Heterocyclic derivatives as Janus kinase inhibitors

Abstract

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

Description

Technology Field

[0001] The present invention relates to chemical compounds that are cyclic and spiro-cyclic oxoxazolidine benzylmethanesulfonamide derivatives, which are useful as JAK inhibitors such as JAK 1, useful for the treatment of various inflammatory diseases including asthma, COPD, and other respiratory diseases. Background Technology

[0002] The JAK family consists of non-receptor tyrosine protein kinases and has four major members: JAK1, JAK2, JAK3, and TYK2. Over 50 types of cytokines and growth factors bind to Type I and Type II receptors, which are non-covalently bound to various JAK kinase combinations. The signaling induced by the ligand consists of the phosphorylation of the receptor's tyrosine by JAK and the recruitment of one or more STAT proteins. Tyrosine-phosphorylated STATs form dimers and are transported across the nuclear membrane to the nucleus to regulate specific genes. JAK has seven homologous domains (JAK homologous domains, JH). Starting from the carboxyl terminus, JH1 is the first JH known as the kinase domain and consists of approximately 250 amino acid residues. JH1 encodes a kinase protein that constitutes a kinase structural domain that phosphorylates substrates; JH2 is a pseudokinase domain that regulates the activity of kinase domains. JAK3 is expressed in endothelial cells and vascular smooth muscle cells, as well as in the bone marrow and lymphatic system, while other members are expressed in almost all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26;6(1):402). Many cellular processes, such as hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis, are located downstream of JAK / STAT signaling. Various biological responses are regulated by specific pairings of JAK isoforms. The JAK1 / JAK3 combination mediates IL-2, -4, -7, -9, -15, and -21 signaling, which is associated with lymphocyte growth / maturation, T cell / NK cell differentiation / homeostasis, B cell class transition, and other inflammatory processes.The combination of JAK1 / TYK2 and JAK1 / JAK2 regulates signals associated with innate immune responses, such as IL-6 and type I interferon, which are involved in naive T cell differentiation, T cell homeostasis, granulopoesis, and other inflammatory processes (Howell MD et al., Front. Immunol. 2019, 10, 2342). JAK2 frequently binds to itself (JAK2 / JAK2) and regulates the signaling 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).

[0003] Genetically modified mouse models and human diseases demonstrate the importance of the JAK / STAT pathway in immunocompatibility. In particular, abnormal JAK / STAT signaling, as well as overexpression or mutations involving certain JAK isoforms, induce inflammatory diseases as well as malignancies in hematopoietic and lymphoid tissues. Currently, several FDA (Food and Drug Administration) and / or EU-approved JAK inhibitors are in clinical use. Two small molecules (ruxolitinib and fedratinib) are being used for hematological diseases such as myelofibrosis and polycythemia vera; Six types of JAK inhibitors (tofacitinib, baricitinib, ruxololitinib, filgotinib, upadicitinib, and delgocitinib (Japan)) are used for immune-mediated diseases such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis, and acute graft-versus-host disease. In addition, some of these drugs, as well as others, are currently undergoing Phase 2 and Phase 3 clinical trials for indications ranging from autoimmune diseases (lupus, vitiligo, etc.) and inflammatory bowel disease to non-Hodgkin lymphoma and COVID-19 (Hu X. et al., Sig Transduct Target Ther 2021, 6: 402).

[0004] Small molecules targeting JAK / STAT also represent attractive options for the treatment of fibrotic diseases. Indeed, inflammatory cytokines (IL-4, IL-3, IL-6, IL-11, IL-31, etc.) and growth factors (FGF, VEGF, etc.) involved in the fibrosis process activate the JAK / STAT pathway. Ruxolitinib, tested in a mouse model of bleomycin-induced fibrosis, improved fibrotic lesions in the lungs and reduced levels of fibrotic molecular markers (Zhang, Y et al., Ann. Rheum. Dis. 2017, 76, 1467-1475), whereas tofacitinib acted as a prophylactic agent in experimental cutaneous and pulmonary fibrosis (Wang, W et al., Scleroderma Relat. Disord. 2020, 5, 40-50). Some case reports in patients have been studied. A single six-case report confirmed the efficacy and safety of tofacitinib in combination with nintedanib in the management of aggressive interstitial lung disease with a poor prognosis (Conca, W et al., Front. Pharmacol. 2020, 11, 5857619). Baricitinib has been proven to be a safe immunomodulator that reduces biomarker levels for pulmonary fibrosis and inflammation in RA patients, including a subgroup of interstitial lung disease (D'Alessandro M et al., Int. Immunopharmacol. 2020, 86, 106748).

[0005] There are several JAK inhibitors currently in clinical trials for COVID-19, including tofacitinib, baricitinib, and ruxolitinib. Baricitinib and ruxolitinib were associated with a reduced risk of death. They reduced the use of invasive mechanical ventilation and had a borderline impact on ICU admission rates and the incidence of acute respiratory distress syndrome (ARDS) (Wijaya, I. et al. Clin. Epidemiol. Glob. Health 2021, 11, 100755). Ruxolitinib was also tested in COVID-19 patients and improved clinical symptoms and chest computed tomography images (Cao Y. et al., J. Allergy Clin. Immunol. 2020 146, 137-146).

[0006] Asthma can be included among numerous immune-mediated diseases in which JAK / STAT signaling plays an essential role in its pathogenesis. Asthma is a chronic inflammatory disease of the airways resulting from a complex interaction between immune responses, genetic susceptibility, and non-specific external stimuli such as colds, allergens, and exercise, which induces hypersensitivity and ultimately contributes to airflow limitation through airway remodeling. Severe asthma affects 5% to 15% of the adult asthma population (300 million worldwide) and represents public health issues associated with increased mortality, increased hospitalizations, severe symptom burden, medical costs, and absenteeism (Steve NG et al., J Allergy Clin Immunol 2021;148:953-63). Severe asthma represents a subset of difficult-to-treat asthma and refers to cases occurring in patients whose disease is not controlled even with the combined use of high-dose inhaled corticosteroids (ICS), long-acting β-agonists, or other controllers. To date, four types of biological agents have been approved for severe asthma: omalizumab (anti-immunoglobulin E antibody), mepolizumab and reslizumab (anti-interleukin [IL]-5 antibodies), benralizumab (anti-IL-5 receptor α antibody), and dupilumab (anti-IL-4 receptor α antibody). Despite their efficacy, many patients continue to experience exacerbations or uncontrolled disease, indicating a need for newer treatments (Israel E, Reddel HK. N Engl J Med 2017; 377:965-76).

[0007] Recent improvements in the pathobiology of asthma have led to a shift from phenotypic classification systems to the introduction of the "endotype" concept. According to the latter, classification is based on the pathophysiological mechanisms and clinical biomarkers associated with the patient (Wenzel SE et al., Am J Respir Crit Care Med 2021;203:809-21). There are two main endotypes of asthma: type 2 and non-type 2. The type 2 pathway is defined by the activation of cytokines derived from TH2 cells and group 2 innate lymphoid cells (ILC2s); these include IL-4, IL-5, and IL-13, which activate eosinophils, B cells, airway epithelial cells, and other cell types to cause airway inflammation. Biomarkers for type 2 asthma include blood / sputum eosinophilia and elevated fractional exhaled nitric oxide (FENO) and IgE levels. The type 2-low pathway is characterized by the absence of type 2-high cytokines and biomarkers, and exhibits an elevated airway neutrophil level or a paucigranulocytic profile with normal airway neutrophil and eosinophil levels. Type 2-low asthma is currently not well understood and may include several distinct endotypes. Potential mediators and / or biomarkers of type 2 low endotypes under investigation include IL-6, IL-17A / F, IL-23, type 1 interferon, CXCL10, TNF, alamin (TSLP, IL-25, IL-33), IL-1β, IL-8, and IFN-γ (Hinks TSC et al., ERJ 2021, 57 (1) 2000528).

[0008] For both type 2 and type 2-low endotypes, almost all of the mediators mentioned above activate the JAK / STAT pathway, and here lies the rationale for the potential use of JAK inhibitors in both endotypes of severe asthma. Simultaneous targeting of multiple cytokines by JAK inhibitors may provide advantages over biological agents (for unresponsive patients) and standard therapy (for uncontrolled patients), considering that they are administered in combination with inhaled corticosteroids (ICS).

[0009] Despite the strong evidence for JAK inhibitors in asthma, the administration of systemic inhibitors may raise safety concerns or limit their use in certain asthma patients, such as children. Given that asthma is a disease limited to the lungs, the inhaled administration route of JAK inhibitors can provide the benefits of therapeutic efficacy while limiting systemic exposure and associated side effects. To date, several companies are developing inhaled JAK inhibitors for the treatment of asthma. AstraZeneca's pipeline includes AZD-0449 (Phase 1 completed) and AZD-4604 (Phase 1 in progress); Theravance Biopharma has launched a new preclinical program for the inhaled JAK inhibitor TD-8236; and Kinaset / Vectura is developing VR588 (Phase 1 in progress) as an inhaled compound. In many preclinical studies sponsored by the aforementioned companies, the efficacy of JAK inhibitors in asthma control has been demonstrated. In the preclinical stage of drug development, the orally administered JAK1 / 3 inhibitor R256 (currently called AZD0449) was shown to be effective in reducing airway resistance, BAL eosinophilia, and mucus production, and when administered during sensitization, TH2 cytokine responses were also reduced (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). Genentech iJak-381, provided as a dry powder, reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in OVA-challenged mice. In addition, this reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in a mouse model chronically exposed to AAH allergens (Dengler HS et al., Sci Transl Med 2018;10:eaao2151).Furthermore, oral JAK inhibitors such as tofacitinib, formulated for aerosol administration, reduced the number of eosinophils in a house dust mite asthma mouse model (Younis US et al., AAPS PharmSci-Tech 2019;20:167).

[0010] Another respiratory disease that can benefit from JAK inhibition limited to the lungs is Chronic Obstructive Pulmonary Disease (COPD), an inflammatory disease of the lungs that is most commonly caused by exposure to tobacco smoke and is characterized by generally irreversible and progressive airflow limitation. Although inflammatory cytokines are the driving force behind chronic airway inflammation, some of which induce JAK / STAT activation (IL-6, IFN-γ, IL-2, etc.), the role of this pathway in the pathogenesis of COPD has not been clearly elucidated. Phosphorylated STAT4+ cells (Di Stefano A et al., Eur Respir J. 2004 Jul; 24(1):78-85) have been found to be increased in COPD compared to healthy non-smoker controls. In another study, the number of phosphorylated STAT3+ and phosphorylated STAT1+ cells was higher in lung biopsies of COPD patients than in non-smoker controls, but could not replicate previous data for phosphorylated STAT4 molecules (Yew-Booth L et al., Eur Respir J 2015; 46(3):843-5). These data may also suggest the therapeutic use of JAK inhibitors in COPD disease. The problem to be solved

[0011] Despite inhalation administration, safety issues may still arise due to the levels of the drug reaching systemic circulation after JAKi inhalation. In addition to a profile highly suitable for inhalation, JAKi should preferably possess additional characteristics that can further limit systemic exposure after inhalation.

[0012] There is still strong demand for JAK inhibitors, particularly inhaled JAK inhibitors that have the potential to provide compounds with improved safety.

[0013] WO 2022 / 194781 A1 discloses structurally similar compounds as JAK inhibitors that differ from the present application in at least the pattern of substituents.

[0014] Given the number of pathological reactions mediated by JAK enzymes, there is a continuing need for JAK enzyme inhibitors that could be useful in treating many disorders, particularly respiratory diseases.

[0015] Therefore, the discovery of novel, safe, and potent JAK inhibitors suitable for local administration to the lungs for the treatment of asthma and respiratory diseases remains an important need. means of solving the problem

[0016] Summary of the present invention

[0017] Accordingly, one object of the present invention is to provide a compound that is a derivative of the formula (Io) of benzylmethanesulfonamide, or a single enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is useful as a JAK kinase inhibitor, wherein

[0018]

[0019] Here, R1, R2, and R3 are as defined in the detailed description of the present invention.

[0020] Another objective of the present invention is to provide a pharmaceutical composition comprising such compounds, a method of using such compounds to treat respiratory diseases, and a manufacturing method and an intermediate useful for manufacturing such compounds.

[0021] In one aspect, the present invention provides a compound of formula (Io) for use as a pharmaceutical agent. In one aspect, the present invention provides the use of the compound of the present invention for the manufacture of a pharmaceutical agent.

[0022] In a further aspect, the present invention provides the use of the compounds of the present invention for the preparation of a drug for the treatment of any disease associated with the JAK enzyme mechanism.

[0023] In another aspect, the present invention provides a method for the prevention and / or treatment of any disease associated with the JAK enzyme mechanism as defined above, and the method comprises administering a therapeutically effective amount of a compound of the present invention to a patient requiring such treatment.

[0024] In certain aspects, the compound of the present invention is used alone or in combination with other active ingredients and may be administered for the prevention and / or treatment of lung diseases including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung disease and idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). Specific details for implementing the invention

[0025] definition

[0026] The term “pharmaceutically acceptable salt” refers to a derivative of the compound of formula (Io), wherein the parent compound is appropriately modified by converting any free acid or base, where present, into a corresponding addition salt with any base or acid ordinarily intended to be pharmaceutically acceptable.

[0027] Accordingly, suitable examples of the above salts may include inorganic or organic base addition salts of acidic residues such as carboxyl groups, as well as inorganic or organic acid addition salts of basic residues such as amino groups.

[0028] The cations of inorganic bases that can be suitably used to produce the salts of the present invention include ions of alkali or alkaline earth metals such as potassium, sodium, calcium, or magnesium. Those that can be obtained by reacting an inorganic or organic acid with a major compound functioning as a base to form a salt include, for example, salts of hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, and citric acid.

[0029] Many organic compounds can form complexes with solvents to which they react, precipitate, or crystallize. Such complexes are known as "solvates," which are an additional object of the present invention. Compounds of formula (Io), or their pharmaceutically acceptable salts, or polymorphs and crystal forms of solvates are additional objects of the present invention.

[0030] The terms "halogen" or "halo-" or "halogen atoms" include fluorine, chlorine, bromine, and iodine atoms, and as substituents mean fluoro, chloro, bromo, and iodo.

[0031] The term "(C1-C6)alkyl" refers to a straight-chain or branched alkyl group, wherein the number of carbon atoms is in the range of 1 to 6. Specific alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methylbutyl, etc.

[0032] The term "(C1-C6)haloalkyl" refers to the "(C1-C6)alkyl" group defined above, wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. Examples include halogenated alkyl groups, poly-halogenated alkyl groups, and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl or difluoromethyl groups.

[0033] In a similar way, the term "(C1-C x )hydroxyalkyl" or "(C1-C x )aminoalkyl" is the "(C1-C x )alkyl" group, wherein one or more hydrogen atoms are each replaced by one or more hydroxy(OH) or amino groups, where x is an integer up to 10. Thus, "(C1-C6)hydroxyalkyl" or "(C1-C6)aminoalkyl" represents the hydroxy- or amino-alkyl group having a number of carbon atoms in the range of 1 to 6.

[0034] The definition of aminoalkyl includes an alkyl group (i.e., a "(C1-C6)alkyl" group) substituted by one or more amino groups (-NR4R5). Examples of aminoalkyls are R4R5N-(C1-C6)alkyl or -(CH2) m It is a mono-aminoalkyl group such as NR4R5. Here, R4, R5 and m are as defined in the detailed description of the invention.

[0035] In relation to substituents R4 and R5 as defined above, where each R4 and R5 forms a 5- or 6-membered heterocyclic radical with the nitrogen atom to which they are connected, cases are further described herein in which at least one additional ring carbon atom in the heterocyclic radical may be replaced by at least one heteroatom or heterogroup (e.g., N, NH, S, or O) or may have an -oxo (=O) substituent. The heterocyclic radical may be further optionally substituted at possible points within the ring, i.e., at the carbon atom, or at a heteroatom or heterogroup that can be substituted. Thus, examples of the heterocyclic radical are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazineyl, 4-morpholinyl, piperazine-4yl-2-one, and 4-methylpiperazine-1-yl.

[0036] term "(C3-C 10 "(C3-C6)cycloalkyl" refers to a saturated cyclic hydrocarbon group containing the indicated number of ring carbon atoms, similar to "(C3-C6)cycloalkyl". Examples include polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and adamantanyl.

[0037] The term "aryl" refers to a mono, bi-, or tri-cyclic carbon ring system having 6 to 20, preferably 6 to 15, ring atoms, wherein at least one ring is aromatic. Examples of suitable aryl ring systems include, for example, phenyl or naphthyl, indenyl, and dihydro-indenyl radicals.

[0038] The term "heteroaryl" refers to a mono-, bi-, or tri-cyclic ring system having 5 to 20, preferably 5 to 15, ring atoms, wherein at least one ring is aromatic and at least one ring atom is a heteroatom (e.g., N, NH, S, or O). Examples of suitable heteroaryl ring systems include, for example, thienyl, pyrroleyl, pyrazolyl, imidazoleyl, isooxazoleyl, oxazoleyl, isothiazolyl, thiazoleyl, pyridineyl, pyrimidineyl, pyrazineyl, pyridazineyl, triazineyl, furanyl, purinyl, indoleyl, isoindoleyl, indazoleyl, etc.

[0039] Derived expression "(C3-C 10 "(C3-C6)heterocycloalkyl" represents a saturated or partially unsaturated mono-, bi-, or tri-cycloalkyl group of the indicated number of carbons, similar to "(C3-C6)heterocycloalkyl", wherein at least one ring atom is a heteroatom (e.g., N, NH, S, or O) and may further have -oxo (=O) substituents (e.g., C(=O), S(=O)2).

[0040] The group may be optionally substituted, where the term “optionally substituted” indicates whether it is substituted or not. When the term “one or more” indicates any atom or group as a substituent of the group of the compound of formula (Io), it is intended that one to three, preferably one to two, more preferably one such substituent may replace the hydrogen on the group or variable group.

[0041] Substitutions include bridged systems, spiro disubstitutions, as well as substitutions at two adjacent atoms, thus forming additional 5- to 6-membered heterocyclic rings in both cases. Examples of (C3-C6) heterocycloalkyls are shown below: oxetanyl, tetrahydro-furanyl, pyrrolidineyl, imidazolidineyl, thiazolidineyl, piperazineyl, piperidineyl, morpholinyl, thiomopolinyl, 9-methyl-3,9-diazaspiro[5.5]undecane-3-yl, and (3aR,6aS)-5-methyl-octahydropyrrolo[3,4-c]pyrrole-2-yl.

[0042] The term "aryl(C1-C6)alkyl" refers to an aryl ring connected to a straight-chain or branched alkyl group having a number of constituent carbon atoms in the range of 1 to 6 (e.g., phenylmethyl (i.e., benzyl), phenylethyl, or phenylpropyl).

[0043] Likewise, the term "heteroaryl(C1-C6)alkyl" refers to a heteroaryl ring connected to a straight-chain or branched alkyl group having a number of constituent carbon atoms in the range of 1 to 6 (e.g., furanylmethyl).

[0044] The term "alkanoyl" refers to HC(O)- or an alkyl carbonyl group (e.g., (C1-C6)alkyl C(O)-), wherein the "alkyl" group has the meaning defined above. Examples include formyl, acetyl, propanoyl, and butanoyl.

[0045] term "(C1-C 10 )alkoxy" or "(C1-C 10 "(C1-C6)alkoxy", likewise "(C1-C6)alkoxy" or "(C1-C6)alkoxy", etc. represent a straight-chain or branched hydrocarbon of an indicated number of carbons connected to the rest of the molecule through an oxygen bridge. "(C1-C6)alkylthio" represents the above hydrocarbon connected through a sulfur bridge.

[0046] The derived expressions "(C1-C6)haloalkoxy" or "(C1-C6)haloalkoxyl" represent the haloalkyl groups defined above, connected via oxygen bridges. Examples of (C1-C6)haloalkoxy are difluoromethoxy and trifluoromethoxy.

[0047] Likewise, the derived expressions "(C3-C6)heterocycloalkyl-(C1-C6)alkyl" and "(C3-C6)cycloalkyl-(C1-C6)alkyl" represent the heterocycloalkyl and cycloalkyl groups defined above connected to the rest of the molecule through the alkyl groups of the indicated number of carbons, e.g., piperidine-4-yl-methyl, cyclohexylethyl.

[0048] The derived expression "(C1-C6)alkoxy(C1-C6)alkyl" refers to the alkoxy group defined above connected to the rest of the molecule through an alkyl group of the indicated number of carbons, e.g., methoxymethyl.

[0049] Likewise, "(C1-C6)haloalkoxy(C1-C6)alkyl" represents the "(C1-C6)haloalkoxy" group defined above, connected to the rest of the molecule through an alkyl group of the indicated number of carbons, e.g., difluoromethoxypropyl.

[0050] Similarly, "(C1-C6)alkoxycarbonyl" refers to the alkoxy group defined above that is connected to the rest of the molecule through a carbonyl group.

[0051] "(C1-C6)alkylthiocarbonyl-" represents the alkylthio group connected to the rest of the molecule through the carbonyl group (C=O).

[0052] "(C1-C6)alkoxycarbonyl-(C1-C6)alkyl" represents the alkoxy group defined above connected to the rest of the molecule through a carbonyl group additionally connected to an alkyl group of the indicated number of carbons, e.g., methoxycarbonylmethyl.

[0053] Therefore, "(C1-C6)alkoxycarbonyl-(C1-C6)alkylthio" represents a linked group such as methoxycarbonylmethylthio.

[0054] The meaning of other derived expressions will be clear.

[0055] For example, "halo-((C1-C6)alkyl(C3-C8)heterocycloalkyl)" represents a linked group such as 4-fluoro-1-methylpyrrolidine-3-yl.

[0056] The oxo moiety is represented by (O) as an alternative to other general expressions, e.g., (=O). The carbonyl group is preferably represented herein as -C(O)- as an alternative to other general expressions such as -CO-, -(CO)-, or -C(=O)-. Generally, a bracketed group is a lateral group that is not included in the chain, and where deemed useful, brackets are used to help clarify linear chemical formulas; for example, the sulfonyl group -SO2- may also be represented as -S(O)2- to clearly show the difference from the sulfin group -S(O)O-.

[0057] In the case of a numerical index, the expression "p is zero" or "p is 0" means that a substituent or group (e.g., Ip) containing the index p is absent, that is, that if necessary, no substituent other than H is present. Likewise, when the index is attached to a bridging divalent group (e.g., (CH2)m), the expression "m is 0 in each case..." or "m is 0" means that the bridging group is absent, that is, that it is a bond.

[0058] As used in the structural formula of this specification A bond that refers to a wave or wavy line like this represents a bond that is a point of attachment of a moiety or substituent to a core or backbone structure.

[0059] The term "bond," used to define substituents, refers to a situation where two functional groups connected by substituents are directly linked to each other without any additional atoms in between.

[0060] A dash ("-") not between two letters or symbols indicates the attachment point of a substituent.

[0061] Whenever a basic amino or quaternary ammonium group is present in the compound of formula (Io), a physiologically acceptable anion selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, malicate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalene disulfonate may be present. Likewise, in the presence of an acidic group such as a COOH group, a corresponding physiological cation salt, including, for example, an alkali or alkaline earth metal ion, may also be present.

[0062] Compounds of formula (Io) may exist as optical stereoisomers if they contain one or more stereogenic centers.

[0063] When the compounds of the present invention have at least one stereocenter, they may therefore exist as enantiomers. When the compounds of the present invention contain two or more stereocenters, they may additionally exist as diastereoisomers. It will be understood that all of the above single enantiomers, diastereoisomers, and mixtures thereof in any proportion are included within the scope of the present invention. The absolute configuration (R) or (S) for the carbon having the stereocenter is assigned based on the Cahn-Ingold-Prelog nomenclature based on the order of groups.

[0064] When "monostereoisomer," "monodiastereoisomer," or "monoenantiomer" is reported near the chemical name of a compound, it indicates that the isomer has been separated into a monodiastereoisomer or enantiomer (e.g., via chiral chromatography), but the absolute configuration at the associated stereocenter has not been determined or assigned.

[0065] Atropisomers are caused by hindered rotation on single bonds, where the steric barrier for rotation is high enough to allow for the separation of the conformer (Bringmann G et al, Angew. Chem. Int. Ed. 44 (34), 5384-5427, 2005. doi:10.1002 / anie.200462661).

[0066] Oki defined rotationally hindered isomers as isoforms that interconvert with a half-life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).

[0067] Rotation-impaired isomers differ from other chiral compounds in that, in many cases, they can reach thermal equilibrium, whereas other forms of chiral isomerization are usually only chemically possible.

[0068] Separation of rotationally hindered isomers is possible by chiral separation methods such as selective crystallization. In atropo-enantioselective or atroposelective synthesis, one rotationally hindered isomer is formed as a sacrifice of the other. Rotationally hindered synthesis can be carried out by using chiral auxiliaries, such as the Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by an approach based on thermodynamic equilibrium where the isomerization reaction favors one rotationally hindered isomer over the other.

[0069] The racemic form of the compound of formula (Io) is included within the scope of the present invention, just like the respective rotationally hindered isomer (which does not substantially contain their corresponding enantiomers) and the stereoisomer-enriched atropisomer mixture.

[0070] The present invention also relates to corresponding deuterated derivatives of the compound of formula (Io). In the context of the present invention, a deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount greater than its natural abundance. Preferably, the percentage of deuterium at that position is at least 90%, more preferably at least 95%, and even more preferably 99%.

[0071] All preferred groups or embodiments described above and below for the compound of formula (Io) can be combined with one another and can also be applied with only minor modifications as needed.

[0072] Term "IC" 50 It represents the half maximal inhibitory concentration as a measure of the potency of a substance that inhibits specific biological or biochemical functions.

[0073] term "pIC" 50 IC expressed in molar concentration 50 Represents the negative logarithm of the value.

[0074] As described above, the present invention provides a compound of the general formula (Io) that acts as a JAK inhibitor, a method for preparing the same, and a pharmaceutical composition comprising the same alone or in combination with one or more active ingredients, or mixed with one or more pharmaceutically acceptable carriers.

[0075] Accordingly, in the first aspect, the present invention relates to a compound of formula (Io), or a single enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0076]

[0077] Here

[0078] R 1 is a heteroaryl selected from the following:

[0079]

[0080] R 2 is the following:

[0081]

[0082] Here

[0083] R 6 is H or Selected from the group consisting of halogens, (C1-C6)alkyls, and (C1-C6)alkylthios;

[0084] R 3 is an expression selected from the following J Cyclic carbamate or spirocyclic carbamate, and:

[0085]

[0086] R 7 H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, -(CH2) m Selected from the group consisting of NR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl;

[0087] Here m is independent in each case It is 0 or an integer from 1 to 4;

[0088] R 4 and R 5 is selected from the group consisting of -H and (C1-C6)alkyl, which are the same or different.

[0089] Therefore, if R2 is as follows:

[0090]

[0091] The present invention also relates to a compound represented by the corresponding general formula (I), or a single enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

[0092]

[0093] Here

[0094] R 1 is a heteroaryl selected from the following:

[0095]

[0096] Here

[0097] R 6 is selected from the group consisting of H or the following:

[0098] Halogen,

[0099] (C1-C6)alkyl,

[0100] (C1-C6)alkylthio-;

[0101] R 3 is an expression selected from the following J of:

[0102]

[0103] R 7 H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, -(CH2) m Selected from the group consisting of NR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl;

[0104] Here m is independent in each case It is 0 or an integer from 1 to 4;

[0105] R 4 and R 5 is selected from the group consisting of the following, which are equal to or different:

[0106] -H,

[0107] (C1-C6)alkyl.

[0108] Variable moiety of the compound of the present invention R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , J2 , J3 ,J4 All devices listed for each of the above are intended to be selectable and may be combined with one another in embodiments included within the scope of the present invention.

[0109] In a preferred embodiment, the present invention relates to compounds of formula (Io) as Jak inhibitors and pharmaceutically acceptable salts and solvates thereof, wherein R 1 It is pyrazolo[1,5-a]pyrimidin-3-yl and R 2 is the following:

[0110]

[0111] Expressed by the general formula (Ia):

[0112]

[0113] Here, R3 is J2 and;

[0114] And R6 is H or a halogen, preferably Cl.

[0115] In another preferred embodiment, the present invention relates to at least one of the compounds listed in Table 1 below, their single enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof.

[0116] Table 1 - List of Desired Compounds

[0117]

[0118]

[0119]

[0120]

[0121] The compounds of the present invention showed high biochemical efficacy against JAK targets (JAK1, JAK2, JAK3, and Tyk2) and high efficacy in representative functional assays in cells (e.g., inhibition of pSTAT6 in IL-13-stimulated BEAS cells).

[0122] Lung retention is a complex interaction between solubility, permeability, and lung protein binding, and the preferred compound of the present invention possesses advantageous physicochemical properties that can lead to an excellent inhalation profile.

[0123] Compounds of the present invention, including all compounds listed above, can be prepared from readily available starting materials by using general methods and procedures as described in the experimental section below, or by using slightly modified procedures readily available to a person skilled in the art. Although specific embodiments of the present invention may be shown or described herein, a person skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared by using the methods described herein or by using other known methods, reagents, and starting materials. Given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise noted. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be easily determined by a person skilled in the art through routine optimization procedures. The manufacturing process described below and reported in the following reaction scheme should not be construed as limiting the range of synthetic methods available for the preparation of the compounds of the present invention.

[0124] In some cases, where a step is required to mask or protect sensitive or reactive moiety, generally known protecting groups (PGs) may be used in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0125] For clarity, including all compounds in Table 1 listed above, represented by Formula (I) here. R 2 go

[0126]

[0127] recognize ( Io The compound of ) can generally be prepared according to the procedure shown in the reaction scheme below. If specific details or steps differ from the general reaction scheme, they are detailed in specific examples and / or additional reaction schemes.

[0128]

[0129] The compound of formula (I) may contain one or more stereocenters. Enantiomerically pure compounds may be prepared according to generally known reactions, for example, according to the reaction described below using enantiomerically pure starting materials and intermediates. These intermediates may be commercially available or may be readily prepared from commercial sources by a person skilled in the art.

[0130] In another approach, enantiomerically pure compounds can be prepared from corresponding racemates and / or scalemic mixtures by chiral chromatography purification.

[0131] The compound of formula (I) is Reaction Equation 1 It can be manufactured according to. Compound Ⅱ is by deprotection of the protector of PG1 and / or PG2. I It is an intermediate that can be converted into a compound. In the absence of PG1 and PG2, the intermediate Ⅱ It is evident that any general approach described for the manufacture of will provide a compound of general formula (I).

[0132] intermediate Ⅱ is an intermediate Ⅳ and intermediateⅢ It can be obtained by the direct introduction of R1 (or R1 appropriately protected with PG2, i.e., r1) through metal / palladium-catalyzed cross-coupling reactions such as Suzuki coupling, Stille coupling, Buchwald-Hartwig or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005).

[0133] For example, if R1 is pyrazolo[1,5-a]pyrimidine-3-yl, the appropriate palladium-catalyzed cross-coupling for introducing R1 is the Suzuki coupling. Suzuki coupling is performed by heating for several hours (typically 1 to 3 hours) (typically in the 50-100°C range) in the presence of an inorganic base such as an alkali carbonate (e.g., Cs2CO3 or K2CO3) or an inorganic phosphate (e.g., K3PO4), in the presence or absence of water, in an organic solvent such as 1,4-dioxane, THF, 1,2-dimethoxyethane, 2-propanol, or DMF, in the presence of a Pd catalyst such as tetracyclophenylphosphine palladium(0), PdCl2(dppf)2, or XPhos-Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate]. In the presence of a ligand-Palladacycle precatalyst, the intermediate Ⅳ Corresponding boronic acid or boron pinacholate (intermediate ⅢThis can be carried out by reacting with , where R1 is pyrazolo[1,5-a]pyrimidine-3-yl and A is dihydroxyboryl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl). Boronic acid and boronic pinacholate esters can generally be easily prepared by a person skilled in the art starting from commercially available or commercially available reagents.

[0134] Reaction Equation 1

[0135]

[0136] When R1 is (3-oxo-3,4-dihydropyrazine-2-yl)amino, the appropriate palladium-catalyzed cross-coupling for introducing R1 is the Buchwald-Hartwick coupling. For synthetic convenience, the carbonyl group of (3-oxo-3,4-dihydropyrazine-2-yl)amino must be masked with PG2 using an alkoxy group, such as a methoxy group, for example. Intermediate Ⅳ and intermediate Ⅲ(where r1 is 3-methoxypyrazine-2-amyl and A is H) is heated at high temperature (typically 80-120°C) for several hours (typically 1-5 hours) in an organic solvent such as 1,4-dioxane, THF, or toluene, in the presence of an inorganic base such as Cs2CO3 or a strong organic base such as sodium tert-butoxide, with a biphenylphosphine ligand type (RuPhos, X-Phos, or similar) generally under a suitable Pd source (e.g., Pd2(dba)3 or Pd(OAc)2), or XPhos-Pd-G3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) or It can react in the presence of a suitable ligand palladacycle system such as RuPhos-Pd-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate).

[0137] In some cases, for synthesis convenience during metal-catalyzed cross-coupling, intermediate Ⅳ The acidic NH group of my sulfonamide may need to be shielded by a suitable protecting group. Suitable protecting groups for shielding the acidic NH group of the sulfonamide may be benzyl-type protecting groups such as DMB (2,4-dimethoxybenzyl) and PMB (para-methoxybenzyl). If PG1 is a DMB group, the removal of PG1 involves an intermediate with an organic or inorganic strong acid under acidic conditions. Ⅱ This can be easily accomplished by processing the intermediate in a mixture with an organic solvent such as DCM, THF, or a similar one, or with trifluoroacetic acid (neat, pure) for several hours (typically 1 to 3 hours) at room temperature. ⅡIt can be deprotected by treatment. In the presence of PG2, the removal of methoxy groups is performed by treating the intermediate with TMS-Cl (trimethylsilyl chloride) and sodium iodide in acetonitrile at 60-100°C for 1 to 5 hours. Ⅱ This can be performed by processing. Under these reaction conditions, PG1 can also be removed simultaneously without the need for additional processing.

[0138] intermediate when PG1 is DMB and R3 is 5-(R7)-substituted 2-oxoxazolidine-3-yl Ⅳ Is Ⅳa It is named as, Reaction Equation 2 It can be manufactured according to. Intermediate Ⅴ and intermediate Ⅵa CN coupling, which can be performed by heating (typically 60-100°C) heteroaromatic iodides and amines in an organic solvent such as DMSO, in the presence of a copper(I) catalyst / promoter such as CuI, Cu2O, or CuTC (copper thiophene carboxylate), with an inorganic base such as K2CO3, K3PO4, or Cs2CO3, without a ligand or with a suitable ligand such as proline, 3,4,7,8-tetramethyl-1,10-phenanthroline, N,N-dimethylglycine, or dimethylcyclohexane-1,2-diamine (DMCHA). Ⅳa It can be converted into. Intermediate Ⅴ is an intermediate through a two-step process including 1) reductive amination using PG1-NH2 (where PG1 is DMB) and 2) sulfamidation Ⅶ It can be manufactured from. In the first step, the intermediate ⅦIt can be reacted with a suitable amine (such as 2,4-dimethoxybenzylamine in the case of PG1-NH2) in an organic solvent such as DCM or THF at reflux temperature to form the corresponding imine / enamine, which can be reduced at room temperature by adding a suitable borohydride such as STAB (sodium triacetoxyborohydride) or NaBH3CN. The second step (sulfamide reaction) can generally be carried out by reacting the amine from the previous step with a suitable sulfonyl chloride, such as methylsulfonyl chloride, in an organic solvent such as DCM in the presence of an organic base such as TEA or pyridine, at a temperature generally from 0°C to room temperature.

[0139] Reaction Equation 2

[0140]

[0141] In another approach, an intermediate in which R3 is N-R7 substituted 5-oxa-2,7-diazaspiro[3.4]octan-6-on-7-yl and N-R7 substituted 1-oxa-3,8-diazaspiro[4.5]decane-2-on-3-yl, respectively, and PG1 is H Ⅳ are each Ⅳb and Ⅳc Named as, Reaction Equation 3 It can be manufactured according to Ⅳb (and Ⅳc The manufacture of ) is an intermediate Ⅴ It can be carried out by three sequential steps from, which include 1) CN coupling, 2) Boc deprotection, and 3) alkylation using halide R7-X. In the first step, the intermediate Ⅴ Is Ⅴ cast Ⅳa By CN coupling using reaction conditions similar to those described above to convert to Ⅷb (or ⅧcIt can react with ). After CN coupling, the resulting intermediate can be treated with an organic acid such as TFA to perform 2) Boc deprotection. Under these conditions, if PG1 is DMB, PG1 can also be removed simultaneously. In the final step (alkylation), the secondary nitrogen of the spiro system can react with R7-X (where X is Br or I) for several hours at a temperature of about 50-60°C in a polar organic solvent such as DMF in the presence of an inorganic base such as TEA. In another approach, if R7 is a methyl group, methylation can be performed by reacting a secondary amine with a mixture of formaldehyde and formic acid for several hours at 70-90°C under Eschweiler-Clarke conditions.

[0142] Reaction Equation 3

[0143]

[0144] intermediate Ⅶ is an intermediate Ⅸ and intermediate Ⅷ by aromatic nucleophilic substitution Reaction Equation 4 It can be prepared according to. Aromatic nucleophilic substitution can be performed by heating the nucleophile and the aromatic electrophile (typically 80-130°C) in a polar organic solvent (e.g., DMF, DMA, or 1,4-dioxane) in the presence of an inorganic base (e.g., K2CO3 or Cs2CO3) or an organic base (e.g., TEA, DBU, or DIPEA).

[0145] Reaction Equation 4

[0146]

[0147] The reaction scheme described above may provide at least one non-limiting example of a synthesis route for the preparation of Examples 1 to 12.

[0148] As described above, the compound of the present invention is an inhibitor of kinase activity, and in particular inhibits JAK kinase activity for the treatment of JAK-dependent diseases.

[0149] In one aspect, the present invention provides a compound according to the present invention, namely a compound of formula (I) or (Io) or a pharmaceutical composition thereof, for use as a pharmaceutical agent, preferably for the prevention and / or treatment of respiratory and particularly lung diseases.

[0150] In a further aspect, the present invention provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a drug for the treatment of diseases associated with the JAK mechanism, particularly for the treatment of diseases such as respiratory and lung diseases.

[0151] In particular, the present invention provides a compound of formula (I) or (Io) for use in the prevention and / or treatment of a lung 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).

[0152] In addition, the present invention provides a method for the prevention and / or treatment of diseases associated with the JAK mechanism, wherein the method comprises administering a therapeutically effective amount of a compound of the present invention to a patient who requires such treatment.

[0153] In particular, the present invention provides a method for prevention and / or treatment, wherein the disease 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).

[0154] It is desirable to use the compound of the present invention for the prevention of the aforementioned disease.

[0155] The use of the compound of the present invention for the treatment of the aforementioned disease is also desirable.

[0156] Generally speaking, compounds that are JAK inhibitors can be useful in the treatment of many diseases associated with the JAK enzyme mechanism.

[0157] In one embodiment, the disease that can be treated by the compound of the present invention is selected from the group consisting of interstitial lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

[0158] In a further embodiment, the disease is selected from asthma and chronic obstructive pulmonary disease (COPD).

[0159] The therapeutic method of the present invention comprises 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, with respect to a compound of formula (I) or (Io) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent, the “effective amount” means an amount of compound sufficient to treat the patient’s condition but sufficiently low to avoid serious side effects, which nevertheless can be ordinarily determined by a person skilled in the art. The compound of formula (I) or (Io) or a pharmaceutically acceptable salt thereof may be administered as a single dose or according to a dosing regimen in which multiple doses are administered at different time intervals over a defined period. Typical daily dosages may vary depending on the selected specific route of administration.

[0160] The present invention also provides a pharmaceutical composition of a compound of formula (I) or (Io) mixed with one or more pharmaceutically acceptable carriers or excipients, such as those described in, for example, Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0161] The present invention also relates to the use of the compounds of the present invention and their pharmaceutical compositions for various routes of administration.

[0162] The compounds of the present invention and their pharmaceutical compositions may be administered according to the patient's needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and ocularly.

[0163] Various solid oral dosage forms may be used for the administration of the compounds of the present invention and include solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known excipients including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants, etc. Time-release capsules, tablets, and gels are also advantageous.

[0164] Various liquid oral formulations, including water-soluble and water-insoluble solutions, emulsions, suspensions, syrups, and elixirs, may also be used to administer the compounds of the present invention. Such formulations may also include known suitable inert diluents, such as water, and known suitable excipients, such as preservatives, humectants, sweeteners, and flavorings, as well as agents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention may be formulated into injectable compositions, for example, in the form of isotonic sterile solutions, which are injected intravenously. Other preparations are also possible.

[0165] A suppository for rectal administration of the compound of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates, and polyethylene glycol.

[0166] A formulation for vaginal administration may be in the form of a cream, gel, paste, foam, or spray formula containing, in addition to the above active ingredient, a suitable carrier also known, for example.

[0167] Pharmaceutical compositions for topical administration may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration into the skin, eyes, ears, or nose. Topical administration may also include transdermal administration through means such as transdermal patches.

[0168] For the treatment of respiratory tract diseases, the compound according to the present invention may be administered, as described above, also preferably by inhalation.

[0169] Some preferred compounds of the present invention exhibit a profile suitable for administration via the inhalation route.

[0170] Drugs optimized for inhalation delivery require specific characteristics that, when administered to the lungs, allow the compound to maintain a local concentration (lung retention) sufficient to exert a pharmacological effect for a desired duration, minimize drug absorption in the GI tract for the swallowed fraction, and maintain irrelevant levels in generally undesirable compartments (i.e., plasma). For this purpose, one or more characteristics of the compound, such as but not limited to membrane permeability, dissolution rate, and basicity of the compound, are optimized to enhance their binding through lysosomal trapping or to phospholipid-rich lung tissues. In some embodiments, the compounds of the present invention exhibit one or more of these characteristics within a desirable range for inhalable compounds.

[0171] The inhalable preparation comprises an inhalable powder, a propellant-containing metering aerosol, or a propellant-free inhalable formulation, and can be administered through a suitable inhalation device selected from a dry powder inhaler, a pressurized metered dosed inhaler, or a nebulizer, respectively.

[0172] To administer as a dry powder, a single- or multi-dose inhaler known from the prior art may be used. In this case, the powder may be filled into a gelatin, plastic, or other capsule, cartridge, blister pack, or reservoir.

[0173] A diluent or carrier, such as lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compound of the present invention.

[0174] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain compounds of the present invention in a solution or dispersed form. Propellant-driven formulations may also contain other components such as co-solvents, stabilizers, and optionally other excipients.

[0175] Propellant-free inhalable formulations comprising the compounds of the present invention may be in the form of solutions or suspensions in aqueous, alcoholic, or hydroalcoholic media, and these may be administered by a jet or ultrasonic nebulizer known in the prior art or by Respimat ® It can be delivered by a soft-mist nebulizer such as (a registered trademark of Boehringer Ingelheim Pharmaceuticals (Wachtel, H., Kattenbeck, S., Dunne, S. et al. Pulm Ther (2017) 3: 19.)).

[0176] The compound of the present invention may be administered as a single active agent or in combination with other pharmaceutical active ingredients (i.e., as a co-therapeutic agent administered as a fixed-dose combination or as a combination therapy of separately formulated active ingredients), regardless of the route of administration.

[0177] The compounds of the present invention, as single active agents or those currently used in the treatment of respiratory disorders and known to those skilled in the art, e.g., beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated kinase (P38 MAP kinase) 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, leukotrienes It may be administered in combination with other pharmaceutical active ingredients, including leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs), and mucus regulators.

[0178] The present invention also relates to a pharmaceutical composition comprising the compound of the present invention alone or in combination or mixed with one or more pharmaceutically acceptable carriers and / or excipients, and a kit comprising a device which may be a single- or multiple-dose dry powder inhaler, a metered-dose inhaler, or a nebulizer.

[0179] The dosage of the compound of the present invention depends on various factors including the specific disease to be treated, the severity of symptoms, the route of administration, the frequency of the dosage interval, the specific compound utilized, efficacy, the toxicological profile, and the pharmacokinetic profile of the compound.

[0180] Pharmaceutical compositions comprising compounds of the present invention suitable for administration by inhalation are in various breathable forms, such as inhalable powders (DPI), propellant-containing metered-dose aerosols (PMDI), or propellant-free inhalable formulations (e.g., UDV).

[0181] The present invention also relates to an apparatus comprising a pharmaceutical composition comprising a compound according to the present invention, which may be a single- or multi-dose dry powder inhaler, a metered-dose inhaler, and a nebulizer, in particular a mist nebulizer.

[0182] The following examples explain the invention in more detail.

[0183] Features of the present invention will become apparent in the following description of exemplary embodiments provided to explain the invention and not intended to limit the invention.

[0184] Preparation of intermediates and examples

[0185] General experiment details

[0186] The chemical name of the compound (IUPAC) was generated using Structure To Name Enterprise 10.0 Cambridge Software or the latest version.

[0187] Purification by flash chromatography refers to purification using Biotage SP1, the Interchim puriFlash purification system, or equivalent MPLC using a pre-packed polypropylene column containing a stationary phase (cartridge). When the product is purified using a Si cartridge, this refers to an Interchim pre-packed polypropylene column containing unbound activated silica in the form of spherical particles with an average size of 15 µm, or an Isolute® pre-packed polypropylene column containing unbound activated silica in the form of irregular particles with an average size of 50 µm. The fraction containing the desired product (identified by TLC and / or LCMS analysis) was collected and concentrated under vacuum. Purification by 'reverse-phase chromatography' refers to Sfar C 18 This indicates purification performed on a Biotage Isolera Four purification system equipped with a Biotage Dalton 2000 mass detector on a polypropylene column duo prepack. When the SCX-2 cartridge was used, the 'SCX-2 cartridge' refers to a Bond Elut® prepacked polypropylene column containing a non-end-capped propylsulfonic acid-functionalized silica strong cation exchange adsorbent. When a preparative HPLC-MDAP was used for purification (MDAP: mass-directed automatic purification), the fraction containing the target product was collected, and the solvent was removed by evaporation or optionally by freeze-drying.

[0188] NMR method

[0189] NMR spectra were obtained using standard Bruker pulse sequences on a Bruker Avance III 600 (5 mm RT inverse probe head), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probe head), or Bruker DPX 300 spectrometer. Optionally, NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400 MHz or a Varian Unity Inova 400 spectrometer equipped with a 5 mm inverse detection triple resonance probe operating at 400 MHz. DMSO-d 6 or CDCl 3 was used as the solvent and tetramethylsilane as the internal standard, except in cases where the solvent residual peak was used in the latter. All experiments were recorded at 298 K unless otherwise noted. Chemical shifts are given relative to the internal standard, tetramethylsilane, or the solvent residual peak. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined.

[0190] LCMS Method 1

[0191] Acquity UPLC connected to SQD mass spectrometer; Column: Acquity UPLC BEH C 18 (50mm x 2.1mm id, 1.7㎛ packing diameter), Mobile phase A: 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile

[0192] inclination

[0193]

[0194] Column temperature: 40℃; UV detection: 210 nm to 350 nm; MS conditions: Ionization mode: Positive and Negative Electrospray (ES+ / ES-) alternating scan, scan range: 100 to 1000 AMU.

[0195] LCMS Method 2

[0196] Acquity UPLC connected to SQD mass spectrometer; Column: Acquity UPLC BEH C 18 (50 mm x 2.1 mm id, 1.7 µm packing diameter), Mobile phase A: 10 mM ammonium bicarbonate aqueous solution (pH adjusted to 10 with ammonia), Mobile phase B: Acetonitrile;

[0197] inclination

[0198]

[0199] Column temperature: 40℃; UV detection: 210 nm to 350 nm; MS conditions: Ionization mode: Positive and Negative Electrospray (ES+ / ES-) alternating scan, scan range: 100 to 1000 AMU.

[0200] LCMS Method 3

[0201] AGILENT LC 1260 Infinity with SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; Column: Acquity UPLC BEH C 18 (100mm x 2.1mm id, 1.7㎛ packing diameter), Mobile phase A: 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile

[0202] inclination

[0203]

[0204] Column temperature: 40℃; UV detection: 210 nm to 350 nm; MS conditions: Ionization mode: Positive and Negative Electrospray (ES+ / ES-) alternating scan, scan range: 100 to 1500 AMU.

[0205] Abbreviations used:

[0206] Boc2O = di- tert -Butyl dicarbonate; aq. = aqueous solution; DCC = dicyclohexylcarbodiimine; DCM = dichloromethane; DIPEA = N,N -Diisopropylethylamine; DMAP = 4-Dimethylaminopyridine; DMCHDA = trans - N,N' -Dimethylcyclohexane-1,2-diamine; DMF = N,N -Dimethylformamide; DMSO = Dimethyl sulfoxide; EtOAc = Ethyl acetate; LCMS = Liquid Chromatography-Mass Spectrometer; 1 H-NMR = Proton Nuclear Magnetic Resonance; RM = Reaction mixture; Rt = Retention time; RT = Room temperature; sat. = Saturated; T3P ® = Propylphosphonic acid 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

[0207] In the following process, some starting materials are identified by "intermediate" or "example" numbers with indications for step numbers. This is provided solely for the assistance of experienced chemists.

[0208] "Similar" or "analogous" processes mean that such processes may involve slight variations, for example, in reaction temperature, amounts of reagent / solvent, reaction time, work-up conditions, or chromatographic purification conditions.

[0209] In the examples, the stereochemistry of the compounds was given under the assumption that, where indicated, the absolute arrangement at the determined stereocenter of the starting material is maintained throughout any subsequent reaction conditions.

[0210] Unless otherwise specified, if an absolute arrangement (R) or (S) is listed in the compound name, ee% should be considered to be 90% or more.

[0211] Preparation of intermediates

[0212] Intermediate 1a

[0213]

[0214] 5-((dimethylamino)methyl)oxazolidin-2-one (intermediate 1a)

[0215] A vial filled 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 minutes under microwave irradiation. After cooling to RT, the RM was concentrated under vacuum. The residue was eluted with 0-100% DCM:MeOH:NH4OH (90:15:1.5) in DCM and purified by flash chromatography on a Si cartridge. The title product was obtained as a solid (399 mg).

[0216] 1 H-NMR (500 MHz, DMSO-d 6) 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).

[0217] Intermediate 1b

[0218]

[0219] ( S )-5-((dimethylamino)methyl)oxazolidin-2-one (intermediate 1b)

[0220] The title compound starts from (S) 5-(chloromethyl)oxazolidin-2-one Intermediate 1a It was manufactured in a similar manner to.

[0221] 1 H-NMR (300 MHz, DMSO-d 6 ) 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).

[0222] Intermediate 2a

[0223] Step 1

[0224]

[0225] 4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzaldehyde (intermediate 2a-1)

[0226] 6-chloro-3-iodo-1 in DMF (50 mL) H -pyrazolo[4,3- cA mixture of 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) was stirred overnight at 105°C. After cooling to RT, the RM was diluted with water. The formed precipitate was filtered, washed with water and acetonitrile, and then dried under vacuum overnight to obtain the title product (4.0 g), which was used in the next synthesis step without further purification.

[0227] LCMS (Method 2): Rt = 1.17 min, ES + m / z 413.8 / 415.7 [M+H] + .

[0228] Step 2

[0229]

[0230] N -(4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methaneamine (intermediate 2a-2)

[0231] (2,4-dimethoxyphenyl)methaneamine (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). The RM was stirred overnight at RT and stirred under reflux for 4 hours. A second equivalent of (2,4-dimethoxyphenyl)methaneamine was added, and the RM was refluxed for an additional 3 hours. After cooling to RT, NaB(AcO)3H (8.40 g, 39.7 mmol) was added, and the RM was stirred overnight at RT. The RM was diluted with DCM, quenched with sat. aq. (saturated aqueous) NaHCO3, the layers were separated, and the aqueous phase was further extracted with DCM. The combined organic layer sat. aq. Washed with NaHCO3 (2 x 20 mL), passed through a phase separator cartridge, and evaporated under vacuum. The residue was eluted with 0-5% MeOH in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (5.0 g).

[0232] LCMS (Method 2): Rt = 1.38 min, ES + m / z 565.1 / 567.1 [M+H] + .

[0233] Step 3

[0234]

[0235] N -(4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)- N -(2,4-dimethoxybenzyl)methanesulfonamide (intermediate 2a)

[0236] A solution of intermediate 2a-2 (400 mg, 0.71 mmol) in dry DCM (10 mL) was treated with TEA (184 μL, 1.3 mmol) and methanesulfonyl chloride (110 μL, 1.4 mmol) under argon. The RM was stirred at RT for 3 hours and then distributed between DCM and sat. aq. NaHCO3. The combined organic matter was washed with sat. aq. NaHCO3, water, and sat. aq. NaCl, dried over Na2SO4, and the solvent was evaporated under vacuum. The residue was eluted with 0-33% EtOAc in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (384 mg).

[0237] LCMS (Method 2): Rt = 1.34 min, ES + m / z 643.1 / 645.1 [M+H] + .

[0238] Intermediate 2b

[0239] Step 1

[0240]

[0241] 2-chloro-4-fluoro-5-methoxybenzaldehyde (intermediate 2b-1)

[0242] In a degassed solution of 1-bromo-2-chloro-4-fluoro-5-methoxy-benzene (1.0 g, 4.2 mmol) in THF (10 mL) maintained at -5℃, while maintaining the temperature below 0℃ iA solution of -Pr-MgCl·LiCl (1.3 M in THF, 6.4 mL, 8.4 mmol) was added dropwise. The RM was stirred at 0°C for 1 hour before the addition of DMF (1.6 mL, 21 mmol). The RM was stirred at RT for 45 minutes, then quenched with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with sat. aq. NaCl (20 mL) and the solvent was removed under vacuum to obtain the title product (800 mg), which was used in the next synthesis step without further purification.

[0243] LCMS (Method 1): Rt = 1.29 min

[0244] 1 H-NMR (600 MHz, DMSO-d 6) 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).

[0245] Step 2

[0246]

[0247] 2-chloro-4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxybenzaldehyde (intermediate 2b-2)

[0248] The title compound is 6-chloro-3-iodo-1 H -pyrazolo[4,3- c Starting from pyridine and intermediate 2b-1 Intermediate 2a-1 It was manufactured in a similar manner to that.

[0249] LCMS (Method 1): Rt = 1.33 min, ES + m / z 448.0 / 450.0 / 452.0 [M+H] + .

[0250] Step 3

[0251]

[0252] N -(2-chloro-4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methaneamine (intermediate 2b-3)

[0253] The title compound starts from intermediate 2b-2 Intermediate 2a-2 It was manufactured in a similar manner to.

[0254] LCMS (Method 1): Rt = 1.48 min, ES + m / z 599.1 [M+H] + .

[0255] Step 4

[0256]

[0257] N -(2-chloro-4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxybenzyl)- N -(2,4-dimethoxybenzyl)methanesulfonamide (intermediate 2b)

[0258] The title compound starts from intermediate 2b-3 Step 3 of intermediate 2a It was manufactured in a similar manner to that.

[0259] LCMS (Method 1): Rt = 1.41 min, ES + m / z 677.1 / 679.1 / 681.1 [M+H] + .

[0260] Intermediate 3a

[0261]

[0262] N -(4-(6-chloro-3-(2-oxoxazolidin-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)- N -(2,4-dimethoxybenzyl)methanesulfonamide (intermediate 3a)

[0263] Intermediate 2a (150 mg, 0.23 mmol), oxazolidin-2-one (81.3 mg, 0.93 mmol), K2CO3 (193 mg, 1.40 mmol) in DMSO (3.8 mL), L A degassed mixture of (-)-proline (16.1 mg, 0.14 mmol) and CuI (17.8 mg, 93 μmol) was stirred overnight at 70°C under argon. After cooling to RT, the RM was quenched with sat. aq. NaHCO3 and extracted with EtOAc (4x). The combined organic layer was washed with sat. aq. NaCl, dried over Na2SO4, and evaporated under vacuum. The residue was eluted with DCM / EtOAc (10:1) and purified by flash chromatography on a Si cartridge to obtain the title product (97 mg).

[0264] LCMS (Method 2): Rt = 1.17 min, ES + m / z 602.2 / 604.2 [M+H] + .

[0265] Intermediates 3b to 3e

[0266] The following intermediates are from the indicated starting materials Intermediate 3a It was prepared in a manner similar to that. If the base, solvent, temperature, ligand, and / or copper source changes, it is further specified.

[0267]

[0268]

[0269] Intermediate 4a

[0270] Step 1

[0271]

[0272] N -(4-(6-chloro-3-(6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4a-1)

[0273] 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 hour. The RM was quenched with sat. aq. NaHCO3 (100 mL), and the layers were separated. The aqueous layer was divided into DCM (50 mL) and DCM: i The combined organic layer was dried over Na2SO4, evaporated under vacuum, and the residue was eluted with 0-100% DCM / MeOH / NH4OH (90:5:0.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (278 mg).

[0274] LCMS (Method 2): Rt = 0.79 min, ES + m / z 493.2 / 495.2 [M+H] + .

[0275] Step 2

[0276]

[0277] N -(4-(6-chloro-3-(2-(2-hydroxyethyl)-6-oxo-5-oxa-2,7-diazaspiro[3,4]octane-7-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4a)

[0278] 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 overnight at 55°C. After cooling to RT, the RM was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water and sat. aq. NaCl, dried over Na2SO4, and concentrated under vacuum. The residue was eluted with 0-75% DCM / MeOH / NH4OH (90:9:1.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (22 mg).

[0279] LCMS (Method 2): Rt = 0.79 min, ES + m / z 537.2 / 539.2 [M+H] + .

[0280] Intermediate 4b

[0281]

[0282] Ethyl 2-(7-(6-chloro-1-(2-methoxy-4-(methylsulfonamideidomethyl)phenyl)-1 H -pyrazolo[4,3- c ]pyridine-3-yl)-6-oxo-5-oxa-2,7-diazaspyr[3,4]octane-2-yl)acetate (intermediate 4b)

[0283] A solution of 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 minutes. The RM was diluted with water (20 mL) and filtered to separate the formed precipitate. The filtrate was extracted with EtOAc (3 x 10 mL), the combined organic layer was washed with water and sat. aq. NaCl, dried over Na2SO4, and then concentrated under vacuum. The residue obtained from evaporation was combined with the previously filtered solid precipitate. The combined material was eluted with 0-100% EtOAc in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (45 mg).

[0284] LCMS (Method 2): Rt = 0.96 min, ES + m / z 579.2 / 581.2 [M+H] + .

[0285] Intermediate 4c

[0286]

[0287] N -(4-(6-chloro-3-(2-methyl-6-oxo-5-oxa-2,7-diazaspiro[3,4]octane-7-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4c)

[0288] 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 90-100°C for 4 hours. After cooling to RT, the RM was diluted with water (20 mL) and extracted with DCM (50 mL + 2 x 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was eluted with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (32 mg).

[0289] LCMS (Method 2): Rt = 0.86 min, ES + m / z 507.2 / 509.2 [M+H] + .

[0290] Intermediate 4d

[0291] Step 1

[0292]

[0293] N -(4-(6-chloro-3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4d-1)

[0294] The title product starts from intermediate 3e and Intermediate 4a-1 It was manufactured in a similar manner to that.

[0295] LCMS (Method 2): Rt = 0.84 min, ES + m / z 521.2 / 523.2 [M+H] + .

[0296] Step 2

[0297]

[0298] N -(4-(6-chloro-3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4d)

[0299] A solution of intermediate 4d-1 (45 mg, 0.09 mmol) in formic acid (81 mL, 27 mmol) and aqueous formaldehyde (37%, 3.0 mL, 40 mmol) was heated at 80°C for 2 hours under microwave irradiation. Additional equivalents of aqueous formaldehyde and formic acid were added to achieve complete conversion. After cooling to RT, the RM was carefully neutralized with sat. aq. NaHCO3 (40 mL), EtOAc (3 x 50 mL), DCM (2 x 30 mL), and DCM: i The combined organic layer was extracted with -PrOH (1:1, 3x40 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was eluted with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (70 mg), which was used in the next synthesis step without further purification.

[0300] LCMS (Method 2): Rt = 0.91 min, ES + m / z 535.2 / 537.2 [M+H] + .

[0301] Intermediate 4e

[0302]

[0303] N -(4-(6-chloro-3-(8-(2-hydroxyethyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate 4e)

[0304] The title product is produced starting from intermediate 4d-1 and bromoethanol (10 μL, 0.14 mmol) Intermediate 4a It was manufactured in a similar manner to.

[0305] LCMS (Method 2): Rt = 0.84 min, ES+ m / z 565.2 / 567.2 [M+H] + .

[0306] Intermediate 5

[0307] Step 1

[0308]

[0309] 2-bromo-4-(6-chloro-3-iodo-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxybenzaldehyde (intermediate 5-1)

[0310] 6-chloro-3-iodo-1 in dry DMF (10 mL) H A mixture of 6-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) was stirred at 50°C for 3.5 hours. A second equivalent of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine was added, and the RM was further stirred at 50°C for 2 hours. After cooling to RT, the RM was diluted with water. The formed precipitate was filtered, washed with water, and triturated with MeOH / DCM to obtain the target product (669 mg), which was used in the next step without further purification.

[0311] LCMS (Method 2): Rt = 1.31 min, ES + m / z 491.9 / 493.9 / 495.9 [M+H] + .

[0312] Step 2

[0313]

[0314] ( R )-2-bromo-4-(6-chloro-3-(5-((dimethylamino)methyl)-2-oxoxazolidine-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxybenzaldehyde (intermediate 5-2)

[0315] 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 minutes. After cooling to RT, the RM was diluted with water (100 mL) and extracted with EtOAc (5x). The combined organic matter was washed with aqueous ammonia (1 M) and sat. aq. NaCl, dried over Na2SO4, and the solvent was evaporated under vacuum. The residue was eluted with 0-60% DCM / MeOH / NH4OH (90:9:0.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (191.4 mg).

[0316] LCMS (Method 2): Rt = 1.14 min, ES + m / z 508.0 / 510.0 / 511.9 [M+H] + .

[0317] Step 3

[0318]

[0319] ( R )-4-(6-chloro-3-(5-((dimethylamino)methyl)-2-oxoxazolidine-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxy-2-(methylthio)benzaldehyde (intermediate 5-3)

[0320] A solution of intermediate 5-2 (190 mg, 0.37 mmol) in DMF (9.5 mL) was cooled to 0°C, sodium methanethioleate (13.6 mg, 0.20 mmol) was added all at once, and the RM was stirred for 1 hour. After heating to RT, the RM was diluted with water and extracted with EtOAc (4x). The combined organic layer was washed with sat. aq. NaCl, dried over Na2SO4, and the solvent was removed under vacuum. The residue was eluted with 0-50% DCM / MeOH / NH4OH (90:9:0.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (47.3 mg).

[0321] LCMS (Method 2): Rt = 1.09 min, ES + m / z 476.1 / 478.1 [M+H] + .

[0322] Step 4

[0323]

[0324] ( R )- N -(4-(6-chloro-3-(5-((dimethylamino)methyl)-2-oxoxazolidine-3-yl)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxy-2-(methylthio)benzyl)- N -(2,4-dimethoxybenzyl)methanesulfonamide (intermediate 5-4)

[0325] The title compound starts from intermediate 5-3 Intermediate 2a-2 It was manufactured in a similar manner to.

[0326] LCMS (Method 1): Rt = 1.26 min, ES + m / z 627.3 / 629.2 [M+H] + .

[0327] Step 5

[0328]

[0329] ( R )-3-(6-chloro-1-(4-(((2,4-dimethoxybenzyl)amino)methyl)-2-methoxy-5-(methylthio)phenyl)-1 H -pyrazolo[4,3- c ]pyridine-3-yl)-5-((dimethylamino)methyl)oxazolidin-2-one (intermediate 5)

[0330] The title compound starts from intermediate 5-4 Step 3 of intermediate 2a It was manufactured in a similar manner to that.

[0331] LCMS (Method 2): Rt = 1.22 min, ES + m / z 705.2 / 707.2 [M+H] + .

[0332] Preparation of the example

[0333] Example 1

[0334]

[0335] N -(3-methoxy-4-(3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl)-6-(pyrazolo[1,5- a ]pyrimidine-3-il)-1 H -pyrazolo[4,3- c ]pyridin-1-yl)benzyl)methanesulfonamide (Example 1)

[0336] Intermediate 4d (60 mg, 0.04 mmol) in water (1.5 mL) / THF (3 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a A degassed mixture of ]pyrimidine (11 mg, 0.05 mmol), K3PO4 (18 mg, 0.08 mmol), and XPhos PdG3 (1.8 mg, 2 μmol) was heated at 70°C under nitrogen for 1 hour. A second equivalent of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- aPyrimidine and XPhos Pd G3 were added, and the RM was further heated at 70°C for 1 hour. After cooling to RT, the RM was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with sat. aq. NaCl, dried over Na2SO4, and the solvent was removed under vacuum. The residue was eluted with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (16 mg).

[0337] LCMS (Method 3): Rt = 3.38 min, ES + m / z 618.2 [M+H] + .

[0338] 1 H-NMR (500 MHz, DMSO - d 6 ) 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, overlap with DMSO), 2.21 (s, 3H), 1.89-2.04 (m, 4H).

[0339] Examples 2 to 5

[0340] The following examples are from the indicated starting materials Example 1 It was prepared in a manner similar to that. If the base, solvent, temperature, ligand, and / or palladium source changes, it is further specified.

[0341]

[0342]

[0343]

[0344] Example 6

[0345] Step 1

[0346]

[0347] N -(2,4-dimethoxybenzyl)- N -(3-methoxy-4-(3-(2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5- a ]pyrimidine-3-il)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)benzyl)methanesulfonamide (intermediate Example 6-1)

[0348] The title compound starts from intermediate 3a Example 1 It was manufactured in a similar manner to that.

[0349] LCMS (Method 2), Rt = 1.10, ES + m / z 685.3 2 [M+H] + .

[0350] Step 2

[0351]

[0352] N -(3-methoxy-4-(3-(2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5- a ]pyrimidine-3-il)-1 H -pyrazolo[4,3- c ]pyridin-1-yl)benzyl)methanesulfonamide (Example 6)

[0353] TFA (1.05 mL, 14.2 mmol) was added to a solution of intermediate Example 6-1 (109 mg, 0.14 mmol) in DCM (2.6 mL), and the RM was stirred at RT for 1 hour. The RM was cooled to 0°C, neutralized with sat. NaHCO3, and extracted with DCM (2x). The combined organic layer was washed with water, sat. aq. NaCl, dried on a phase separator cartridge, and evaporated under vacuum. The residue was eluted with 0-10% methanol in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (8 mg).

[0354] LCMS (Method 3), Rt = 4.03 min, ES + m / z 535.1 [M+H] + .

[0355] 1 H-NMR (600 MHz, DMSO - d 6 ) 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).

[0356] Examples 7 to 8

[0357] The following examples are from the indicated starting materials Example 6 It was manufactured in a two-step process in a manner similar to that. If the base, solvent, temperature, ligand, and / or palladium source changes, it is further specified.

[0358] Step 1

[0359]

[0360] Step 2

[0361]

[0362]

[0363] Examples 10 and 11

[0364]

[0365] ( S )- N -(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5- a ]pyrimidine-3-il)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (Example 10) and ( R )- N -(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5- a ]pyrimidine-3-il)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (Example 11)

[0366] Examples 10 and 11 are of Example 7 (281 mg) by chiral chromatography separation ( S )--rich scalemic mixtures were obtained from chiral resolution. Samples were dissolved in a DCM / MeOH (1:1) mixture and chromatographed on a Chiralpapak IH column (20 mm x 250 mm, 5 μm) at 40°C under 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 obtain Example 10 (117 mg) and Example 11 (23 mg).

[0367] Chiral purity analysis method

[0368] Chiralpapak IH column (4.6 mm x 250 mm, 5 μm), at 40°C, isosolvent 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.

[0369] Example 10

[0370] LCMS (Method 3), Rt = 3.28 min, ES + m / z 592.2 [M+H] +

[0371] Chiral chromatography (chiral purity analysis method): Rt = 5.72 min, ee = 99.6 %

[0372] 1 H-NMR (600 MHz, DMSO-d 6 ) 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).

[0373] Example 11

[0374] LCMS (Method 3), Rt = 3.32 min, ES + m / z 592.2 [M+H] +

[0375] Chiral chromatography (chiral purity analysis method): Rt = 6.52 min, ee = 99.0 %

[0376] 1 H-NMR (600 MHz, DMSO-d 6 ) 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).

[0377] Chiral allocation

[0378] Example 7's ( S The synthesis of the )-rich scalemic mixture was carried out according to the process of Example 7, using 5-(chloromethyl)oxazolidin-2-one ( R It was made from a )-rich scalemic mixture (ee%=60%). Assuming that no racemization occurred during the conversion of scalemic 5-(chloromethyl)oxazolidin-2-one to scalemic intermediate 1a and the conversion of scalemic intermediate 1a to scalemic Example 7, the separated main peak during chiral separation was assigned to the product derived from (R)-5-(chloromethyl)oxazolidin-2-one (Example 10).

[0379] Example 12

[0380] Step 1

[0381]

[0382] ( R )- N -(2,4-dimethoxybenzyl)- N -(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidine-3-yl)-6-((3-methoxypyrazine-2-yl)amino)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxy-2-(methylthio)benzyl)methanesulfonamide (intermediate Example 12-1).

[0383] Intermediate 5 (40 mg, 57 μmol) in dioxane (1.1 mL), 3-methoxypyrazine-2-amine (9.2 mg, 74 mmol), sodium tert A degassed mixture of butoxide (8.2 mg, 85 μmol) and RuPhos Pd G3 (7.1 mg, 8.5 μmol) was stirred at 85°C for 90 minutes. After cooling to RT, a second equivalent of RuPhos Pd G3 was added, and the RM was further stirred at 85°C for 1 hour. The RM was cooled to RT, diluted with DCM, and evaporated. The residue was eluted with 0-100% DCM:MeOH:NH4OH (90:9:0.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (17.7 mg).

[0384] LCMS (Method 2): Rt = 1.17 min, ES + m / z 679.2 [M+H] + .

[0385] Step 2

[0386]

[0387] ( R )- N -(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidine-3-yl)-6-((3-oxo-3,4-dihydropyrazine-2-yl)amino)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-5-methoxy-2-(methylthio)benzyl)methanesulfonamide (Example 12)

[0388] 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 hours. The RM was cooled to RT and the solvent was evaporated. The residue was eluted with 0-50% DCM:MeOH:NH4OH (90:9:0.5) in DCM and purified by flash chromatography on a Si cartridge to obtain the title product (3.5 mg).

[0389] LCMS (Method 3): Rt = 3.56 min, ES + m / z 630.3 [M+H] + .

[0390] 1 H-NMR (500 MHz, DMSO - d 6 ) 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).

[0391] Example A

[0392] Step 1

[0393]

[0394] N -(4-(6-chloro-3-((2,4-dimethoxybenzyl)amino)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)- N -(2,4-dimethoxybenzyl)methanesulfonamide (intermediate Example A-1)

[0395] The title compound is formed by starting from intermediate 2a and replacing oxazolidin-2-one with (2,4-dimethoxyphenyl)methaneamine Intermediate 3a It was manufactured in a similar manner to.

[0396] LCMS (Method 2): Rt = 1.33 min, ES + m / z 682.2 / 684.2 [M+H] + .

[0397] Step 2

[0398]

[0399] N -(4-(3-amino-6-chloro-1 H -pyrazolo[4,3- c ]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide (intermediate Example A-2)

[0400] The title compound starts from intermediate Example A-1 and Intermediate 4a-1 It was manufactured in a similar manner to that.

[0401] LCMS (Method 1): Rt = 0.73 min, ES + m / z 382.1 / 384.0 [M+H] + .

[0402] Step 3

[0403]

[0404] 2-(dimethylamino)ethyl (6-chloro-1-(2-methoxy-4-(methylsulfonamideidomethyl)phenyl)-1 H -pyrazolo[4,3- c ]pyridine-3-yl)carbamate (intermediate Example A-3)

[0405] 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 overnight at 90°C in a sealed vial. A second equivalent of 2-(dimethylamino)ethanol was added, and the reaction mixture was further heated at 90°C for 4 hours. After cooling to RT, the RM was divided between DCM and water. The aqueous layer was further extracted with DCM (3 x). The combined organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The residue was eluted with DCM / MeOH (20:1 to 10:1) and finally with DCM / MeOH / NH4OH (90:9:1.5), and purified by flash chromatography on a Si cartridge to obtain the title product (7.0 mg).

[0406] LCMS (Method 1): Rt = 0.63 min, ES + m / z 497.1 / 499.0 [M+H] + .

[0407] Step 3

[0408]

[0409] 2-(dimethylamino)ethyl (1-(2-methoxy-4-(methylsulfonamideidomethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-yl)carbamate (Example A)

[0410] The title product starts from intermediate Example A-3 and Example 1 It was manufactured in a similar way to that.

[0411] LCMS (Method 3), Rt = 3.27 min, ES + m / z 580.2 [M+H] +

[0412] 1 H-NMR (500 MHz, DMSO - d 6) 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).

[0413] Pharmacological activity of the compound (1-12) of the present invention

[0414] Biochemical efficacy against JAK1, JAK2, JAK3, and Tyk2

[0415] Assay Principles

[0416] The purpose of this study was to evaluate the ability of compounds to inhibit the activity of all four JAK isoforms in a cell-free environment. Assays for JAK 1, JAK 2, JAK 3, and TYK2 were performed using Time-resolved fluorescence resonance energy transfer (TR-FRET) technology. This consists of the interaction between two labeled binding partners, detected by the energy transfer from an excited donor to a receptor dye and the measurement of photoemission by the receptor dye. The LANCE Ultra kinase assay was used. In the 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. Then, when this is captured by an Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 Anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), it brings the Eu-chelate donor and the ULight acceptor dye into close proximity. Upon excitation at 320 nm, the Eu-chelate transfers its energy to the ULight dye, thereby causing fluorescence emission at 665 nm.

[0417] Compound test

[0418] Serial dilutions of the compounds in pure DMSO were prepared from 10 mM DMSO stock solutions. The compounds were tested in 384-well plates for 11 consecutive 5-fold dilutions (20 μM–2 pM), starting from a peak concentration of 20 μM. 200 nL of the compounds were transferred from the mother plate to the test plate using a Mosquito (TTP labtech). The assay was performed in 384-well Perkin Elmer test plates with an assay volume of 20 μL (kinase reaction) and a total volume of 40 μL (stop reagent and antibody detection reagent). For JAK 1, JAK 2, JAK 3, and TYK2, respectively, 30 / 50 / 20 / 10 nM of peptide and 20 / 0.7 / 0.2 / 12 μM of ATP were added to 10 μL of substrate solution (peptide + ATP). 10 μL of enzyme solution was added to the kinase reaction with JAK 1, JAK 2, JAK 3, and TYK2 at the following concentrations: 0.15 / 0.083 / 0.025 / 0.144 ng / μL, respectively. After shaking and incubating at room temperature (rt) for 1.5 hours, 20 μL of stop (10 μL EDTA) and detection mixture (10 μL europium-anti-phospho antibody, final: 0.5 nM) were added. After 1 hour of incubation, readings were performed on an EnVision 2104 reader (Perkin Elmer).

[0419] The calculation, curves, and QC analysis of IC50 data were performed using Excel and GraphPadPrism software, v9. In summary, individual concentration-effect curves are generated by plotting the log value (X) of the test concentration of the test compound against the corresponding percentage inhibition value (Y) using least squares (normal) fitting. The best-fit IC50 value is calculated using the Log(inhibitor) versus normalized response-variable slope equation, where Y = 100 / (1 + 10^((LogIC50-X)*HillSlope)). QC reference parameters (Z', S:B, R2, HillSlope) were verified for all IC50 curves. The calculation, curves, and QC analysis of IC50 data were performed using Excel and GraphPadPrism software. QC reference parameters: Z' ≥ 0.5, Hill Slope range 0.5 to 5, S:B > 2.

[0420] The compounds according to the present invention exhibited a pIC50 value higher than 6 in relation to their inhibitory activity against all JAK isoforms, which corresponds to ≤ 1 μM in relation to inhibitory concentration. Most compounds exhibited a value preferably higher than 7.3, much more preferably higher than 8.3, in relation to their inhibitory activity against at least JAK1; which corresponds to ≤50 nM, much more preferably ≤5 nM in relation to inhibitory concentration.

[0421] Data for compounds 1-12 are reported in the table below.

[0422]

[0423] The compounds were classified in the table above in terms of efficacy regarding their inhibitory activity against JAK1, JAK2, JAK3, and Tyk2 isoforms according to the classification criteria below:

[0424] + + + : pIC 50 ≥ 8.3

[0425] + + : 8.3 > pIC 50 ≥ 7.3

[0426] + : pIC 50 < 7.3

[0427] Inhibition of IL-13-induced pSTAT6 in BEAS

[0428] BEAS-2B human cell lines were seeded (100,000 cells / well) and incubated for 48 hours at 37°C, 5% CO2, and 95% humidity. Compounds were added and incubated for 30 minutes, followed by the addition of IL-13 as a trigger. After 30 minutes of incubation, cells were lysed, and pSTAT6 was measured using the Fastscan phospho-stat6 (Tyr641) sandwich ELISA kit (cell signaling). Inhibitors were tested in duplexes starting at 10 μM with 11 consecutive 5-fold dilutions (10 μM–40 pM). Calculation of IC50 data, curves, and QC analysis were performed using Excel and GraphPadPrism software. QC reference parameters: Z' ≥ 0.35, Hill Slope range 0.5 to 5, S:B > 2.

[0429] The compound according to the present invention showed a measurable value higher than 5.6 in terms of pIC50 (BEAS).

[0430]

[0431] The compounds were classified in the table above in terms of efficacy regarding their functional activity in BEAS according to the following classification criteria:

[0432] §§§§ : pIC 50 ≥ 7.8

[0433] §§§ : 7.8 > pIC 50 ≥ 6.8

[0434] §§ : 6.8 > pIC 50 ≥ 5.8

[0435] § : pIC50 < 5.8

[0436] Comparative Example A versus Example 10 and Example 11

[0437]

[0438] Where numerical limits or ranges are specified herein, endpoints are included. Additionally, all values ​​and sub-ranges within the numerical limits or ranges are specifically included, even if not explicitly stated.

[0439] The singular expressions (a, an, etc.) used in this text have the meaning of "one or more."

[0440] Clearly, in light of the foregoing teachings, numerous variations and modifications of the present invention are possible. Accordingly, it should be understood that within the scope of the appended claims, the present invention may be practiced differently from as specifically described herein.

Claims

Claim 1 Compounds of formula (Io), or their single enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof: Here R 1 is a heteroaryl selected from the following: R 2 is the following: Here R 6 is H or selected from the group consisting of halogens, (C1-C6)alkyls, and (C1-C6)alkylthios; R 3 is an expression selected from the following J Cyclic carbamate or spirocyclic carbamate, and: R 7 H, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, -(CH2) m Selected from the group consisting of NR4R5, (C1-C6)alkoxycarbonyl-(C1-C6)alkyl; wherein m is independent in each case It is 0 or an integer from 1 to 4; R 4 and R 5 is selected from the group consisting of -H and (C1-C6)alkyl, which are the same or different. Claim 2 In paragraph 1, expressed by the general formula (Ia): Here, R3 is J2; R6 is a compound of formula (Io), which is H or a halogen, preferably Cl, or a single enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof. Claim 3 In claim 1, N-(3-methoxy-4-(3-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-3-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)benzyl)methansulfonamide; N-(4-(3-(2-(2-hydroxyethyl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-methoxybenzyl)methansulfonamide; ethyl 2-(7-(1-(2-methoxy-4-(methylsulfonamideidomethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-6-oxo-5-oxa-2,7-diazaspyrodo[3,4]octane-2-yl)acetate;N-(3-methoxy-4-(3-(2-methyl- 6-oxo-5-oxa-2,7-diazaspyr[3,4]octan-7-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)benzyl)methanesulfonamide;N-(4-(3-(8-(2-hydroxyethyl)-2-oxo-1-oxa-3,8-diazaspyr[4.5]decane-3-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide;N-(3-methoxy-4-(3-(2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)benzyl)methanesulfonamide;N-(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-(pyrazolo[ 1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-methoxybenzyl)methanesulfonamide; (R)-N-(2-chloro-4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-5-methoxybenzyl)methanesulfonamide; (R)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3 -yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-5-methoxy-2-(methylthio)benzyl)methansulfonamide;(R)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-methoxybenzyl)methansulfonamide;(S)-N-(4-(3-(5-((dimethylamino Compounds selected from the list of (R)-N-(4-(3-(5-((dimethylamino)methyl)-2-oxoxazolidin-3-yl)-6-((3-oxo-3,4-dihydropyrazine-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide; or single enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof. Claim 4 A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, mixed with one or more pharmaceutically acceptable carriers or excipients. Claim 5 In paragraph 4, a pharmaceutical composition suitable for administration by inhalation, selected from inhalable powders, metered-quantity aerosols containing propellants, or inhalable formulations without propellants. Claim 6 A device comprising a pharmaceutical composition according to claim 5, which may be a single- or multi-dose dry powder inhaler, a metered-dose inhaler, or a mist atomizer. Claim 7 A compound or pharmaceutical composition according to any one of claims 1 to 5 for use as a pharmaceutical agent. Claim 8 A compound or pharmaceutical composition for use in the prevention and / or treatment of a lung 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). Claim 9 Compounds as defined in any one of claims 1 to 3, and beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated kinase (P38 MAP kinase) 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, nonsteroidal A combination of one or more active ingredients selected from a class commonly used in the treatment of respiratory disorders and known to a person skilled in the art, such as non-steroidal anti-inflammatory agents (NSAIDs) and mucus regulators.

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