H), 9.14 - 10.30 (m, 2 H), 8.90 (d, J=1.5 Hz, 1 H), 7.59 (s, 1 H), 6.92 (s, 1 H), 4.97 (s, 2 H), 4.92 (s, 2 H), 4.09 - 4.33 (m, 4

[0405] H), 3.71 (s, 3 H), 3.57 - 3.83 (m, 4 H), 2.05 (s, 3 H).

[0406] Example 96: l-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophen-3-yl)amino)-2- oxoethyl)-l-(2-(isoxazol-3-ylamino)-2-oxoethyl)azepan-l-ium chloride hydrochloride

[0407] Intermediate 130 (117 mg, 0.174 mmol) was dissolved in DCM (3.0 mL) and HC1 2 M in Et2O (1.7 mL, 3.48 mmol) was added dropwise atRT. After 16 h, a solid was formed. Liquid phase was removed and the solid was triturated with DCM affording the title compound (Example 96, 92 mg, 0.163 mmol, 94% yield) as a colorless solid.

[0408] LC-MS Method 1 : t« = 0.38 min, m / z = 246.9 [(M+H) / 2]+; 492.4 [M]+

[0409] 'HNMR (400 MHz, DMSO-d6 ) 5 ppm 8.89 (d, J = 1.8 Hz, 1H), 7.58 (s, 1H), 13.16 - 7.12 (m, 5H), 6.91 (d, J = 1.5 Hz, 1H), 4.87 - 4.67 (m, 4H), 4.16 (t, J = 6.0 Hz, 2H), 4.07 - 3.75 (m,

[0410] 4H), 2.81 (t, J = 7.2 Hz, 2H), 2.21 - 1.90 (m, 7H), 1.79 - 1.52 (m, 8H).

[0411] The following examples have been prepared analogously to the procedure described for Example 96, starting from the suitable intermediate.

[0412] Desalification of the salt forms of the compounds of the invention to obtain the corresponding zwitterionic forms may be performed as described for the following Example 89.

[0413] Example 89 as zwitterion: 6-(2-(isoxazol-3-ylamino)-2-oxoethyl)-6-(2-((2- (methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octan-6-ium Example 89 as formate salt (37 mg, 0.070 mmol) was purified by FCC on Sfar amino (from DCM 100% to DCM / MeOH 95:5) affording the title compound (Example 89 as zwitterion, 25 mg, 0.052 mmol, 74 % yield) as a white powder.

[0414] LC-MS Method 1 : tz? = 0.66 min, m / z = 483.4 [M]+

[0415] 'H NMR (400 MHz, DMSO-d6 ) 5 ppm 13.00 (s, 1H), 8.65 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.48 (ddd, J = 1.3, 7.1, 8.1 Hz, 1H), 7.33 (ddd, J = 1.0, 7.1,

[0416] 8.0 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.48 (s, 2H), 3.98 - 3.79 (m, 4H), 3.75 (s, 3H), 1.95 - 1.64 (m, 4H), 0.47 (s, 4H)

[0417] Conversion of the zwitterionic forms of the compounds of the invention into the corresponding salt forms may be performed as described for the following Example 89 as chloride salt.

[0418] Example 89 as chloride salt: 6-(2-(isoxazol-3-ylamino)-2-oxoethyl)-6-(2-((2-

[0419] (methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octan-6-ium chloride Example 89 as zwitterion (18 mg, 0.037 mmol) was dissolved in DCM (2.0 mL) and HC1 2 M in Et20 (28 pL, 0.056 mmol) was added dropwise at RT. After 5 min volatiles were removed under reduced pressure affording the title compound (Example 89 as chloride salt, 20 mg, 0.037 mmol, quant, yield) as a white powder. LC-MS Method 1 : ta = 0.65 min, m / z = 483 A [M]+

[0420] 'H NMR (400 MHz, DMSO-d6 ) 5 ppm 12.45 - 10.43 (m, 2H), 8.90 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.58 (ddd, J= 1.1, 7.1, 8.2 Hz, 1H), 7.49 - 7.35 (m, 1H), 6.96 (d, J = 1.2 Hz, 1H), 4.93 (s, 2H), 4.84 (s, 2H), 4.11 - 3.88 (m, 4H), 3.80 (s, 3H), 2.04 - 1.67 (m, 4H), 0.51 (br s, 4H) The following examples have been prepared analogously to the procedure described for

[0421] Example 89 as chloride salt, starting from the suitable Example as zwitterionic forms.

[0422] Example 40 as bromide salt: l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((2- (methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-l-ium bromide

[0423] Example 40 as zwitterion (65 mg, 0.15 mmol) was dissolved in DCM (2.0 mL) and HBr 2 M in H2O (400 pL, 0.8 mmol) was added dropwise at RT. After 4 h volatiles were removed under reduced pressure affording the title compound (Example 40 as bromide salt, 77 mg, 0.15 mmol, quant, yield) as a white powder.

[0424] LC-MS Method 1 : tR = 0.60 min, m / z = 449.2 [M]+

[0425] 1HNMR (600 MHz, DMSO-d6) 5 ppm 11.76 (1 H, s), 10.53 (1 H, br s), 8.89 (1 H, d, J=1.61 Hz), 7.59 (1 H, s), 6.93 (1 H, d, J=1.47 Hz), 4.82 (4 H, br d, J=6.90 Hz), 3.88 (4 H, br s), 3.71 (3

[0426] H, s), 2.03 (3 H, s), 1.75 (4 H, br s), 1.10 (3 H, s), 1.07 (3 H, s)

[0427] Comparative compounds Ci and C2 were prepared as described below.

[0428] Ci is characterized by having a phenyl ring replacing the ester- substituted tiophene or benzothiophene ring of the compounds of the invention.

[0429] C2 is characterized by having a different heteroaryl ring replacing the ester-substituted tiophene or benzothiophene ring of the compounds of the invention.

[0430] Compound Ci: N,N-bis(phenylcarbamoylmethyl)dimethylammonium chloride (aka Carcainium chloride) was prepared as described in WO99 / 63985, pag. 6.

[0431] Compound C2: l-(2-(isoxazol-3-ylamino)-2-oxoethyl)-l-(2-((5-(methoxy carbonyl)-3- methylisoxazol-4-yl)amino)-2-oxoethyl)azepan-l-ium (zwitterion)

[0432] To a stirred solution of Intermediate 79 (40 mg, 0.180 mmol) in ACN (1.2 mL), Intermediate 46 (50 mg, 0.180 mmol) was added. The mixture was stirred at RT for 24h. Then the mixture was concentrated under reduced pressure and the residue was purified by FCC, Sfar amino, (0-5% MeOH in DCM) affording the title compound (Compound C2: 57 mg, 0.114 mmol, 75% yield).

[0433] LC-MS Method 2: tz? = 0.52 min, MS (ESI) m / z = 420.1 [M]+

[0434] 'HNMR (500 MHz, DMSO-d6) 5 ppm 12.25 - 14.42 (m, 1 H), 8.76 (d, J=1.6 Hz, 1 H), 6.92 (d, J=1.6 Hz, 1 H), 4.61 (s, 2 H), 4.14 (s, 2 H), 3.74 (s, 3 H), 3.68 - 3.85 (m, 4 H), 2.11 (s, 3 H),

[0435] I.93 (br s, 4 H), 1.63 (br s, 4 H)

[0436] PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION hNav 1.7 cellular assay Protocol

[0437] Representative examples of the invention were tested for intracellular and extracellular inhibition of NaV 1.7 in the automated patch clamp assay herein described.

[0438] Cell Culture

[0439] CHO cells stably expressing human NaV 1.7 channel were obtained from B’SYS GmbH, Switzerland. Cells were cultured in F12 Nutmix (Gibco, Carlsbad CA) supplemented with 10% Fetal Bovine Serum (Invitrogen, Waltham MA), 1% Penicillin-Streptomycin (Gibco, Carlsbad CA) and 200 pg / ml Hygromycin B (Invitrogen, Waltham MA). Cells were grown and maintained at 37 °C in a humidified environment containing 5% CO2 in air. Cells were detached from the culture flask for passage and harvested using TrypLE Express (Sigma-Aldrich, St. Louis, MO). Experiment flasks were prepared with 2-4 days cells without antibiotics and used with -80% confluency. Before experiments, cells were washed with Ca2+and Mg2+free PBS and detached with pre-warmed TrypLE Express. After a brief centrifugation step, cells were resuspended in CHO-S-Serum Free Media II (Life Technologies, Carlsbad CA). Cells were counted and the final concentration was set at 3-4 million cells per mL.

[0440] Patch Clamp Solutions & Drugs

[0441] The intracellular solution (or internal solution) contained the following: 140 mM CsF, 10 mM NaCl, 1 mM EGTA and 10 mM HEPES, adjusted to pH 7.2 with CsOH, and osmolarity to 325 with sucrose. The extracellular solution (or external solution) contained the following: 40 mM NMDG, 100 mMNaCl, 4 mMKCl, 1 mMMgCh, 2 mM CaCh, 10 mM HEPES, lO mM glucose, adjusted to pH 7.4 with HC1 and osmolality to 310 with sucrose. All chemicals were from Sigma- Aldrich, St. Louis, MO.

[0442] For both intracellular and extracellular application of test compounds, the spotted compound was dissolved in the intracellular and extracellular solution respectively and tested up to 60 pM, which results in a pICso not lower than 4.2 value.

[0443] Automated Patch Clamp Assay Protocol

[0444] Automated Patch Clamp was performed on Qube 384 (Sophion Bioscience A / S, Ballerup, Denmark) with multihole QChips at a temperature setting of 22 °C. The whole cell configuration was formed with default Qube seal and break-in parameter. The membrane potential was held at - 100 mV before the voltage protocol began. The voltage protocol consisted of 20 pulse protocols with 30 sweeps for intracellular and 55 sweeps for extracellular applications for both pre- and postcompound applications. Cells were held at -100 mV with a depolarizing pulse to -20 mV for 10 ms. The interval between sweeps was set at 9 s when the holding potential was -100 mV.

[0445] Internal Block by Test Compounds (intracellular inhibition)

[0446] For intracellular application of the compounds, the QChip was removed from the recording chamber. The intracellular solution was replaced with the solution containing the test compound. After the intracellular solution exchange, QChip was placed back in the recording chamber and the voltage pulses were applied.

[0447] Data filtering was performed by Sophion Analyzer software. Only wells with minimum 40 MQ seal resistance and 1 nA pre-compound current were used for further analysis using Aplus software. The average of the peak current amplitude of the 20th pulse of the last three trains applied in pre-compound and post-compound were calculated. For each well, post- / pre-compound ratios were calculated. The results were then normalized to 0.3% DMSO control, which was considered as 0%, and to full block (100 pM N-(2,6-dimethylphenylcarbamoylmethyl)tri ethylammonium chloride, aka QX314, for internal application), considered as 100% inhibition. The values of % activity were plotted and concentration response curves were fitted using the 4-parameters logistic Hill equation. From the fitted curves, ICso values were estimated and intracellular pICso values calculated.

[0448] External Block by Test Compounds (extracellular inhibition)

[0449] For extracellular application of the compounds, the extracellular solution was replaced with the solution containing the test compound. After the extracellular solution exchange, voltage pulses were applied.

[0450] Data filtering was performed by Sophion Analyzer software. Only wells with minimum 50 MQ seal resistance and 1 nA pre-compound current were used for further analysis using Aplus software. The average of the peak current amplitude of the 20th pulse of the last three trains applied in pre-compound and post-compound were calculated. For each well, post- / pre-compound ratios were calculated.

[0451] The results were then normalized to 0.3% DMSO control, which was considered as 0%, and to full block (300 pM tetracaine for external application), considered as 100% inhibition. The values of % activity were plotted and concentration response curves were fitted using the 4- parameters logistic Hill equation. From the fitted curves, ICso values were estimated and extracellular pICso values calculated.

[0452] A pICso of < 4.2 was obtained when the inhibition was minor or equal to 50% at the maximum compound concentration tested of 60 pM.

[0453] Intracellular and Extracellular inhibition data for representative Examples are reported in

[0454] Table 2.

[0455] Table 2 - Intracellular and Extracellular inhibition for representative Examples, hNav 1.7

[0456] As it can be appreciated, the compounds of Table 2, i.e. compounds according to the invention, show a high intracellular inhibitory activity on NaV 1.7 receptor. Conversely, the compounds of Table 2 show a lower extracellular inhibitory activity on NaV 1.7 receptor.

[0457] Table 3 shows inhibition data for selected Examples that were tested both in their zwitterionic and salt (chloride) forms. As it can be appreciated, both forms possess high intracellular inhibitory activity on NaV 1.7 receptor. Negligible variations were observed between corresponding zwitterionic and salt forms in some instances, that can be considered within the experimental error range.

[0458] Table 3 - Comparison of Intracellular and Extracellular inhibition for representative

[0459] Examples in zwitterionic or salt form, hNav 1.7 Accordingly, the compounds of the invention, in both zwitterionic and salt forms, may be used for treating respiratory diseases such as, for example, cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), and in particular chronic cough.

[0460] Comparative Compounds Compounds Ci and C2 were tested in the same binding assay described above and their intracellular and extracellular pICso are reported in Table 4.

[0461] Table 4 - Intracellular and Extracellular inhibition for Comparative Compounds

[0462] As shown in Table 2, 3 and 4 (Example 25), the compounds of formula (I) of the present invention show an intracellular inhibitory activity on NaV 1.7 expressed as pICso value higher than 5, between 5 and 5.5, higher than 5.5 or between 5.5 and 6.

[0463] These data show that, unlike the comparative Compound Ci, the presence of an estersubstituted thiophene or benzothiophene ring in the compounds of the present invention causes unexpectedly and notably a significant increase in the intracellular inhibitory activity on NaV 1.7 and increases the difference between NaV 1.7 intracellular and extracellular inhibition, reported in Table 2, 3 and 4 as DELTA.

[0464] Furthermore, as indicated in the same section of the experimental part, the reported data show that, contrary to the comparative Compound C2, the presence of the ester-substituted thiophene ring, in place of a different heteroaryl ring, in the compounds of the present invention, in particular in Example 25, unexpectedly and noticeably determines a significant increase in the intracellular inhibitory activity on the NaV 1.7 receptors and increases the difference between NaV 1.7 intracellular and extracellular inhibition (DELTA). hERG assay Protocol

[0465] The effect of test substances on the human Ether-a-go-go-Related Gene (hERG) tail current was assessed in automated patch clamp protocol by QPatch instrument (Sophion Bioscience A / S, Ballerup, Denmark).

[0466] Cell Culture hERG was expressed in HEK293 cells upon induction with tetracycline.

[0467] Cells were cultured in minimum essential medium (MEM) supplemented with 10% heat inactivated Fetal Bovine Serum, 1% Non-essential Amino Acids, 1% Sodium Pyruvate, 2mM L- Glutamine, 1% Penicillin-Streptomycin, 15pg / ml Blasticidin and lOOpg / ml Hygromycin. hERG cells were induced with 10 pg / ml Tetracycline for 24 to 72 h before recording.

[0468] Before experiments, cells were washed with Dulbecco's Phosphate Buffered Saline (DPBS), without calcium and without magnesium, detached with TrypLE and then triturated in serum-free media containing 25 mM HEPES and Soybean Trypsin inhibitor to resuspend the cells and to break apart cell aggregates. Cells were counted and the final concentration was set at 4-6 million cells per mL. All chemicals for cell culture were from Life Technologies Italia Sri, Monza, Italy.

[0469] Patch Clamp Solutions & Drugs

[0470] The intracellular solution contained the following (in mM): KC1 130, MgCh 1, EGTA 5, MgATP 5, HEPES 10, pH 7.2 with 1 M KOH.

[0471] The external solution contained the following (in mM): NaCl 137; KC1 4; CaCh 1.8; MgCh 1; d-glucose 10; HEPES 10; pH 7.4 with NaOH.

[0472] All chemicals for patch clamp solutions were from Merck Life Science Sri, Milano, Italy.

[0473] To evaluate the degree of external block, compounds were first dissolved in DMSO and then diluted in extracellular buffer to achieve final test concentrations of 0.6 pM, 6 pM, 60 pM, in 0.3% DMSO.

[0474] Voltage Protocol

[0475] Single hole QPlate chips (Sophion Bioscience, Denmark) were used for voltage clamp experiments. The membrane potential was held at -80 mV before the voltage protocol began. The voltage protocol included the following sequential steps: -50 mV for 200 ms, +20 mV for 4.8 s, -50 mV for 5 s, then back to holding potential. hERG tail current was measured during the repolarisation step to -50 mV from +20 mV. Every voltage protocol sweep lasted 15 s and was continuously repeated at a frequency of 0.066 Hz during the experiment. Liquid Protocol

[0476] External solution then vehicle solution, corresponding to 0.3% DMSO in external solution, were applied for 3 min 45 s each, to reach a stable current recording. Then, three increasing concentrations (0.6, 6 and 60 pM in 0.3% DMSO) of the test compound were applied for 5 min each. Data Analysis

[0477] Average tail current was measured from last four voltage sweeps during each compound application protocol and used to calculate the % inhibition, compared to vehicle pre-treatment, for every tested concentration in every cell, using Sophion Analyser software (Sophion Bioscience, Denmark). ICso values were estimated using Hill Fit equation in Sophion Analyser software.

Claims

1. Compound of formula (I) (I), where at least one of Y and Z is S and the other is CR4; R1 and R2 are independently selected from the group consisting of -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C 10 )heterocycloalkyl, where the specified -(C3-C 10 )heterocycloalkyl is optionally substituted with one or more groups selected from halogen, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl; R3 and R4 are independently H or selected from the group consisting of CN, -(C1-C6)alkyl and aryl, or if Y is CR4, R3 and R4 are fused together to form aryl; R5 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R 7, -(C1-C6)alkyl-OR 6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C 10 )heterocycloalkyl and -(C3-C7)cycloalkyl; R6 and R7 are independently H or selected from the group consisting of -(C1-C6)alkyl and -(C1-C6)alkyl-aryl; L1 is a bond or is selected from the group consisting of -(C1-C6)alkylene-, -(C1-C6)heterocycloalkylene- and -(C1-C6)cycloalkylene-; and A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-C 10 )cycloalkyl and -(C3-C 10 )heterocycloalkyl, where any of such aryl, heteroaryl, -(C3-C 10 )cycloalkyl or -(C3-C 10 )heterocycloalkyl is optionally substituted with one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7; provided that when L1 is a bond, any of such aryls is not substituted with -(C1-C6)alkyl; in the form of a zwitterion or a pharmaceutically acceptable salt.

2. A compound of formula (I) according to claim 1, wherein Z, Y, R1, R2, R3, R 4, R 5,R6 and R7 are as defined in paragraph 1; L1 is selected from the group consisting of -(C1-C6)alkylene-, -(C1-C6)heterocycloalkylene- and -(C1-C6)cycloalkylene-; and A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-C 10 )cycloalkyl and -(C3-C 10 )heterocycloalkyl, where any of such aryl, heteroaryl, -(C3-C 10 )cycloalkyl or -(C3-C 10 )heterocycloalkyl is optionally substituted with one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; in the form of a zwitterion or a pharmaceutically acceptable salt.

3. A compound of formula (I) according to claim 1, wherein L1 is a bond represented by formula (Ia) (Ia) Where Z, Y, R1, R2, R3, R 4, R 5, R 6, and R7 are as defined in paragraph 1; and A is a ring selected from the group consisting of aryl, heteroaryl, -(C3-C 10 )cycloalkyl and -(C3-C 10 )heterocycloalkyl, where any of such heteroaryl, -(C3-C 10 )cycloalkyl or -(C3-C 10 )heterocycloalkyl is optionally substituted with one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; and wherein any of such aryl is optionally substituted with one or more groups selected from halogen, -C(O)OR6, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; in the form of a zwitterion or a pharmaceutically acceptable salt.

4. A connection according to any of the preceding paragraphs, where R1 and R2 are independently selected from the group consisting of -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C 10 )heterocycloalkyl, where the specified -(C3-C 10)heterocycloalkyl is optionally substituted with one or more groups selected from halogen, -OR6, -(C1-C6)alkyl and -C(O)OR6-; R3 and R4 are independently H or -(C1-C6)alkyl, or if Y is CR4, R3 and R4 are fused together to form aryl; R5 is selected from the group consisting of -(C1-C6)alkyl and -(C3-C6)cycloalkyl; in the form of a zwitterion or a pharmaceutically acceptable salt.

5. A connection according to any of the preceding paragraphs, where R1 and R2 are condensed together to form -(C3-C 10 )heterocycloalkyl, where the specified -(C3-C 10 )heterocycloalkyl is optionally substituted with one or more groups selected from -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl; in the form of a zwitterion or a pharmaceutically acceptable salt.

6. A connection according to any of the preceding paragraphs, where R3 and R4 independently represent H or -(C1-C6)alkyl; in the form of a zwitterion or a pharmaceutically acceptable salt.

7. A connection according to any of the preceding paragraphs, where Z is S and Y is CH, or Z is CH and Y is S, and R3 is H or methyl; in the form of a zwitterion or a pharmaceutically acceptable salt.

8. A connection according to any of the preceding paragraphs, where A is heteroaryl, optionally substituted with one or more groups selected from halogen, -OR6, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-NR6R7, and -(C1-C6)alkyl-C(O)NR6R7.

9. The compound according to claim 1, selected from the group consisting of: 1,1-bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ium (Example 1); 2-((3-carbamoyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl (Primary 2); 2-((3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane (1-amisoethyl)-N-3); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-(pyrimidine-5-ylamino)ethyl)ethane-1-aminium (Case 4); 2-(isoquinoline-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Case 5); 2-(benzylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Case 6); 2-(isoxazole-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Case 7); 2-((cyclohexylmethyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 8); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-amine (Primer 9); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 10); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)ethane-1-aminium (Example 11); 2-(benzylamino)-N,N-dimethyl-N-(2-((4-methyl-2-(propoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-2-oxoethane-1-aminium (Example 12); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 13); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N,N-dimethyl-N-(2-((2-methylbenzyl)amino)-2-oxoethyl)-2-oxoethane-1-aminium (Example 14); 2-(benzylamino)-N-(2-((2-(isopropoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 15); 2-((2,6-dimethylbenzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 16); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 19); 2-(((2,3-dihydro-1H-inden-2-yl)methyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 20); 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 22); 1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 23); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-(((5-(methoxycarbonyl)thiophen-3-yl)methyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 24); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 25); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-((2-(methoxymethyl)benzyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 26); 1-(2-((2-((2-(benzylamino)-2-oxoethoxy)carbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(benzylamino)-2-oxoethyl)azepan-1-ia (Example 27); 1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(tert-butoxycarbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 28); 1,1-bis(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 29); 2-((2-(isopropoxycarbonyl)benzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethane-1-aminium (Example 30); 1,1-bis(2-((2-(methoxycarbonyl)benzo[b]thiophene-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 31); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophene-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 32); 1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 33); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 34); 1,1-bis(2-((4-(methoxycarbonyl)-2-methylthiophene-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 35); 1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 36); (R)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophene-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azepan-1-ia (Case 37); (R)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azepan-1-ia (Case 38); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 39); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ia (Example 40); 1-(2-((2-(tert-butoxycarbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)azepan-1-ia (Example 41); 4-hydroxy-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 42); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-4-methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 43); 4-(2-(isoxazole-3-ylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)morpholin-4-ium (Example 44); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-5-phenylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 45); (R)-1-(2-((5-(tert-butyl)-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azepan-1-ia (Case 46); 4-(2-(benzylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)thiomorpholin-4-ium (Case 47); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylcyclopropyl)amino)ethyl)azepan-1-ia (Example 50); 7-(2-(benzylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonan-7-ia (Example 51); (S)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)pyrrolidin-1-ium (Example 52); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)pyrrolidin-1-ium (Example 53); 7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonan-7-ia (Primary 55); 4-(ethoxycarbonyl-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazin-1-ium (Example 56); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N,N-dimethyl-N-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)-2-oxoethane-1-aminium (Example 57); 4-(tert-butoxycarbonyl-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperazine-1-ium (Example 58); 2-(isoxazole-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-bis(2-methoxyethyl)-2-oxoethane-1-aminium (Case 59); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperazin-1-ia (Example 60); 4-methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 62); 4-hydroxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 63); 1-(2-((2-(cyclopropoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 64); 4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-methyl-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 65); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((3-methylisothiazol-5-yl)amino)-2-oxoethyl)azepan-1-ia (Example 66); (2-((1r,4r)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-ia-1-yl)acetyl)(4-methylisoxazol-3-yl)amide (Primary 67); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidin-1-ium (Example 68); 2,2-difluoro-7-(2-(isoxazole-3-ylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7-ia (Primer 69); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetan-3-yl)amino)ethyl)piperidin-1-ium (Example 70); 4,4-difluoro-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 71); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ia (Example 72); 1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((4-methyl-2-((piperidin-4-yloxy)carbonylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 73); 1-(2-((2-((2-hydroxyethoxy)carbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ium (Example 74); (1s,4s)-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidin-1-ium (Primer 75); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-(pyrazine-2-ylamino)ethyl)piperidin-1-ium (Example 76); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ium (Example 77); 2-(2-(isoxazol-3-ylamino)-2-oxoethyl)-2-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)isoindolin-2-ium (Example 78); 1-(2-((4-cyano-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ium (Example 79); 1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-1-(2-((2-((2-methoxyethoxy)carbonyl-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ium (Example 80); 1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((oxetan-3-yloxy)carbonylthiophen-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 81); 1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-(((tetrahydro-2H-pyran-4-yl)oxy)carbonylthiophen-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 82); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyridin-2-yl)cyclopropyl)amino)ethyl)piperidin-1 (Primer 83); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-(pyrimidine-5-ylamino)ethyl)piperidin-1-ium (Example 84); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((methylamino)methyl)thiophene-3-yl)amino)-2-oxoethyl)piperidine (Primeria-85); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((3-methylpyrazine-2-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 86); 1-(2-((4-chloroisoxazol-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ium (Example 87); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetan-3-yl)amino)ethyl)azepan-1-ia (Case 88); 6-(2-(isoxazole-3-ylamino)-2-oxoethyl)-6-(2-((2-(methoxycarbonyl)benzo[b]thiophene-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octan-6-ium (Case 89); 1-(2-(benzylamino)-2-oxoethyl)-4,4-bis(hydroxymethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidin-1-ium (Example 90); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyrimidin-2-yl)cyclopropyl)amino)ethyl)piperidin-1 (Primer 91); 1-(2-((5-(methoxycarbonyl)-3-methylisoxazol-4-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine (Primera-1-92); 1-(2-((3,4-dimethylisoxazol-5-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ia (Example 93); 1-(2-((2-(hydroxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azepan-1-ia (Example 94); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-((6-methoxypyrazine-2-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidin-1-ium (Example 95); 1-(2-((2-((4-aminobutoxy)carbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)azepan-1-ia (Example 96); 1-(2-((2-((4-aminobutoxy)carbonyl-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(benzylamino)-2-oxoethyl)azepan-1-ia (Case 97); (2-((1s,4s)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-ium-1-yl)acetyl)(4-methylisoxazol-3-yl)amide (Primary 98); and (1r,4r)-1-(2-(isoxazole-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidin-1-ium (Primer 99); in the form of a zwitterion or pharmaceutically acceptable salt.

10. Use of an intermediate compound selected from the group consisting of compound (III), (V), (VII) and (X) for the preparation of a compound of formula (I) according to any one of claims 1 to 9 where R1, R2, R3, R5, L1 and A are as defined in paragraphs 1-9, and X2 is halogen, preferably chlorine or bromine.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, in admixture with one or more pharmaceutically acceptable carriers or excipients.

12. A pharmaceutical composition according to claim 11, formulated for administration by inhalation.

13. A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 11 or 12 for use as a medicine.

14. A compound of formula (I) or a pharmaceutical composition for use according to claim 13 for the prevention and / or treatment of diseases, disorders or conditions associated with sodium channel receptor mechanisms.

15. A compound of formula (I) or a pharmaceutical composition for use according to claim 13 or 14 for the prevention and / or treatment of diseases of the respiratory system selected from cough, subacute or chronic cough, treatment-resistant cough, refractory chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

16. A compound of formula (I) or a pharmaceutical composition for use according to claim 15 for the prevention and / or treatment of chronic cough.

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