Heterocyclic derivatives as janus kinase inhibitors

Abstract

The present invention relates to a compounds that are cyclic and spiro-cyclic carbamate benzylmethansulfonamide derivatives of general formula (Io) inhibiting the JAK family of non- receptor tyrosine protein kinases (JAK1, JAK2, JAK3, and TYK2); methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of diseases or conditions associated with a dysregulation of the JAK family non-receptor kinases; in particular for the treatment of various inflammatory disease including asthma, COPD and other respiratory diseases.

Description

[0001] HETEROCYCLIC DERIVATIVES AS JANUS KINASE INHIBITORS FIELD OF THE INVENTION The present invention relates to chemical compounds that are cyclic and spiro-cyclic oxooxazolidine benzylmethansulfonamides derivatives useful as JAK inhibitors, such as JAK 1, useful for the treatment of various inflammatory disease including asthma, COPD and other respiratory diseases. BACKGROUND OF THE INVENTION The JAK family consists of non-receptor tyrosine protein kinases and has four main members, JAK1, JAK2, JAK3, and TYK2. More than 50 cytokines and growth factors bind to type I and II receptors noncovalently associated with different combinations of JAK kinases. The signalling triggered by the ligands consists in tyrosine phosphorylation of receptors by JAK and recruitment of one or more STATs proteins. Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus through the nuclear membrane to regulate specific genes. JAKs have seven homology domains (the JAK homology domain, JH). Starting from the carboxyl terminus, JH1 is the first JH, known as the kinase domain, and is composed of approximately 250 amino acid residues. JH1 encodes a kinase protein that constitutes the kinase structure domain that phosphorylates a substrate; JH2 is a pseudokinase domain which regulates the activity of the kinase domain. JAK3 is expressed in the bone marrow and lymphatic system, as well as endothelial cells and vascular smooth muscle cells; other members are expressed in almost all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26;6(1):402). Many cellular processes are downstream JAK / STAT signalling: hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis. Different biological responses are regulated by specific pairing of JAK isoforms. JAK1 / JAK3 combination mediates IL-2, -4, -7, -9, -15, and -21 signalling that is relevant for growth / maturation of lymphoid cells, differentiation / homeostasis of T-cells / NK cells, B-cell class switching and other inflammatory processes. Combinations of JAK1 / TYK2-JAK1 / JAK2, regulate the signal associated with the innate immune response, such as IL-6 and the type I interferons, involved into naïve T cell differentiation, T cell homeostasis, granulopoiesis and other inflammatory processes. (Howell MD et al., Front. Immunol. 2019, 10, 2342). JAK2 frequently associates with itself (JAK2 / JAK2) controlling the signalling of various cytokines and growth factors, such as IL-3, IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Hodge et al., Clin Exp Rheumatol 2016; 34(2):318-28). Genetically modified mouse models and human diseases prove the importance of JAK / STAT pathways in immune fitness. In particular, overexpression or mutations involving some JAK isoforms as well as aberrant JAK / STAT signalling drive malignancies of hematopoietic and lymphoid tissues as well as inflammatory disorders. Currently, several Food and Drug Administration (FDA)- and / or EU- approved JAK inhibitors are in clinical use. Two (ruxolitinib and fedratinib) small molecules are in use for hematologic disorders as myelofibrosis and polycythemia vera; six JAK inhibitors (tofacitinib, baricitinib, ruxololitinib, filgotinib, upadicitinib and delgocitinib in Japan) result in use for immune-mediated disorders as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis and acute graft-versus-host disease. Moreover, some of these drugs as well as others are currently under phase II and III of clinical trials for indications that span from autoimmune diseases (lupus, vitiligo, etc.), inflammatory bowel disease to Non-Hodgkin lymphoma and COVID-19 (Hu X. et al., Sig Transduct Target Ther 2021, 6: 402). The small molecules targeting JAK / STAT represent an attractive option also for the therapy of fibrotic disorders. In fact, inflammatory cytokines (IL-4, IL-3, IL-6, IL-11, IL-31, etc) and growth factors (FGF, VEGF, etc.) involved in the fibrotic processes activate JAK / STAT pathway. Ruxolitinib tested in a bleomycin-induced fibrosis mouse model ameliorated the fibrotic lesions in lung, and reduced levels of fibrotic molecular markers (Zhang, Y et al., Ann. Rheum. Dis.2017, 76, 1467–1475) while tofacitinib acted as a preventive agent in experimental dermal and pulmonary fibrosis (Wang, W et al., Scleroderma Relat. Disord.2020, 5, 40–50). In patients, some case reports were studied. A single-6case report corroborated the efficacy and safety of tofacitinib in combination with nintedanib in the management of an aggressive interstitial lung disease with poor prognosis (Conca, W et al., Front. Pharmacol. 2020, 11, 5857619). Baricitinib was demonstrated to be a safe immune modulator that reduces the biomarkers’ levels of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung disease (D’Alessandro M et al., Int. Immunopharmacol.2020, 86, 106748). In COVID-19, there are some JAK inhibitors undergoing clinical trials, and they are tofacitinib, baricitinib, and ruxolitinib. Baricitinib and ruxolitinib were associated with a reduced risk of mortality. They reduced the use of invasive mechanical ventilation and had a borderline impact on the admission rate of the intensive care unit and the incidence of acute respiratory distress syndrome (ARDS). (Wijaya, I. et al. Clin. Epidemiol. Glob. Health 2021, 11, 100755). Ruxolitinib also was tested in COVID-19 patients. and improved the clinical symptoms and chest computed tomography images (Cao Y. et al., J. Allergy Clin. Immunol.2020146, 137–146). Asthma can be included in the plethora of immune-mediated diseases for which pathogenesis is characterized by an essential role of JAK / STAT signalling. Asthma is a chronic inflammatory disease of the airways due to a complex interplay between immune response, genetic susceptibility and nonspecific external stimuli like cold, allergens and exercise leading to hyperresponsiveness, remodelling of the airways, ultimately contributing to airflow limitation. Severe asthma affects 5% to 15% of the population with adult asthma (which is 300 million people worldwide) and represents a public health issue associated with increased mortality, increased hospitalizations, significant burden of symptoms, health care costs, and missed work and school (Steve NG et al., J Allergy Clin Immunol 2021;148:953-63). Severe asthma represents a subset of difficult-to-treat asthma and occurs in patients whose disease remains uncontrolled despite the use of high doses of inhaled corticosteroids (ICSs) combined with long-acting β-agonists or other controllers. To date, four types of biologics are licensed for severe asthma, i.e. omalizumab (anti-immunoglobulin E) antibody, mepolizumab and reslizumab (anti-interleukin [IL]-5antibody), benralizumab (anti-IL- 5 receptor a antibody) and dupilumab (anti-IL-4 receptor alpha antibody). Despite their efficacy, many patients continue to experience exacerbations or uncontrolled disease, indicating a need for more novel therapies (Israel E, Reddel HK. N Engl J Med 2017; 377:965-76). Recently, the better understanding of asthma pathobiology brought to a shift from a phenotypic classification system to the introduction of the “endotype” concept. According to the latter, classification is performed on the basis of pathophysiologic mechanisms and clinical biomarkers associated with a given patient (Wenzel SE et a., Am J Respir Crit Care Med 2021;203:809-21). There are two major endotypes in asthma: type 2 and non–type 2. The type 2 pathway is defined by activation of cytokines derived from TH2 cells and group 2 innate lymphoid cells (ILC2s); these include IL-4, IL-5, and IL-13 that cause airway inflammation by activating eosinophils, B cells, airway epithelial cells, and other cell types. Biomarkers of type 2 asthma include blood / sputum eosinophilia and elevated levels of fractional exhaled nitric oxide (FENO) and IgE. The type 2–low pathway is characterized by absence of type 2–high cytokines and biomarkers, and it manifests either increased levels of neutrophils in the airways or a paucigranulocytic profile, with normal levels of airway neutrophils and eosinophils. Type 2–low asthma is currently not well understood, and it likely encompasses multiple distinct endotypes. Potential mediators and / or biomarkers of T2 low endotypes under investigation include IL-6, IL- 17A / F, IL-23, Type I interferons, CXCL10, TNF, alarmins (TSLP, IL-25, IL-33), IL-1β, IL-8, IFN-γ (Hinks TSC et al., ERJ 2021, 57 (1) 2000528). Almost all the mediators mentioned above both for T2 and T2-low endotypes activate JAK / STAT pathway, here the rationale for the potential use of JAK inhibitors in both endotypes of severe asthma. Targeting simultaneously several cytokines by JAK inhibitors may offer advantage over the biologics (for no-responder patients) and standard therapies (for patients who remain uncontrolled) considering their administration on top of ICS. Despite strong rationale of JAK inhibitors in asthma, safety concerns may arise by administration of systemic inhibitors or may limits administration into particular asthma subjects such as children. Considering that Asthma is a lung restricted disease, inhalatory route of administration for a JAK inhibitor may offers the advantage of therapeutic efficacy while limiting systemic exposure and correlated side effects. To date, some companies are developing inhaled JAK inhibitor for asthma treatment. Astrazeneca pipeline include AZD-0449 (completed Phase I clinical trial) and AZD-4604 (ongoing Phase I clinical trial); Theravance Biopharma is starting a new preclinical program on TD-8236 inhaled JAK inhibitor and Kinaset / Vectura is developing VR588 (ongoing Phase I clinical trial) as inhalatory compound. Many preclinical studies sponsored by the companies mentioned above demonstrated the efficacy of JAK inhibitors in the modulation of asthma. In the preclinical phase of drug development, JAK1 / 3 inhibitor R256 (now referred as AZD0449) orally given showed be effective in decreasing airway resistance, BAL eosinophilia, mucus production and if administered during sensitization, also TH2 cytokine responses (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). iJak-381 from Genentech given as dry powder reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in OVA- challenged mice. Moreover, it reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in a in mouse model of chronic exposure to AAH allergens (Dengler HS et al., Sci Transl Med 2018;10:eaao2151). Moreover, an oral JAK inhibitor as Tofacitinib, formulated for being administered as aerosol, reduced eosinophils count in a house dust mite mouse model of asthma (Younis US et al., AAPS PharmSci-Tech 2019;20:167). Another respiratory disease that could benefit from lung restricted JAK inhibition is Chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, most commonly resulting from cigarette smoke exposure, characterised by a largely irreversible and progressive airflow limitation. Despite inflammatory cytokines are drivers of chronic airway inflammation and some of them trigger JAK / STAT activation (IL-6, IFN-γ, IL-2, etc.), the role of this pathway in COPD pathogenesis is poorly characterized. Phosphorylated-STAT4+ cells (Di Stefano A et al., Eur Respir J. 2004 Jul; 24(1):78-85) were found to be increased in COPD compared to non- smokers healthy controls. In another study, phosphorylated-STAT3+ and phosphorylated- STAT1+ cells counts were higher in lung biopsies of COPD patients than non-smokers controls while it was not possible to reproduce previous data on phosphorylated-STAT4 molecule (Yew- Booth L et al., Eur Respir J 2015; 46(3):843-5). These data might also suggest a therapeutic use of JAK inhibitors also in COPD disease. Despite inhalatory administration, safety concerns may still arise by drug levels reaching systemic circulation following inhalation of a JAKi. In addition to a well suited profile for inhalation, a JAKi should preferably possess additional properties that may further limit the systemic exposure after inhalation. Strong need remains for JAK inhibitors, and particularly inhaled JAK inhibitors that have potential for giving compounds with an improved safety. WO 2022 / 194781 Al discloses structurally similar compounds as JAK inhibitors differing from the present application at least for the pattern of substituents. In view of the number of pathological responses which are mediated by JAK enzymes, there is a continuing need for inhibitors of JAK enzymes which can be useful in the treatment of many disorders and particularly respiratory diseases. Thus, the finding of novel safe and potent JAK inhibitor suitable for local administration to the lungs for treatment of asthma and respiratory disease still remains an important need. SUMMARY OF THE INVENTION Accordingly, it is one object of the present invention to provide compounds that are benzylmethansulfonamide derivatives of formula (Io) R1 Wherein R1, R2, R3 are as defined in the detailed description of the invention; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt thereof, that are useful as JAK kinase inhibitors. It is another object of the present invention to provide pharmaceutical compositions comprising such compounds, methods of using such compounds to treat respiratory diseases, and processes and intermediates useful for preparing such compounds. In one aspect, the present invention provides a compound of formula (Io) for use as a medicament. In one aspect the present invention provides the use of a compound of the invention for the manufacture of a medicament. In a further aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of any disease associated with JAK enzyme mechanisms. In another aspect, the present invention provides a method for prevention and / or treatment of any disease associated with JAK enzyme mechanisms as above defined, said method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention. In a particular aspect the compounds of the invention are used alone or combined with other active ingredients and may be administered for the prevention and / or treatment of a pulmonary disease including asthma, Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung diseases and idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). DETAILED DESCRIPTION OF THE INVENTION Definitions The term “Pharmaceutically acceptable salts” refers to derivatives of compounds of formula (Io) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups. Cations of inorganic bases which can be suitably used to prepare salts of the invention comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, camphor sulfonic, acetic, oxalic, maleic, fumaric, succinic and citric acids. Many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates” which are a further object of the invention. Polymorphs and crystalline forms of compounds of formula (Io), or of pharmaceutically acceptable salts, or solvates thereof are a further object of the invention. The term “Halogen” or “Halo-“ or “halogen atoms” includes fluorine, chlorine, bromine, and iodine atom ; meaning Fluoro, Chloro, Bromo, Iodo as substituent. The term “(C1-C6)Alkyl” refers to straight-chained or branched alkyl groups wherein the number of carbon atoms is in the range 1 to 6. Particular alkyl groups are for example methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methylbutyl and the like. The term “(C1-C6)Haloalkyl” refer to the above defined “(C1-C6)alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other. Examples include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl groups. By way of analogy, the terms “(C1-Cx) hydroxyalkyl” or “(C1-Cx) aminoalkyl” refer to the above defined “(C1-Cx) alkyl” groups wherein one or more hydrogen atoms are replaced by one or more hydroxy (OH) or amino group respectively, and wherein x is an integer up to 10. Thus, “(C1- C6)hydroxyalkyl” or “(C1-C6)aminoalkyl” refers to said hydroxy- or amino-alkyl groups wherein the number of carbon atoms is in the range 1 to 6. The definition of aminoalkyl encompasses alkyl groups (i.e. “(C1-C6)alkyl” groups) substituted by one or more amino groups (-NR4R5). An example of aminoalkyl is a mono- aminoalkyl group such as R4R5N-(C1-C6)alkyl, or –(CH2)mNR4R5. Wherein R4 and R5 and m are as defined in the detailed description of the invention. With reference to the substituent R4and R5as above defined, it is here further explained that when either R4 and R5 are taken together with the nitrogen atom they are linked to form a 5 to 6 membered heterocyclic radical, at least one further ring carbon atom in the said heterocyclic radical may be replaced by at least one heteroatom or hetero-group (e.g. N, NH, S or O) or may bear an - oxo (=O) substituent group. The said heterocyclic radical might be further optionally substituted on the available points in the ring, namely on a carbon atom, or on an heteroatom or hetero-group available for substitution. Thus, Examples of said heterocycle radicals are 1-pyrrolidinyl, 1- piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4yl-2-one, 4-methylpiperazine-1-yl. The term “(C3-C10)cycloalkyl” likewise “(C3-C6)cycloalkyl” refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and polycyclic ring systems such as adamantan-yl. The term “Aryl” refers to mono, bi- or tri-cyclic carbon ring systems which have 6 to 20, preferably from 6 to 15 ring atoms, wherein at least one ring is aromatic. Examples of suitable aryl ring systems include, for instance, phenyl or naphthyl, indenyl, dihydro-indenyl radicals . The term “heteroaryl” refers to mono-, 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 suitable heteroaryl ring systems include, for instance, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl purinyl, indolyl, isoindolyl, indazolyl,and the like. The derived expression “(C3-C10)heterocycloalkyl” likewise “(C3-C6)heterocycloalkyl” refers to saturated or partially unsaturated mono, bi- or tri- cycloalkyl groups of the indicated number of carbons, in which at least one ring atom is a heteroatom (e.g. N, NH, S or O) and may further bear an -oxo (=O) substituent group (e.g. C(=O), S(=O)2). 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 (Io), it is intended that from 1 to 3, preferably 1 to 2, more preferably 1 of such substituents may replace hydrogens on such groups or variables. Substitution includes bridged system, spiro disubstitution as well as substitution on two adjacent atoms, in both cases thus form additional 5 to 6 membered heterocyclic ring. Examples of (C3-C6) heterocycloalkyl are represented by: oxetanyl, tetrahydro-furanyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, 9-methyl- 3,9-diazaspiro[5.5]undecan-3-yl, and (3aR,6aS)-5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl. The term “Aryl(C1-C6)alkyl” refers to an aryl ring linked to a straight-chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. phenylmethyl (i.e. benzyl), phenylethyl or phenylpropyl. Likewise the term “Heteroaryl(C1-C6)alkyl” refers to an heteroaryl ring linked to a straight- chained or branched alkyl group wherein the number of constituent carbon atoms is in the range from 1 to 6, e.g. furanylmethyl. The term “alkanoyl”, refers to HC(O)- or to alkylcarbonyl groups (e.g. (C1-C6)alkylC(O)-) wherein the group “alkyl” has the meaning above defined. Examples include formyl, acetyl, propanoyl, butanoyl. The term “(C1-C10) alkoxy” or “(C1-C10) alkoxyl”, likewise “(C1-C6) alkoxy” or “(C1-C6) alkoxyl” etc., refers to a straight or branched hydrocarbon of the indicated number of carbons, linked to the rest of the molecule through an oxygen bridge. “(C1-C6)Alkylthio” refers to the above hydrocarbon linked through a sulfur bridge. The derived expression “(C1-C6)haloalkoxy” or “(C1-C6)haloalkoxyl” refers to the above defined haloalkyl, linked through an oxygen bridge. Example of (C1-C6)haloalkoxy is difluoromethoxy, trifluoromethoxy. Likewise derived expression “(C3-C6)heterocycloalkyl-(C1-C6)alkyl” and “(C3- C6)cycloalkyl-(C1-C6)alkyl” refer to the above defined heterocycloalkyl and cycloalkyl groups linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example piperidin-4-yl-methyl, cyclohexylethyl. The derived expression “(C1-C6)alkoxy (C1-C6)alkyl” refers to the above defined alkoxy group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example methoxymethyl. Likewise “(C1-C6)haloalkoxy(C1-C6)alkyl” refers to the above defined (C1-C6)haloalkoxy” group linked to the rest of the molecule via an alkyl group of the indicated number of carbons, for example difluoromethoxypropyl. Likewise “(C1-C6)alkoxycarbonyl” refers to the above defined alkoxy group linked to the rest of the molecule via an carbonyl group. “(C1-C6)alkylthiocarbonyl-” refers to the above alkylthio group linked to the rest of the molecule via a carbonyl group (C=O). “(C1-C6)alkoxycarbonyl-(C1-C6)alkyl” refers to the above defined alkoxy group linked to the rest of the molecule via an carbonyl group further enchained with an alkyl group of the indicated number of carbons, for example methoxycarbonylmethyl. “(C1-C6)alkoxycarbonyl-(C1-C6)alkylthio” consequently refer to the indicated enchained groups like methoxycarbonylmethylthio. Other derived expression will be apparent in their meaning e.g. “halo-((C1-C6)alkyl(C3-C8)heterocycloalkyl)” refer to enchained groups like 4-fluoro-1- methylpyrrolidin-3-yl. An oxo moiety is represented by (O) as an alternative to the other common representation, e.g. (=O). The carbonyl group is herein preferably represented as –C(O)– as an alternative to the other common representations such as –CO–, –(CO)– or –C(=O)–. In general the bracketed group is a lateral group, not included into the chain, and brackets are used, when deemed useful, to help disambiguating linear chemical formulas; e.g. the sulfonyl group -SO2- might be also represented as–S(O)2– to disambiguate e.g. with respect to the sulfinic group –S(O)O–. When a numerical index the statement (value) “p is zero” or “p is 0” means that the substituent or group bearing the index p (e.g. Ip) is absent, that is to say no substituent, other than H when needed, is present. Likewise when the index is attached to a bridging divalent group (e.g. (CH2)m) the statement “m in each occurrence is zero…” or “m is 0” means that the bridging group is absent, that is to say it is a bond. A bond pointing to a wavy or squiggly line, such 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. 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. A dash (“-”) that is not between two letters or symbols is meant to represent the point of attachment for a substituent. Whenever basic amino or quaternary ammonium groups are present in the compounds of formula (Io), physiological acceptable anions, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate may be present. Likewise, in the presence of acidic groups such as COOH groups, corresponding physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions. Compounds of formula (Io) when they contain one or more stereogenic center, may exist as optical stereoisomers. Where the compounds of the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. It is to be understood that all such single enantiomers, diastereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. The absolute configuration (R) or (S) for carbon bearing a stereogenic center is assigned on the basis of Cahn-Ingold-Prelog nomenclature rules based on groups’ priorities. “Single stereoisomer”, “single diastereoisomer” or “single enantiomer”, when reported near the chemical name of a compound indicate that the isomer was isolated as single diastereoisomer or enantiomer (e.g via chiral chromatography) but the absolute configuration at the relevant stereogenic center was not determined / assigned. Atropisomers result from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers (Bringmann G et al, Angew. Chem. Int. Ed.44 (34), 5384-5427, 2005. doi:10.1002 / anie.200462661). Oki defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983). Atropisomers differ from other chiral compounds in that in many cases they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible chemically. Separation of atropisomers is possible by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other. Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other. Racemic forms of compounds of formula (Io) as well as the individual atropisomers (substantially free of its corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are included in the scope of the present invention. The invention further concerns the corresponding deuterated derivatives of compounds of formula (Io). In the context of the present invention, deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount above its natural abundance. Preferably, the percent of deuterium at that position is at least 90%, more preferably at least 95%, even more preferably 99%. All preferred groups or embodiments described above and here below for compounds of formula (Io) may be combined among each other and apply as well mutatis mutandis. The term “IC50” refers to the half maximal inhibitory concentration as a measure of the potency of a substance in inhibiting a specific biological or biochemical function. The term “pIC50” refers to the negative logarithm of the IC50 value expressed as molar concentration. As above mentioned, the present invention provides compounds of general formula (Io), acting as JAK inhibitors, to processes for the preparation thereof, pharmaceutical compositions comprising them either alone or in combination with one or more active ingredient, in admixture with one or more pharmaceutically acceptable carriers. Thus, in a first aspect the present invention relates to a compound of formula (Io): wherein R1is a heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl (3-oxo-3,4-dihydropyrazin-2-yl)amino ; R2is O wherein R6is H or selected in the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkylthio; R3is a cyclic carbamate or spirocyclic carbamate group of formula J selected from O R7is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, - (CH2)mNR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl; wherein m is in each occurrence independently 0 or an integer from 1 to 4; R4and R5, the same or different, are selected from the group consisting of -H and (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof. Thus, being R2: O the present invention relates to represented by a corresponding general formula (I): O wherein R1is a heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl (3-oxo-3,4-dihydropyrazin-2-yl)amino wherein R6is H or selected in the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkylthio-; R3is a group of formula J selected from O R7is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, - (CH2)mNR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl; wherein m is in each occurrence independently 0 or an integer from 1 to 4; R4and R5,the same or different, are selected from the group consisting of -H, (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof. All the listed groups for each of the variable moieties R1, R2, R3, R4, R5, R6, R7, J2, J3, J4 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. In a preferred embodiment, the invention refers to a compound of formula (Io) as Jak inhibitor, wherein R1is pyrazolo[1,5-a]pyrimidin-3-yl and R2is O represented by the general O O wherein R3 is J2 and R6is H or Halogen, preferably Cl, and pharmaceutically acceptable salts and solvates thereof. In another preferred embodiment, the invention refers to at least one of the compounds, listed in Table 1 below, single enantiomers, diastereoisomers and mixtures thereof and pharmaceutically acceptable salts thereof. Table 1 - List of preferred compounds Example NoStructure Chemical NameOS ON HON-(3-methoxy-4-(3-(8-methyl-2-oxo-1- O oxa-3,8-diazaspiro[4.5]decan-3-yl)-6- 1NN(pyrazolo[1,5-a]pyrimidin-3-yl)-1H- NON pyrazolo[4,3-c]pyridin-1- yl)benzyl)methanesulfonamide N N N N O S HN O N N N-(4-(3-(2-(2-hydroxyethyl)-6-oxo-5- N oxa-2,7-diazaspiro[3.4]octan-7-yl)-6- N O 2 N (pyrazolo[1,5-a]pyrimidin-3-yl)-1H- N pyrazolo[4,3-c]pyridin-1-yl)-3- N O methoxybenzyl)methanesulfonamide O N OHO S HN O N N ethyl 2-(7-(1-(2-methoxy-4- N O (methylsulfonamidomethyl)phenyl)-6- N 3 N (pyrazolo[1,5-a]pyrimidin-3-yl)-1H- N pyrazolo[4,3-c]pyridin-3-yl)-6-oxo-5- N O oxa-2,7-diazaspiro[3.4]octan-2- O yl)acetate N O O O H S N O N N N-(3-methoxy-4-(3-(2-methyl-6-oxo-5- N N O oxa-2,7-diazaspiro[3.4]octan-7-yl)-6- N (pyrazolo[1,5-a]pyrimidin-3-yl)-1H- N pyrazolo[4,3-c]pyridin-1- N O yl)benzyl)methanesulfonamide O N O O S NH N N N N-(4-(3-(8-(2-hydroxyethyl)-2-oxo-1- N O N oxa-3,8-diazaspiro[4.5]decan-3-yl)-6- N (pyrazolo[1,5-a]pyrimidin-3-yl)-1H- N O pyrazolo[4,3-c]pyridin-1-yl)-3- O methoxybenzyl)methanesulfonamide N OHO S OHN N-(3-methoxy-4-(3-(2-oxooxazolidin-3- O yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)- NNO 1H-pyrazolo[4,3-c]pyridin-1- N yl)benzyl)methanesulfonamide N NON NO S OHN N-(4-(3-(5-((dimethylamino)methyl)-2- O oxooxazolidin-3-yl)-6-(pyrazolo[1,5- NNO a]pyrimidin-3-yl)-1H-pyrazolo[4,3- N c]pyridin-1-yl)-3- N NOmethoxybenzyl)methanesulfonamide N N NO S OHN (R)-N-(2-chloro-4-(3-(5- Cl O ((dimethylamino)methyl)-2- oxooxazolidin-3-yl)-6-(pyrazolo[1,5- NNO N a]pyrimidin-3-yl)-1H-pyrazolo[4,3- N c]pyridin-1-yl)-5- NON methoxybenzyl)methanesulfonamide N NO S OHN (R)-N-(4-(3-(5- S O ((dimethylamino)methyl)-2- oxooxazolidin-3-yl)-6-(pyrazolo[1,5- NNO N a]pyrimidin-3-yl)-1H-pyrazolo[4,3- NOc]pyridin-1-yl)-5-methoxy-2- N N (methylthio)benzyl)methanesulfonamide N NO S OHN (R)-N-(4-(3-(5- O ((dimethylamino)methyl)-2- oxooxazolidin-3-yl)-6-(pyrazolo[1,5- NNO N a]pyrimidin-3-yl)-1H-pyrazolo[4,3- NOc]pyridin-1-yl)-3- N N methoxybenzyl)methanesulfonamide N NO S OHN (S)-N-(4-(3-(5- O ((dimethylamino)methyl)-2- oxooxazolidin-3-yl)-6-(pyrazolo[1,5- 11NNO N a]pyrimidin-3-yl)-1H-pyrazolo[4,3- N c]pyridin-1-yl)-3- NON methoxybenzyl)methanesulfonamide N N O HN S (R)-N-(4-(3-(5- O ((Dimethylamino)methyl)-2- S O oxooxazolidin-3-yl)-6-((3-oxo-3,4- 12N NO dihydropyrazin-2-yl)amino)-1H- N HNNpyrazolo[4,3-c]pyridin-1-yl)-5- NOmethoxy-2- OH NN (methylthio)benzyl)methanesulfonamide The compounds of the invention showed high biochemical potency on JAKs targets (JAK1, JAK2, JAK3 and Tyk2) and high potency on a representative functional assay in cells (such as inhibition of pSTAT6 in BEAS cells stimulated with IL-13). Lung retention is a complex interplay among solubility, permeability and lung protein binding, preferred compounds of the invention possess favourable phys-chem properties that could translate in a good inhalatory profile. The compounds of the invention, including all the compounds hereabove listed, can be prepared from readily available starting materials using general methods and procedures as described in the experimental part below or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or by using other known methods, reagents and starting materials. When typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. While the optimum 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. Processes of preparation described below and reported in the following schemes 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 a step is needed in order to mask or protect sensitive or reactive moieties, generally known protective groups (PG) could be employed, in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts). Compounds of formula (Io) wherein R2is O here represented for clarity by , all here above listed compounds of table 1, can be usually prepared according to the procedures shown in the schemes below. Where a specific detail or step differs from the general schemes it has been detailed in the specific examples, and / or in additional schemes. Compounds of formula (I) can contain one or more stereogenic centre. Enantiomerically pure compounds can be prepared according to generally known reactions, e.g. according to the reactions described below, by means of enantiomerically pure starting materials and intermediates. These intermediates may be commercially available or readily produced from commercial sources by those of ordinary skill in the art. In another approach, enantiomerically pure compounds can be prepared from the corresponding racemates and / or scalemic mixture by means of chiral chromatography purification. Compounds of formula (I) can be prepared according to scheme 1. Compound II is an intermediate that can be converted to compounds of formula I by protective groups deprotection of PG1and / or PG2. It is apparent that in the case PG1and PG2are not present, any general approach described for the preparation of intermediate II will provide a compound of general formula (I). Intermediate II can be obtained by direct introduction of R1 (or a suitably protected R1 with PG2, named r1) through a metal / palladium catalyzed cross coupling reaction such as Suzuki coupling, Stille coupling, Buchwald-Hartwig or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005) by reaction of intermediate IV with intermediate III. For example, a suitable palladium catalyzed cross coupling for introducing R1, when it is an pyrazolo[1,5-a]pyrimidin-3-yl, is a Suzuki coupling. Suzuki coupling can be performed by reacting intermediate IV with the corresponding boronic acid or boron pinacolate (intermediate III, where R1is pyrazolo[1,5-a]pyrimidin-3-yl and A is dihydroxyboryl or 4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl) in the presence of a Pd catalyst such as tetrakistriphenylphosphinepalladium(0), PdCl2(dppf)2, or a ligand-palladacycle precatalyst such as XPhos-Pd-G3 [(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate], in an organic solvent such as 1,4-dioxane, THF, 1,2- dimethoxyethane, 2-propanol or DMF, with or without water, in the presence of an inorganic base such as an alkaline carbonate (for example Cs2CO3 or K2CO3) or an inorganic phosphate (for example K3PO4), under heating (typically in the range of 50-100ºC) for few hours (typically 1 to 3h). Boronic acid and boronic pinacolate esters are generally commercially available or may be readily prepared by those skilled in the art starting from commercially available reagents.

[0002] A suitable palladium catalyzed cross coupling for introducing R1, when it is an (3-oxo-3,4- dihydropyrazin-2-yl)amino, is a Buchwald-Hartwig coupling. For synthetic convenience the carbonyl group of (3-oxo-3,4-dihydropyrazin-2-yl)amino needs to be masked with a PG2, for example using an alkoxy group such as methoxy group. Intermediate IV and intermediate III (where r1 is 3-methoxypyrazin-2-aminyl and A is H) can be reacted in the presence of a suitable ligand palladacyle system such as XPhos-Pd-G3 (2-Dicyclohexylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate) or RuPhos-Pd-G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino- 1,1′-biphenyl)]palladium(II) methanesulfonate) or in general a suitable Pd source (for example Pd2(dba)3 or Pd(OAc)2) with a suitable biphenylphosphine ligand type (RuPhos, X- Phos, or similar), in the presence of a strong organic base such as sodium tert-butoxyde or an inorganic base such as Cs2CO3, in an organic solvent such 1,4-dioxane, THF or toluene, under heating at high temperature (typically 80-120ºC), for few hours (typically 1-5 h). In some cases, for synthetic convenience during metal catalyzed cross coupling, acidic NH from sulfonamide in intermediate IV migth need to be masked with a suitable protective groups. A suitable protective group for protecting acidic NH from sulfonamide can be benzyl type protective groups such as DMB (2,4-dimethoxybenzyl), PMB group (para-methoxybenzyl). Removal of PG1when it is a DMB groups can be easily performed by treating intermediate II in acidic conditions with an organic or an inorganic strong acid. For example, DMB can be deprotected by treating the intermediate II with trifluoroacetic acid neat or in mixture with an organic solvent such as DCM, THF or similar, typically at room temperature for few hours (typically 1 to 3 h). When PG2is present, removal of methoxy group can be performed by treatment of intermediate II with TMS-Cl (trimethylsilyl chloride) and sodium iodide in acetonitrile for 1 to 5 h at 60 - 100ºC. Under these reaction conditions also PG1can be concurrently removed without need of further treatments. Intermediate IV, when PG1 is DMB and R3 is a 5-(R7)-substituted 2-oxooxazolidin-3-yl, named as IVa, can be prepared according to scheme 2. Intermediate V and intermediate VIa can be converted to IVa by a C-N coupling that can be performed by heating (typically 60-100ºC) the heteroaromatic iodide and the amine in an organic solvent like DMSO, in the presence of copper(I) catalyst / promoter such as CuI, Cu2O or CuTC (copper thiophene carboxylate), ligandless or with a suitable ligand such as proline, 3,4,7,8-tetramethyl-1,10-phenantroline, N,N-dimethylglicine, dimethylcyclohexane-1,2-diamine (DMCHA), an inorganic base as K2CO3, K3PO4 or Cs2CO3. Intermediate V can be prepared from intermediate VII by a twostep process that involve: 1) reductive amination with PG1-NH2(where PG1is DMB) and 2) sulfamidation. In the first step, intermediate VII can be reacted at reflux temperature with a suitable amine (for PG1-NH2like 2,4- dimethoxybenzylamine) in an organic solvent as DCM or THF to form the corresponding immine / enammine that can be reduced at room temperature by the addition of a suitable borohydryde as STAB (sodium triacetoxyborohydride) or NaBH3CN. The second step (sulfamidation reaction) can be performed by reacting the amine from previous step with a suitable sulfonyl chloride such as methylsulfonyl chloride, in an organic solvent like DCM, in the presence of an organic base like TEA or pyridine, at temperature typically from 0ºC to room temperature.

[0003] In another approach intermediates IV, when R3 are respectively N-R7 substituded 5-oxa-2,7- diazaspiro[3.4]octan-6-one-7-yl and N-R7substituded 1-oxa-3,8-diazaspiro[4.5]decan-2-one-3-yl and PG1 is H, named respectively IVb and IVc, can be prepared according to scheme 3. Preparation of IVb (and IVc) can be carried out by three sequential steps from intermediate V, that include 1) C-N coupling, 2) Boc deprotection and 3) alkylation with halide R7-X. In the first step, intertmediate V can be reacted with VIIIb (or VIIIc) by a C-N coupling using similar reaction conditions described above for the conversion of V to IVa. After C-N coupling, the resulting intermediate can be treated with an organic acid such as TFA to perform 2) Boc deprotection. In these conditions also PG1, when it is DMB, can be concurrently removed. In the last step (alkylation), the secondary nitrogen of spirosystem can be reacted with R7-X (where X is Br or I) in the presence of an inorganic base such as TEA, in an organic polar solvent like DMF at a temperature around 50-60°C for several hours. In another approach, when R7 is a methyl group, methylation can be performed under Eschweiler–Clarke conditions by reacting seconday amine with a mixture of formaldehyde and formic acid at 70-90°C for several hours. Intermediate VII can be prepared according to scheme 4 by means of aromatic nucleophilic substitution of intermediate IX with intermediate VIII. An aromatic nulceophilic subtitution can be performed by heating (typically 80 - 130ºC) in a polar organic solvent (for example DMF, DMA or 1,4-dioxane) the nucleophile and the aromatic electrophile in the presence of an inorganic base (such as K2CO3or Cs2CO3) or an organic base (such as TEA, DBU or DIPEA). The above described schemes may provide at least one non limiting example of synthetic route for the preparation of example 1 to 12. As herein described in detail, the compounds of the invention are inhibitors of kinase activity, in particular inhibiting JAK kinase activity for the treatment of JAK-dependent diseases. In one aspect the invention provides compounds according to the invention, i.e. a compound of formula (I) or (Io) or a pharmaceutical composition thereof, for use as a medicament, preferably for the prevention and / or treatment of respiratory and specifically pulmonary disease. In a further aspect the invention provides the use of a compound (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disorders associated with JAK mechanisms, particularly for the treatment of disorders such as respiratory and pulmonary diseases. In particular the invention provides compounds of formula (I) or (Io) for use in the prevention and / or treatment of pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF)acute lung injury and acute respiratory distress syndrome (ARDS). Moreover, the invention provides a method for the prevention and / or treatment of disorders associated with JAK mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention. In particular, the invention provides methods for the prevention and / or treatment wherein the disorder is a respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). Preferred is the use of the compounds of the invention for the prevention of the aforesaid disorders. Equally preferred is the use of the compounds of the invention for the treatment of the aforesaid disorders. Generally speaking, compounds which are JAK inhibitors may be useful in the treatment of many disorders associated with JAK enzyme mechanisms. In one embodiment, the disorder that can be treated by the compound of the present invention is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease such as idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). In a further embodiment, the disorder is selected from asthma and chronic obstructive pulmonary disease (COPD). The methods of treatment of the invention comprise administering an effective amount of a compound of formula (I) or (Io) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, " effective amount" in reference to a compound of formula (I) or (Io) or a pharmaceutically acceptable salt thereof 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. The compounds of formula (I) or (Io) or pharmaceutically acceptable salts thereof 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 particular route of administration chosen. The invention also provides pharmaceutical compositions of compounds of formula (I) or (Io) 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. The present invention is also directed to use of the compounds of the invention and their pharmaceutical compositions for various route of administration. 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, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present 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. Time release capsules, tablets and gels are also advantageous. Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms 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. The compounds of the present invention may be formulated as injectable composition, for example to be injected intravenously, in the form of an isotonic sterile solution. Other preparations are also possible. Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known. For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches. For the treatment of the diseases of the respiratory tract, the compounds according to the invention, as above said, may also preferably be administered by inhalation. Some preferred compounds of the invention exhibit profile suitable for inhalatory route administration. Drugs optimized for inhaled delivery require certain characteristics that allow the compound, when administered to the lung to maintain a sufficient local concentration (lung retention) to exert a pharmacological effect of the desired duration, with minimal drug absorption in the GI tract for the swallowed fraction and in general non-relevant levels in unwanted compartments (i.e. plasma). For this purpose, one or more features of a compounds were optimized such as, and not limited to, membrane permeability, dissolution rate and the compound’s basicity to enhance its binding to the phospholipid-rich lung tissue or through lysosomal trapping. In some embodiments, compounds of invention show one or more of the features above in the range desirable for an inhaled compound. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations and may be administered through a suitable inhalation device which may be respectively selected from dry powder inhaler, pressurized metered dosed inhaler, or a nebulizer. 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. A diluent or carrier, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention. 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. The propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat^, a registered trademark of Boehringer Ingelheim Pharmaceuticals (Wachtel, H., Kattenbeck, S., Dunne, S. et al. Pulm Ther (2017) 3: 19. The compounds of the invention, regardless of the route of administration, can be administered as the sole active agent or in combination (i.e. as co-therapeutic agents administered in fixed dose combination or in combined therapy of separately formulated active ingredients) with other pharmaceutical active ingredients. The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, and known to the skilled person, such as beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated kinases (P38 MAP kinases) inhibitors, PI3K inhibitors (phosphoinositide 3-kinases), nuclear factor kappa-B kinase subunit beta inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs) and mucus regulators. The invention is also directed to a kit comprising the pharmaceutical compositions of compounds of the invention alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and / or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer. The dosages of the compounds of the invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound. A pharmaceutical composition comprising a compound of the invention suitable to be administered by inhalation is in various respirable forms, such as inhalable powders (DPI), propellant-containing metering aerosols (PMDI) or propellant-free inhalable formulations (e.g. UDV). The invention is also directed to a device comprising the pharmaceutical composition comprising a compound according to the invention, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a nebulizer particularly soft mist nebulizer. The following examples illustrate the invention in more detail. The features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof. PREPARATION OF INTERMEDIATES AND EXAMPLES General Experimental details Chemical Names (IUPAC) of the compounds were generated with Structure To Name Enterprise 10.0 Cambridge Software or latest. Purification by flash chromatography refers to purification using a Biotage SP1 or Interchim puriFlash purification system or equivalent MPLC using a pre-packed polypropylene column containing stationary phase (cartridge). Where products were purified using a Si cartridge, this refers to an Interchim pre-packed polypropylene column containing unbounded activated silica with spherical particles with average size of 15 μm or Isolute® pre-packed polypropylene column containing unbounded activated silica with irregular particles with average size of 50 μm. Fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and concentrated in vacuo. Purification by 'reverse phase chromatography' refers to purification on Biotage Isolera Four purification system equipped with BIotage Dalton 2000 mass detector on Sfar C18 polypropylene columns duo prepacked Where an SCX-2 cartridge was used, ‘SCX-2 cartridge’ refers to a Bond Elut ® pre-packed polypropylene column containing a non-end-capped propylsulphonic acid functionalised silica strong cation exchange sorbent. Where preparative HPLC-MDAP was used for purification (MDAP: mass directed automatic purification) fractions containing the desired product were pooled and the solvent removed by evaporation or alternatively lyophilised. NMR Methods NMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probe head), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probehead) or Bruker DPX 300 spectrometers using standard Bruker pulse sequences. Alternatively, NMR spectra were recorded with Varian MR-400 spectrometer operating at 400 MHz or a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz. DMSO-d6 or CDCl3 were used as solvents and tetramethylsilane as the internal standard unless in the latter case where solvent residual peak was used. All experiments were recorded at 298 K, unless stated differently. Chemical shifts are given in relative to internal standard tetramethylsilane or solvent residual peak. Coupling constants, (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined. LCMS Method 1 Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile Gradient Gradient-Time Flow (mL / min) A % B% 0.00 0.9 97 3 1.50 0.9 3 97 1.90 0.9 3 97 2.00 0.05 97 3 Column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-), Scan Range: 100 to 1000 AMU. LCMS Method 2 Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7μm packing diameter), mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; Gradient Gradient-Time Flow (mL / min) A % B% 0.00 0.9 97 3 1.50 0.9 3 97 1.90 0.9 3 97 2.00 0.05 97 3 Column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-), Scan Range: 100 to 1000 AMU. LCMS Method 3 AGILENT LC 1260 Infinity with SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; Column: Acquity UPLC BEH C18 (100mm x 2.1mm i.d., 1.7μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile Gradient Gradient-Time Flow (mL / min) A % B% 0.00 0.5 97 3 8.00 0.5 0 100 10.00 0.5 97 3 12.00 0.05 97 3 Column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-), Scan Range: 100 to 1500 AMU. Abbreviations used: Boc2O = Di-tert-butyl dicarbonate; aq.=aqueous; DCC = Dicyclohexylcarbodiimine; DCM = Dichloromethane; DIPEA = N,N-Diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMCHDA = trans-N,N′-Dimethylcyclohexane-1,2-diamine; DMF = N,N-Dimethylformamide; DMSO = Dimethylsulfoxide; EtOAc = Ethyl acetate; LCMS = Liquid chromatography-mass spectrometry;1H-NMR = Proton nuclear magnetic resonance; RM = Reaction mixture; Rt = Retention time; RT = Room temperature; sat.=saturated; T3P®= Propylphosphonic anhydride; TEA = Triethylamine; TFA = Trifluoroacetic acid; THF = Tetrahydrofuran; Xphos–Pd-G3-(2- Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate 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. A “similar” or “analogous” procedure means that such a procedure may involve minor variations, for example reaction temperature, reagent / solvent amount, reaction time, work-up conditions or chromatographic purification conditions. The stereochemistry of the compounds in the Examples, where indicated, has been assigned on the assumption that absolute configuration at resolved stereogenic centres of starting materials is maintained throughout any subsequent reaction conditions. Unless otherwise stated, where absolute configuration (R) or (S) is reported in the compound name, ee% has to be considered equal or greater than 90%. PREPARATION OF INTERMEDIATES Intermediate 1a O 5-((Dimethylamino)methyl) 1a) A vial charged with 5-(chloromethyl)oxazolidin-2-one (1.0 g, 7.4 mmol) and dimethylamine (2.0 M in methanol, 13.0 mL, 26.0 mmol) was heated at 150 °C for 30 min under microwave irradiation. After cooling to RT, RM was concentrated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-100 % DCM:MeOH:NH4OH (90:15:1.5) in DCM. Title product was obtained as solid (399 mg). 1H-NMR (500 MHz, DMSO-d6) δ: 7.44 (brs, 1H), 4.61-4.67 (m, 1H), 3.50 (t, J=8.6 Hz, 1H), 3.13 (t, J=9.0 Hz, 1H), 2.94 (dd, J=13.0, 6.5 Hz, 1H), 2.43 (dd, J=13.0, 5.5 Hz, 1H), 2.18 (s, 6H). Intermediate 1b O (S)-5-((Dimethylamino)methyl)oxazolidin-2-one (Intermediate 1b) Title compound was prepared on a similar manner as Intermediate 1a, starting from (S) 5- (chloromethyl)oxazolidin-2-one. 1H-NMR (300 MHz, DMSO-d6) δ: 6.75 (bs, 1H); 4.70-4.58 (m, 1H); 3.58 (t, J=8.9 Hz, 1H); 3.23 (t, J=7.9 Hz, 1H); 2.60-2.40 (m, 2H); 2.22 (s, 6H). Intermediate 2a Step 1 4-(6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzaldehyde (Intermediate 2a-1) A mixture of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (5.00 g, 17.9 mmol), 4-fluoro-3- methoxy-benzaldehyde (2.76 g, 17.9 mmol) and K2CO3(7.42 g, 53.7 mmol) in DMF (50 mL) was stirred at 105 °C overnight. After cooling to RT, RM was diluted with water. The formed precipitate was filtered, washed with water and acetonitrile, then dried under vacuum overnight to afford the title product (4.0 g) that was used in the next synthetic step without further purifications. LCMS (Method 2): Rt = 1.17 min, ES+m / z 413.8 / 415.7 [M+H]+. Step 2 HN I N-(4-(6-chloro-3-iodo- 3-methoxybenzyl)-1-(2,4- dimethoxyphenyl)methanamine (Intermediate 2a-2) (2,4-dimethoxyphenyl)methanamine (2.08 mL, 13.9 mmol) and acetic acid (2.84 mL, 49.6 mmol) were added to a suspension of Intermediate 2a-1 (4.10 g, 9.91 mmol) in dry DCM (80 mL). RM was stirred at RT overnight and 4 h at reflux. A second equivalent of (2,4- dimethoxyphenyl)methanamine was added and RM refluxed for further 3h. After cooling to RT, NaB(AcO)3H (8.40 g, 39.7 mmol) was added and RM stirred at RT overnight. RM was diluted with DCM and quenched with sat. aq. NaHCO3, layers were separated and aqueous phase further extracted with DCM. Combined organic layers were washed with sat. aq. NaHCO3 (2x20 mL), passed through a phase separator cartridge and evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-5 % MeOH in DCM to give the title product (5.0 g). LCMS (Method 2): Rt = 1.38min, ES+m / z 565.1 / 567.1 [M+H]+. Step 3 I N-(4-(6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)-N-(2,4- dimethoxybenzyl)methanesulfonamide (Intermediate 2a) A solution of Intermediate 2a-2 (400 mg, 0.71 mmol) in dry DCM (10 mL) was treated under argon with TEA (184 µL, 1.3 mmol) and methanesulfonyl chloride (110 µL, 1.4 mmol). RM was stirred at RT for 3 h, then partitioned between DCM and sat. aq. NaHCO3. Combined organics were washed with sat. aq. NaHCO3, water, sat. aq. NaCl, dried over Na2SO4 and solvent evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-33 % EtOAc in DCM to afford the title product (384 mg). LCMS (Method 2): Rt = 1.34 min, ES+m / z 643.1 / 645.1 [M+H]+. Intermediate 2b Step 1 O 2-Chloro-4-fluoro-5- 2b-1) To a degassed solution of 1-bromo-2-chloro-4-fluoro-5-methoxy-benzene (1.0 g, 4.2 mmol) in THF (10 mL) kept at -5 °C, a solution of i-Pr-MgCl.LiCl (1.3 M in THF, 6.4 mL, 8.4 mmol) was added dropwise keeping the temperature below 0 °C. RM was stirred at 0°C for 1h prior to DMF (1.6 mL, 21 mmol) addition. RM was stirred at RT for 45 minutes, then quenched with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (30 mL). Organic layer was washed with sat. aq. NaCl (20 mL) and solvent removed in vacuo to afford the title product (800 mg) that was used in the next synthetic steps without further purification. LCMS (Method 1): Rt = 1.29 min 1H-NMR (600 MHz, DMSO-d6) δ: 10.2 (s, 1H), 7.68 (d, J=10.9 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 3.93 (s, 3H). Step 2 2-Chloro-4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxybenzaldehyde (Intermediate 2b-2) Title compound was prepared on a similar manner as Intermediate 2a-1 starting from 6- chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine and Intermediate 2b-1. LCMS (Method 1): Rt = 1.33 min, ES+m / z 448.0 / 450.0 / 452.0 [M+H]+. Step 3 HN O I N-(2-Chloro-4-(6-chloro- 1-yl)-5-methoxybenzyl)-1- (2,4-dimethoxyphenyl)methanamine (Intermediate 2b-3) Title compound was prepared on a similar manner as Intermediate 2a-2 starting from Intermediate 2b-2. LCMS (Method 1): Rt = 1.48 min, ES+m / z 599.1 [M+H]+. Step 4 was on a manner as step Intermediate 2b-3. LCMS (Method 1): Rt = 1.41 min, ES+m / z 677.1 / 679.1 / 681.1 [M+H]+. Intermediate 3a N-(4-(6-chloro-3-(2-oxooxazolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3- A degassed mixture of Intermediate 2a (150 mg, 0.23 mmol), oxazolidin-2-one (81.3 mg, 0.93 mmol, K2CO3(193 mg, 1.40 mmol), L(-)-Proline (16.1 mg, 0.14 mmol) and CuI (17.8 mg, 93 µmol) in DMSO (3.8 mL) was stirred under argon at 70 °C overnight. After cooling to RT, RM was quenched with sat. aq. NaHCO3and extracted with EtOAc (4x). Combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with DCM / EtOAc (10:1) to afford the title product (97 mg). LCMS (Method 2): Rt = 1.17 min, ES+m / z 602.2 / 604.2 [M+H]+. Intermediate 3b to 3e The following intermediates were prepared in a similar manner to Intermediate 3a from the indicated starting materials. It is additionally stated if base, solvent, temperature ligand and / or copper source were varied. Intermediate Structure / nameStartingLCMS Material OS ON O O O Intermediate NNO (Method 1): 1a and Rt = 0.85 Intermediate Intermediate N O min,+ClES N 2a 3b m / z N 659.3 / 661.3 ligandless @ N-(4-(6-chloro-3-(5- 100o[M+H]+C ((dimethylamino)methyl)-2-oxooxazolidin- 3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3- methoxybenzyl)-N-(2,4- dimethoxybenzyl)methanesulfonamide OS ON O Cl O O Intermediate (Method 1): NNO 1b and Rt = 0.90 Intermediate N O min, ES+IntermediateCl2b m / z 3cNN 693.2 / 695.3 ligandless, / 697.3 (R)-N-(2-chloro-4-(6-chloro-3-(5- temperature: [M++((dimethylamino)methyl)-2-oxooxazolidin- 0oH] 10 C 3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5- methoxybenzyl)-N-(2,4- dimethoxybenzyl)methanesulfonamideO S OIntermediate N 2a and tert- O butyl 6-oxo-5- O O oxa-2,7- NNdiazaspiro[3.4] O octane-2- (Method 2): N O carboxylate Rt = 1.30 IntermediateClNmin, ES+3d N 1,10- m / z O phenonthroline 743.2 / 745.2 O as a ligand and [M+H]+tert-butyl 7-(6-chloro-1-(4-((N-(2,4- potassium dimethoxybenzyl)methylsulfonamido)methy phosphate as a l)-2-methoxyphenyl)-1H-pyrazolo[4,3- base, c]pyridin-3-yl)-6-oxo-5-oxa-2,7- temperature: diazaspiro[3.4]octane-2-carboxylate 110oC OS OIntermediate N 2a and tert- O butyl 6-oxo-5- O O oxa-2,7- NNdiazaspiro[3.4] O octane-2- (Method 2): N O carboxylate Rt = 1.39 IntermediateClNmin, ES+3e 1,10- m / z N phenonthroline 771.3 / 773.2 O as a ligand a+O nd [M+H] tert-butyl 3-(6-chloro-1-(4-((N-(2,4- potassium dimethoxybenzyl)methylsulfonamido)methy phosphate as a l)-2-methoxyphenyl)-1H-pyrazolo[4,3- base, c]pyridin-3-yl)-2-oxo-1-oxa-3,8- temperature: diazaspiro[4.5]decane-8-carboxylate 110oC

[0004] Intermediate 4a Step 1 OS O N-(4-(6-Chloro-3-(6-oxo-5-oxa- 7-yl)-1H-pyrazolo[4,3- c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide (Intermediate 4a-1) A solution of Intermediate 3d (418 mg, 0.56 mmol) and TFA (8.4 mL, 113 mmol) in DCM (10 mL) was stirred at RT for 1 h. RM was quenched with sat. aq. NaHCO3 (100 mL) and layers were partitioned. Aqueous layer was extracted with DCM (50 mL) and DCM:i-PrOH (1:1; 3x50 mL). Combined organic layers were dried over Na2SO4, evaporated in vacuo and the residue purified by flash chromatography on Si cartridge eluting with 0-100 % DCM / MeOH / NH4OH (90:5:0.5) in DCM to afford the title product (278 mg). LCMS (Method 2): Rt = 0.79 min, ES+m / z 493.2 / 495.2 [M+H]+. Step 2 N-(4-(6-Chloro-3-(2-(2-hydroxyethyl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide (Intermediate 4a) A solution of Intermediate 4a-1 (60 mg, 0.12 mmol), bromoethanol (11 µL, 0.16 mmol) and DIPEA (31 mg, 0.21 mmol) in dry DMF (2 mL) was stirred at 55 °C overnight. After cooling to RT, RM was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). Combined organic layers were washed with water and sat. aq. NaCl, dried over Na2SO4and concentrated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-75 % DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (22 mg). LCMS (Method 2): Rt = 0.79 min, ES+m / z 537.2 / 539.2 [M+H]+. Intermediate 4b O OSNO Ethyl 2- phenyl)-1H- pyrazolo[4,3-c]pyridin-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-yl)acetate Intermediate 4a-1 (108 mg, 0.19 mmol), ethyl bromoacetate (21 µL, 0.19 mmol) and DIPEA (74 mg, 0.38 mmol) in dry DMF (2 mL) was stirred at RT for 15 min. RM was diluted with water (20 mL) and filtered to isolate the formed precipitate. The filtrate was extracted with EtOAc (3x10 mL) and combined organic layers washed with water and sat. aq. NaCl, dried over Na2SO4then concentrated in vacuo. The residue from evaporation was combined with the previously filtered solid precipitate. Combined materials were submitted to purification by flash cromatography on Si cartridge by eluting with 0-100 % EtOAc in DCM to afford the title product (45 mg). LCMS (Method 2): Rt = 0.96 min, ES+m / z 579.2 / 581.2 [M+H]+. Intermediate 4c A mixture of Intermediate 4a-1 (56 mg, 0.11 mmol) in aqueous formaldehyde (37%, 7.0 mL, 94 mmol) and formic acid (3.0 mL, 80 mmol) was heated in a MW reactor at 90-100oC for 4 hours. After cooling to RT, RM was diluted with water (20 mL) and extracted with DCM (50 mL + 2x20 mL). Combined organic layers were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM to afford the title product (32 mg). LCMS (Method 2): Rt = 0.86 min, ES+m / z 507.2 / 509.2 [M+H]+. Intermediate 4d Step 1 O S O N-(4-(6-Chloro-3-(2- yl)-1H-pyrazolo[4,3- c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide 1) Title product was prepared on a similar manner to Intermediate 4a-1 starting from Intermediate 3e. LCMS (Method 2): Rt = 0.84 min, ES+m / z 521.2 / 523.2 [M+H]+. Step 2 O N-(4-(6-Chloro-3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide (Intermediate 4d) A solution of Intermediate 4d-1 (45 mg, 0.09 mmol) in formic acid 81 mL, 27 mmol) and aq. Formaldehyde (37 %, 3.0 mL, 40 mmol) was heated at 80 °C for 2 h under microwave irradiation. A further equivalent of aq. formaldehyde and formic acid was added to achieve full conversion. After cooling to RT, RM was carefully neutralised with sat. aq. NaHCO3(40 mL) and extracted with EtOAc (3x50 mL), DCM (2x30 mL) and DCM:i-PrOH (1:1, 3x40 mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-100 % DCM / MeOH / NH4OH (90:9:1.5) in DCM to afford the title product (70 mg) that was used in the next synthetic steps without further purifications. LCMS (Method 2): Rt = 0.91 min, ES+m / z 535.2 / 537.2 [M+H]+. Intermediate 4e HN O S N-(4-(6-Chloro-3-(8- [4.5]decan-3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide (Intermediate Title product was prepared on a similar manner as Intermediate 4a starting from 4d-1 and bromoethanol (10 µL, 0.14 mmol) LCMS (Method 2): Rt = 0.84 min, ES+m / z 565.2 / 567.2 [M+H]+. Intermediate 5 Step 1 O 2-Bromo-4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxybenzaldehyde (Intermediate 5-1) A mixture of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (400 mg, 1.43 mmol), 2-bromo- 4-fluoro-5-methoxy-benzaldehyde (334 mg, 1.43 mmol), and K2CO3(593 mg, 4.29 mmol) in dry DMF (10 mL) was stirred at 50 °C for 3.5 h. A second equivalent of 6-chloro-3-iodo-1H- pyrazolo[4,3-c]pyridine was added and RM further stirred at 50 °C for 2 h. After cooling to RT, RM was diluted with water. Formed precipitate was filtered, washed with water and triturated with MeOH / DCM to afford the desired product (669 mg) that was used in the next steps without further purifications. LCMS (Method 2): Rt = 1.31 min, ES+m / z 491.9 / 493.9 / 495.9 [M+H]+. Step 2 (R)-2-Bromo-4-(6-chloro-3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)-5-methoxybenzaldehyde (Intermediate 5-2) A degassed mixture of Intermediate 5-1 (450 mg, 0.91 mmol), Intermediate 1b (527 mg, 3.65 mmol), K3PO4 (582 mg, 2.74 mmol), CuI (69.6 mg, 0.36 mmol) and 3,4,7,8-tetramethyl-1,10- phenanthroline (54.0 mg, 0.228 mmol) in DMSO (10 mL) was stirred under argon at 90 °C for 45 min. After cooling to RT, RM was diluted with water (100 mL) and extracted with EtOAc (5x). Combined organics were washed with aq. ammonia (1M), sat. aq. NaCl, dried over Na2SO4 and solvents evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-60 % DCM / MeOH / NH4OH (90:9:0.5) in DCM to afford the title product (191.4 mg). LCMS (Method 2): Rt = 1.14 min, ES+m / z 508.0 / 510.0 / 511.9 [M+H]+. Step 3 O (R)-4-(6-Chloro-3-(5-( - 3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-2-(methylthio)benzaldehyde (Intermediate 5-3) To a solution of Intermediate 5-2 (190 mg, 0.37 mmol) in DMF (9.5 mL) was cooled to 0oC, sodium methanethiolate (13.6 mg, 0.20 mmol) was added in one portion and RM stirred for 1h. After warming to RT, RM was diluted with water and extracted with EtOAc (4x). Combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4and solvent removed in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-50% DCM / MeOH / NH4OH (90:9:0.5) in DCM to afford the title product (47.3 mg). LCMS (Method 2): Rt = 1.09 min, ES+m / z 476.1 / 478.1 [M+H]+. Step 4 (R)-N-(4-(6-Chloro-3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-1H- c]pyridin-1-yl)-5-methoxy-2-(methylthio)benzyl)-N-(2,4- methanesulfonamide (Intermediate 5-4) Title compound was prepared on a similar manner as Intermediate 2a-2 starting from Intermediate 5-3. LCMS (Method 1): Rt = 1.26 min, ES+m / z 627.3 / 629.2 [M+H]+. Step 5 OS O(R)-3-(6-Chloro-1-(4-( -2-methoxy-5- (methylthio)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-5-((dimethylamino)methyl)oxazolidin- 2-one (Intermediate 5) Title compound was prepared on a similar manner as step 3 of Intermediate 2a starting from Intermediate 5-4. LCMS (Method 2): Rt = 1.22 min, ES+m / z 705.2 / 707.2 [M+H]+. PREPARATION OF EXAMPLES Example 1 N-(3-Methoxy-4-(3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1- yl)benzyl)methanesulfonamide (Example 1) A degassed mixture of Intermediate 4d (60 mg, 0.04 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (11 mg, 0.05 mmol), K3PO4(18 mg, 0.08 mmol) and XPhos PdG3 (1.8 mg, 2 μmol) in water (1.5 mL) / THF (3 mL) was heated at 70 °C under nitrogen for 1h. A second equivalent of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyrimidine and XPhos Pd G3 was added and RM further heated at 70 °C for 1h. After cooling to RT, RM was diluted with water (20 mL) and extracted with DCM (3x20 mL). Combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4and solvent was removed in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-100 % DCM / MeOH / NH4OH (90:9:1.5) in DCM to afford the title product (16 mg). LCMS (Method 3): Rt = 3.38 min, ES+m / z 618.2 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ: 9.64 (d, J=1 Hz, 1H), 9.22 (dd, J=7.1 Hz, 1.6 Hz, 1H), 8.89 (s, 1H), 8.68 (dd, J=4.1 Hz, 1.8 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.71 (t, J =6.3 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36 (d, J=1.2 Hz, 1H), 7.14-7.19 (m, 2H), 4.31 (d, J=6.5 Hz, 2H), 4.02 (s, 2H), 3.84 (s, 3H), 2.95 (s, 3H), 2.39-2.58 (m, 4H, overlapped with DMSO), 2.21 (s, 3H), 1.89-2.04 (m, 4H). Examples 2 to 5 The following Examples were prepared in a similar manner to Example 1 from the indicated starting materials. It is additionally stated if base, solvent, temperature ligand and / or palladium source were varied. Analytical ample Structure / nameStaData ExrtingMaterial(LCMS and 1H-NMR) O S HN O LCMS (Method 3): Rt = 3.22 min, ES+m / z 620.2 [M+H]+N N1HNMR (600 MHz, DMSO-d6) N O N δ: 9.60 (d, J=1.2 Hz, 1H), 9.22 N N (dd, J=7.0 Hz, 1.9 Hz, 1H), 8.89 N O (s, 1H), 8.69 (dd, J=4.0 Hz, 1.6 O Hz, 1H), 8.17 (d, J=1.3 Hz, 1H), Example Intermed 7.72 (t, J= 6.9 Hz, 1H), 7.51 (d, 2 N iate 4a J= 8.0 Hz, 1H), 7.37 (d, J= 1.7 OHHz, 1H), 7.17 (dd, J=8.2 Hz, 1.6 N-(4-(3-(2-(2-hydroxyethyl)-6- Hz, 1H), 7.15 (dd, J=7.2 Hz, 4.3 oxo-5-oxa-2,7- Hz, 1H), 4.45 (t, J= 6.1 Hz, 1H), diazaspiro[3.4]octan-7-yl)-6- 4.41 (s, 2H), 4.32 (d, J=6.7 Hz, (pyrazolo[1,5-a]pyrimidin-3-yl)- 2H), 3.85 (s, 3H), 3.58 (d, J=9.6 1H-pyrazolo[4,3-c]pyridin-1-yl)- Hz, 2H), 3.48 (d, J=9.2 Hz, 2H), 3- 3.38 (q, J=6.4 Hz, 2H), 2.96 (s, methoxybenzyl)methanesulfona 3H), 2.54 (t, J= 5.6 Hz, 2H) mide O S HN O LCMS (Method 3): Rt = 3.70 min, ES+m / z 662.2 [M+H]+N N1HNMR (600 MHz, DMSO-d6) N O N δ: 9.60 (d, J=1.0 Hz, 1H), 9.22 N N (dd, J=7.1 Hz, 1.8 Hz, 1H), 8.89 N O (s, 1H), 8.69 (dd, J=4.7, 2.0 Hz, 1H), 8.17 (d, J=1 Hz, 1H), 7.72 Example O Intermed (bs, 1H), 7.51 (d, J=7.8 Hz, 1H), 3 iate 4b N 7.37 (d, J=1.9 Hz, 1H), 7.18 (dd, O J=8.0, 1.5 Hz, 1H), 7.15 (dd, O J=7.0, 4.2 Hz, 1H), 4.42 (s, 2H), 4.32 (s, 2H), 4.07 (q, J=7.4 Hz, ethyl 2-(7-(1-(2-methoxy-4- 2H), 3.84 (s, 3H), 3.67 (d, J=8.7 (methylsulfonamidomethyl)phen Hz, 2H), 3.64 (d, J=9.3 Hz, 2H), yl)-6-(pyrazolo[1,5-a]pyrimidin- 3.37 (s, 2H), 2.95 (s, 3H), 1.19 3-yl)-1H-pyrazolo[4,3-c]pyridin- (q, J=7.5 Hz, 3H) 3-yl)-6-oxo-5-oxa-2,7- diazaspiro[3.4]octan-2-yl)acetate O H S N O LCMS (Method 3): Rt = 3.26 min, ES+m / z 590.2 [M+H]+N N N N O1HNMR (500 MHz, DMSO-d6) N δ: 9.59 (s, 1H), 9.22 (dd, J=7.4 N Hz, 2.2 Hz, 1H), 8.89 (s, 1H), N O 8.68 (dd, J=4.2 Hz, 1.7 Hz, 1H), Example Intermed O 8.17 (s, 1H), 7.71 (t, J=6.2 Hz, 4 iate 4c 1H), 7.50 (d, J=7.9 Hz, 1H), N 7.37 (d, J=1.2 Hz, 1H), 7.14- N-(3-methoxy-4-(3-(2-methyl-6- 7.19 (m, 2H), 4.41 (s, 2H), 4.32 oxo-5-oxa-2,7- (d, J=6.5 Hz, 2H), 3.85 (s, 3H), diazaspiro[3.4]octan-7-yl)-6- 3.55 (d, J=8.7 Hz, 2H), 3.43 (d, (pyrazolo[1,5-a]pyrimidin-3-yl)- J=8.4 Hz, 2H), 2.95 (s, 3H), 2.31 1H-pyrazolo[4,3-c]pyridin-1- (s, 3H) yl)benzyl)methanesulfonamide O O S NH LCMS (Method 3): Rt = 3.33 N N min, ES+m / z 648.2 [M+H]+N N O1N HNMR (500 MHz, DMSO-d6) N δ: 9.64 (s, 1H), 9.22 (dd, J=7.4 N O Hz, 1.8 Hz, 1H), 8.89 (s, 1H), O 8.68 (dd, J =4.3 Hz, 1.8 Hz, 1H), 8.16 (s, 1H), 7.71 (t, J=6.2 Hz, Example Intermed N 1H), 7.51 (d, J=8.3 Hz, 1H), 5 iate 4e 7.36 (d, J=0.9 Hz, 1H), 7.14- OH7.19 (m, 2H), 4.39 (t, J=4.9 Hz, N-(4-(3-(8-(2-hydroxyethyl)-2- 1H), 4.31 (d, J=6.4 Hz, 2H), oxo-1-oxa-3,8- 4.02 (s, 2H), 3.84 (s, 3H), 3.50 diazaspiro[4.5]decan-3-yl)-6- (q, J=6.1 Hz, 2H), 2.95 (s, 3H), (pyrazolo[1,5-a]pyrimidin-3-yl)- 2.47-2.59 (m, overlapped with 1H-pyrazolo[4,3-c]pyridin-1-yl)- DMSO, 4H), 2.45 (t, J=6.4 Hz, 3- 2H), 1.90-2.03 (m, 4H) methoxybenzyl)methanesulfona mide Example 6 Step 1 N-(2,4-Dimethoxybenzyl)-N-(3-methoxy-4-(3-(2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Intermediate example 6-1) Title compound was prepared on a similar manner as Example 1 starting from Intermediate 3a. LCMS (Method 2), Rt = 1.10, ES+m / z 685.32 [M+H]+. Step 2O S ON-(3-Methoxy-4-(3-(2- [1,5-a]pyrimidin-3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Example 6) To a solution of intermediate example 6-1 (109 mg, 0.14 mmol) in DCM (2.6 mL), TFA (1.05 mL, 14.2 mmol) was added and RM stirred at RT for 1 h. RM was cooled to 0oC and neutralised with sat. NaHCO3and extracted with DCM (2x). Combined organic layers were washed with water, sat. aq. NaCl, dried over a phase separator cartridge and evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-10% methanol in DCM to afford the title product (8 mg). LCMS (Method 3), Rt = 4.03 min, ES+m / z 535.1 [M+H]+. 1H-NMR (600 MHz, DMSO-d6) δ: 9.59-9.63 (m, 1H), 9.23 (dd, J=7.0, 1.7 Hz, 1H), 8.90 (s, 1H), 8.70 (dd, J=4.1, 1.7 Hz, 1H), 8.17 (d, J=1.1 Hz, 1H), 7.73 (br s, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.10-7.21 (m, 2H), 4.54-4.72 (m, 2H), 4.33 (br d, J=1.1 Hz, 2H), 4.23 (dd, J=8.9, 7.2 Hz, 2H), 3.85 (s, 3H), 2.96 (s, 3H). Examples 7 to 8 The following Examples were prepared in a two step process similar manner Example 6 from the indicated starting materials. It is additionally stated if base, solvent, temperature ligand and / or palladium source were varied. Step 1 Starting Intermediate Structure / name MaterialLCMSOS ON O (Method 1): O Rt = 0.72 Intermediate O Intermediate min, ES+7aN NO N 3b m / z 742.4 N O+N [M+H] N N NO S ON O (Method 1): Cl O O Rt = 0.78 Intermediate Intermediate NNO min, ES+8a N 3c m / z 776.4 N O [M+N +H] N N N OS ON O LCMS S O (Method 2): Intermediate O Intermediate Rt = 1.14 9aNNO 5+N min, ES N m / z 78 NO8.5 [M+H]+N N N Step 2 Starting Analytica cture / name Materia l Data Example Stru l (from (LCMS and 1H-NMR) step 1) OS OHN LCMS (Method 3): Rt = 3.28 min, ES+m / z 592.1 [M+H]+O 1NNO HNMR (500 MHz, DMSO-d6) δ: N 9.62 (s, 1H), 9.23 (d, J=7.0 Hz, N NO1H), 8.89 (s, 1H), 8.69 (d, J=2.4 N N Hz, 1H), 8.17 (s, 1H), 7.73 (t, Example N Intermed J=6.4 Hz, 1H), 7.52 (d, J=7.9 Hz, 7 iate 7a N-(4-(3-(5- 1H), 7.37 (s, 1H), 7.14-7.19 (m, ((dimethylamino)methyl)-2- 2H), 4.97-5.03 (m, 1H), 4.32 (d, oxooxazolidin-3-yl)-6- J=6.1 Hz, 2H), 4.27 (t, J=9.0 Hz, (pyrazolo[1,5-a]pyrimidin-3-yl)- 1H), 3.94 (dd, J=9.2, 7.3 Hz, 1H), 1H-pyrazolo[4,3-c]pyridin-1-yl)- 3.85 (s, 3H), 2.95 (s, 3H), 2.65- 3- 2.72 (m, 2H), 2.26 (s, 6H). methoxybenzyl)methanesulfona mideO S OHN LCMS (Method 3): Rt = 3.59 min, ES+m / z 626.1 [M+H]+Cl O 1NNO HNMR (600 MHz, DMSO-d6) δ: N 9.63 (d, J= 1.1 Hz,1H), 9.24 (dd, N NOJ= 7.2, 1.6 Hz, 1H), 8.89 (s, 1H), N N 8.71 (dd, J=4.1, 1.6 Hz, 1H), 8.21 Example N Intermed (d, J=1.1 Hz, 1H), 7.79 (bs, 1H), 8 iate 8a (R)-N-(2-chloro-4-(3-(5- 7.67 (s, 1H), 7.53 (s, 1H), 7.17 ((dimethylamino)methyl)-2- (dd, J=7.2, 4.0 Hz, 1H), 5.03-4.97 oxooxazolidin-3-yl)-6- (m,1H), 4.39 (s, 2H), 4.29 (t, (pyrazolo[1,5-a]pyrimidin-3-yl)- J=9.0 Hz, 1H), 3.96 (dd, J=9.5, 1H-pyrazolo[4,3-c]pyridin-1-yl)- 7.2 Hz, 1H), 3.90 (s, 3H), 3.04 (s, 5- 3H), 2.72-2.66 (m, 2H), 2.27 (s, methoxybenzyl)methanesulfona 6H). mide OS OHN LCMS (Method 3): Rt = 3.69 min, ES+m / z 638.3 [M+H]+S O 1NNO HNMR (600 MHz, DMSO-d6) δ: N 9.63 (d, J=1.2 Hz, 1H), 9.24 (dd, N NOJ=7.0, 1.7 Hz, 1H), 8.90 (s, 1H), N N 8.69 (dd, J=4.1, 1.7 Hz, 1H), 8.21 Example N Intermed (d, J=1.1 Hz, 1H), 7.71 (br.s, 1H), 9 iate 9a (R)-N-(4-(3-(5- 7.53 (s, 1H), 7.47 (s, 1H), 7.17 ((dimethylamino)methyl)-2- (dd, J=7.0, 4.1 Hz, 1H), 5.04-4.98 oxooxazolidin-3-yl)-6- (m, 1H), 4.38 (s, 2H), 4.32-4.28 (pyrazolo[1,5-a]pyrimidin-3-yl)- (m, 1H), 3.96 (dd, J=9.3, 7.1 Hz, 1H-pyrazolo[4,3-c]pyridin-1-yl)- 1H), 3.86 (s, 3H), 3.02 (s, 3H), 5-methoxy-2- 2.71-2.68 (m, 2H), 2.48 (s, 3H), (methylthio)benzyl)methanesulf 2.27 (s, 6H) onamide Examples 10 and 11 OS O O S OHN HN (S)- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide -6- 3- methoxybenzyl)methanesulfonamide (Example 11) Example 10 and example 11 were obtained from chiral resolution of a (S)-rich scalemic mixture of Example 7 (281 mg) by means of chiral chromatographic separation. Samples were dissolved in mixture of DCM / MeOH (1:1) and chromatographed on Chiralpapak IH column (20mm x 250mm, 5μm) at 40oC, isocratic conditions (40:60 MeOH:CO2 (0.2% v / v NH3), flow rate 50 mL / min, BPR 100 BarG, detector at 210 nm, injection volume 500 μL to afford example 10 (117mg) and example 11 (23 mg). Chiral Purity Analysis Method Chiralpapak IH column (4.6 mm x 250mm, 5μm) at 40oC, isocratic conditions (45:55 MeOH:CO2(0.1% v / v NH3), flow rate 4 mL / min, BPR 125 BarG, detector at 210-400 nm, injection volume 1 μL. Example 10 LCMS (Method 3), Rt = 3.28 min, ES+m / z 592.2 [M+H]+Chiral chromatography (Chiral purity analysis Method): Rt = 5.72 min, ee = 99.6 % 1H-NMR (600 MHz, DMSO-d6) δ: 9.63 (d, J=1.3 Hz, 1H), 9.24 (dd, J=7.0, 1.7 Hz, 1H), 8.90 (s, 1H), 8.70 (dd, J=4.0, 1.7 Hz, 1H), 8.18 (d, J=1.1 Hz, 1H), 7.74 (br s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.15-7.19 (m, 2H), 5.01 (m, 1H), 4.33 (s, 2H), 4.27-4.30 (m, 1H), 3.95 (dd, J=9.4, 7.2 Hz, 1H), 3.86 (s, 3H), 2.96 (s, 3H), 2.66-2.72 (m, 2H), 2.27 (s, 6H). Example 11 LCMS (Method 3), Rt = 3.32 min, ES+m / z 592.2 [M+H]+Chiral chromatography (Chiral purity analysis Method): Rt = 6.52 min, ee = 99.0 % 1H-NMR (600 MHz, DMSO-d6) δ: 9.63 (d, J=1.3 Hz, 1H), 9.24 (dd, J=7.0, 1.7 Hz, 1H), 8.90 (s, 1H), 8.70 (dd, J=4.0, 1.7 Hz, 1H), 8.18 (d, J=1.1 Hz, 1H), 7.74 (br s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.15-7.19 (m, 2H), 5.01 (m, 1H), 4.33 (s, 2H), 4.27-4.30 (m, 1H), 3.95 (dd, J=9.4, 7.2 Hz, 1H), 3.86 (s, 3H), 2.96 (s, 3H), 2.66-2.72 (m, 2H), 2.27 (s, 6H). Chiral assignment Syntheses of (S)-rich scalemic mixture of example 7 was made from a scalemic mixture of (R)-rich (ee%=60%) of 5-(chloromethyl)oxazolidin-2-one following the procedure of example 7. Assuming no racemization occurred during conversion of scalemic 5-(chloromethyl)oxazolidin-2- one to scalemic intermediate 1a, and scalemic intermediate 1a to scalemic example 7, the major isolated peak during chiral separation was assigned to the product derived from (R)-5- (chloromethyl)oxazolidin-2-one (example 10). Example 12 Step 1 O (R)-N-(2,4- - methyl)-2-oxooxazolidin-3- yl)-6-((3-methoxypyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-2- (methylthio)benzyl)methanesulfonamide (Intermediate example 12-1). A degassed mixture of Intermediate 5 (40 mg, 57 µmol), 3-methoxypyrazin-2-amine (9.2 mg, 74 mmol), sodium tert-butoxide (8.2 mg, 85 µmol) and RuPhos Pd G3 (7.1 mg, 8.5 µmol) in dioxane (1.1 mL) was stirred at 85 °C for 90 min. After cooling to RT, a second equivalent of RuPhos Pd G3 was added and RM further stirred at 85°C for 1 h. RM was cooled to RT, diluted with DCM and evaporated. The residue was purified by flash chromatography on Si cartridge by eluting with 0-100 % DCM:MeOH:NH4OH (90:9:0.5) in DCM to afford the title product was obtained (17.7 mg). LCMS (Method 2): Rt = 1.17 min, ES+m / z 679.2 [M+H]+. Step 2 O HN S (R)-N-(4-(3-(5-( 3-yl)-6-((3-oxo-3,4- dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-2- (methylthio)benzyl) A mixture of Intermediate example 12-1 (10.0 mg, 12.6 µmol), NaI (5.7 mg, 37.8 µmol) and TMS-Cl (4.77 µL, 37.8 µmol) in MeCN (0.6 mL) was stirred in a sealed vial at 85 °C for 2 h. RM was cooled to RT and solvent evaporated. The residue was purified by flash chromatography on Si cartridge by eluting with 0-50 % DCM:MeOH:NH4OH (90:9:0.5) in DCM to afford the title product (3.5 mg). LCMS (Method 3): Rt = 3.56 min, ES+m / z 630.3 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ: 12.20 (br.s, 1H), 9.35 (br.s, 1H), 8.77 (s, 1H), 8.14 (br.s, 1H), 7.67 (br.s, 1H), 7.48 (s, 1H), 7.44 (s, 1H), 6.92-6.87 (m, 2H), 5.02-4.95 (m, 1H), 4.36 (br.s, 2H), 4.27 (t, J=9.0 Hz, 1H), 3.95-3.90 (m, 1H), 3.84 (s, 3H), 3.00 (s, 3H), 2.69-2.66 (m, 2H), 2.46 (s, 3H), 2.26 (s, 6H). Example A Step 1 N-(4-(6-Chloro-3-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3- methoxybenzyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (Intermediate example A-1) Title compound was prepared on a similar manner as intermediate 3a starting from Intermediate 2a by replacing oxazolidin-2-one with (2,4-dimethoxyphenyl)methanamine. LCMS (Method 2): Rt = 1.33 min, ES+m / z 682.2 / 684.2 [M+H]+. Step 2 OS ON-(4-(3-Amino-6-chloro-1H- 1-yl)-3- methoxybenzyl)methanesulfonamide (Intermediate example A-2) Title compound was prepared on a similar manner as intermediate 4a-1 starting from Intermediate example A-1. LCMS (Method 1): Rt = 0.73 min, ES+m / z 382.1 / 384.0 [M+H]+. Step 3 2-(Dimethylamino)ethyl (6-chloro-1-(2-methoxy-4- (methylsulfonamidomethyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (Intermediate example A-3) A mixture of Intermediate example A-2 (28 mg, 67 µmol), imidazole (14 mg, 0.20 mmol) and CDI (44 mg, 0.27 mmol) in 2-Me THF (1.3 mL) was stirred in a closed vial at 90°C overnight. A second equivalent of 2-(Dimethylamino)ethanol was added and reaction further heated at 90°C for 4 h. After cooling to RT, RM was partitioned between DCM and water. Aqueous layer was further extracted with DCM (3 x). Combined organic layers were dried over Na2SO4and solvent removed in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with DCM / MeOH (20:1 to 10:1) and finally with DCM / MeOH / NH4OH, (90:9:1.5) to afford the title product (7.0 mg). LCMS (Method 1): Rt = 0.63 min, ES+m / z 497.1 / 499.0 [M+H]+. Step 3 OS OHN 2-(dimethylamino)ethyl phenyl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (Example A) Title product was prepared on a similar way to Example 1 starting from Intermediate example A-3. LCMS (Method 3), Rt = 3.27 min, ES+m / z 580.2 [M+H]+1H-NMR (500 MHz, DMSO-d6) δ: 10.56 (br s, 1H), 9.29 (s, 1H), 9.22 (dd, J=7.0, 1.5 Hz, 1H), 8.88 (s, 1H), 8.68 (dd, J=4.1, 1.7 Hz, 1H), 8.16 (s, 1H), 7.72 (t, J=6.3 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.36 (d, J=0.9 Hz, 1H), 7.13-7.18 (m, 2H), 4.31 (d, J=6.4 Hz, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.84 (s, 3H), 2.95 (s, 3H), 2.56-2.61 (m, 2H), 2.24 (s, 6H). PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION (1-12) Biochemical Potency on JAK1, JAK2 , JAK3 and Tyk2 Assay principle The objective of this study was to assess the capability of compounds to inhibit all 4 JAK isoforms activity in a cell-free environment. Assay for JAK 1, JAK 2, JAK 3 and TYK2 were performed by Time-resolved fluorescence resonance energy transfer (TR-FRET) technology. It consists in the interaction of two labelled binding partners detected by the energy transfer from an excited donor to an acceptor dye and measurement of light emission by the acceptor dye. LANCE Ultra kinase assay was used. In presence of JAK 1, JAK 2, JAK 3 and TYK2 kinases and ATP (corresponding to Km), the ULight peptide substrate (LANCE Ulight-JAK-1 (Tyr1023) Peptide, Perkin Elmer, TRF0121) is phosphorylated. It is then captured by Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 Anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), which bring the Eu-chelate donor and ULight acceptor dyes into close proximity. Upon excitation at 320 nm, the Eu-chelate transfers its energy to the ULight dye, resulting in a fluorescent light emission at 665 nm. Compound testing Serial dilutions of compounds in pure DMSO are prepared from 10 mM DMSO stock solutions. Compounds were tested in 384-well plate for 11 consecutive 5-fold dilutions starting from 20 µM highest concentration (20 µM – 2 pM).200 nL of compound were transferred from mother plate to test plate by using Mosquito (TTP labtech). Assay was performed in 384-well Perkin Elmer test plate in 20 µL assay volume (kinase reaction) and 40 µL total volume (stopping reagent and antibody detection reagents). In 10 µL of substrate solution (peptide + ATP) 30 / 50 / 20 / 10nM of peptide and 20 / 0.7 / 0.2 / 12µM of ATP were added for JAK 1, JAK 2, JAK 3 and TYK2 respectively. 10 µL of enzyme solution was added to kinase reaction at these concentrations: 0.15 / 0.083 / 0.025 / 0.144 ng / µL of JAK 1, JAK 2, JAK 3 and TYK2 respectively. After shaking and 1.5h of incubation at r.t., 20 µL of Stop (10 µL EDTA) and Detection mixture (10 µL Europium-anti-phospho antibody, final: 0.5 nM) were added. Reading was performed after 1h of incubation on a EnVision 2104 reader (Perkin Elmer). Calculation of IC50 data, curves and QC analysis was performed by using Excel tool and GraphPadPrism software, v9. Briefly, individual concentration-effect curves are generated by plotting the logarithm of the tested concentration of tested compounds (X) vs. corresponding percent inhibition values (Y) using least squares (ordinary) fit. Best fit IC50 values are calculated using Log(inhibitor) vs. normalized response - Variable slope equation, where Y=100 / (1+10^((LogIC50-X)*HillSlope)). QC criteria parameters (Z’, S:B, R2, HillSlope) were checked for every IC50 curve. Calculation of IC50 data, curves and QC analysis were made using Excel tools and GraphPadPrism software. QC criteria parameters: Z' ≥ 0.5, Hill Slope range 0.5 to 5, S:B > 2. Compounds according to the invention showed values in terms of pIC50 higher than 6 with respect to their inhibitory activity on all JAK isoforms corresponding to ≤ 1 µM in terms of inhibitory concentration. Most compounds preferably showed values higher than 7.3, even more preferably higher than 8.3, at least with respect to their inhibitory activity on JAK1; corresponding to ≤50 nM, even more preferably ≤5 nM, in terms of inhibitory concentration. Data for compounds 1-12 are reported in the table hereinbelow Example No JAK1 JAK2 JAK3 TYK2 1 +++ +++ +++ ++ 2 +++ ++ ++ ++ 3 +++ +++ +++ ++ 4 +++ +++ +++ ++ 5 +++ +++ +++ ++ 6 +++ +++ +++ ++ 7 +++ +++ +++ ++ 8 +++ +++ +++ ++ 9 ++ ++ ++ + 10 +++ +++ +++ ++ 11 +++ +++ +++ ++ 12 + ++ ++ + The compounds are classified in the table above in term of potency with respect to their inhibitory activity on JAK1, JAK2, JAK3 and Tyk2 isoforms according to the following classification criterion: + + + : pIC50≥ 8.3 + + : 8.3 > pIC50 ≥ 7.3 + : pIC50 < 7.3 Inhibition of IL-13 induced pSTAT6 in BEAS BEAS-2B human cell line was seeded (100.000 cells / well) and incubated for 48h at 37°C, 5% CO2, 95% humidity. Compounds were added and incubated 30 min followed by IL-13 as trigger. After 30 min incubation, cells were lysed and pSTAT6 determined by Fastscan phospho- stat6 (Tyr641) sandwich ELISA kit (cell signaling). Inhibitors were tested at 11 consecutive 5-fold dilutions starting from 10 µM (10 µM – 40 pM) in duplicate. Calculation of IC50 data, curves and QC analysis were made using Excel tools and GraphPadPrism software. QC criteria parameters: Z' ≥ 0.35, Hill Slope range 0.5 to 5, S:B > 2.

[0005] Compounds according to the invention showed measurable values in terms of pIC50 (BEAS) higher than 5.6. Example pIC50No (BEAS) 1§§§§2§§§3§§§4§§§§5§§§§6§§§7§§§§8§§§§9§§§10§§§§11§§§§12§The compounds are classified in the table above in term of potency with respect to their functional activity in BEAS according to the following classification criterion: §§§§ : pIC50≥ 7.8 §§§ : 7.8 > pIC50 ≥ 6.8 §§ : 6.8 > pIC50 ≥ 5.8 § : pIC50< 5.8 Comparative example A vs Example 10 and Example 11 Example No JAK1 A ++ 10 +++ 11 +++ Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and subranges within a numerical limit or range are specifically included when not explicitly written out. As used herein the words “a” and “an” and the like carry the meaning of “one or more.” Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

CLAIMS 1. A compound of formula (Io) R1whereinR1is a heteroaryl selected fromyl)amino ; R2iswherein R6is H or selected in the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkylthio;R3is a cyclic carbamate or spirocyclic carbamate group of formula J selected from OR7is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, - (CH2)mNR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl; wherein m is in each occurrence independently 0 or an integer from 1 to 4; R4and R5,the same or different, are selected from the group consisting of -H and (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of formula (Io) according to claim 1, represented by the general formula (Ia): O S Owherein R3is J2, and R6 is H or halogen, preferably Cl single enantiomers, diastereoisomers and mixtures thereof and pharmaceutically acceptable salts and solvates thereof.

3. A compound according to claim 1 selected from the list of N-(3-methoxy-4-(3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1- yl)benzyl)methanesulfonamide; N-(4-(3-(2-(2-hydroxyethyl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3- methoxybenzyl)methanesulfonamide; ethyl 2-(7-(1-(2-methoxy-4-(methylsulfonamidomethyl)phenyl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan- 2-yl)acetate; N-(3-methoxy-4-(3-(2-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1- yl)benzyl)methanesulfonamide; N-(4-(3-(8-(2-hydroxyethyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3- methoxybenzyl)methanesulfonamide; N-(3-methoxy-4-(3-(2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(4-(3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide; (R)-N-(2-chloro-4-(3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5- methoxybenzyl)methanesulfonamide; (R)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-2- (methylthio)benzyl)methanesulfonamide; (R)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide; (S)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6-(pyrazolo[1,5- a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide;(R)-N-(4-(3-(5-((Dimethylamino)methyl)-2-oxooxazolidin-3-yl)-6-((3-oxo-3,4- dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-2- (methylthio)benzyl)methanesulfonamide; single enantiomers, diastereoisomers and mixtures thereof or pharmaceutical acceptable salts and solvates thereof.

4. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carrier or excipient.

5. A pharmaceutical composition according to claim 4 suitable to be administered by inhalation, selected from inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.

6. A device comprising the pharmaceutical composition according to claim 5, which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler or a soft mist nebulizer.

7. A compound or a pharmaceutical composition according to any one of claims 1 to 5 for use as a medicament.

8. A compound or a pharmaceutical composition for use according to claim 7 in the prevention and / or treatment of a pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

9. A combination of a compound as defined in any one of the claims 1 to 3 with one or more active ingredients selected from the classes currently used in the treatment of respiratory disorders, and known to the skilled person, such as beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated kinases (P38 MAP kinases) inhibitors, PI3K inhibitors (phosphoinositide 3-kinases), nuclear factor kappa-B kinase subunit beta inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti- inflammatory agents (NSAIDs) and mucus regulators.

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