Heterocyclic derivatives as Janus kinase inhibitors

Abstract

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

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to chemical compounds that are derivatives useful as JAK, such as JAK1, inhibitors, useful in the treatment of various inflammatory diseases, including asthma, COPD, and other respiratory diseases. [Background technology]

[0002] Background of the Invention The JAK family consists of non-receptor tyrosine protein kinases and has four major members: JAK1, JAK2, JAK3, and TYK2. Over 50 cytokines and growth factors bind to type I and type II receptors, which non-covalently associate with various combinations of JAK kinases. Ligand-induced signal transduction involves tyrosine phosphorylation of the receptor by JAK and recruitment of one or more STAT proteins. Tyrosine-phosphorylated STATs dimerize and are then transported across the nuclear membrane to the nucleus, where they regulate specific genes. JAKs contain seven homology domains (JAK homology domains, or JHs). 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 the kinase structural domain, which phosphorylates substrates; JH2 is a pseudokinase domain that regulates the activity of the kinase domain. JAK3 is expressed in the bone marrow and lymphoid system, as well as in endothelial and vascular smooth muscle cells; other members are expressed in nearly all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26;6(1):402). Many cellular processes are downstream of JAK / STAT signaling: hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis. 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 lymphoid cell proliferation / maturation, T cell / NK cell differentiation / homeostasis, B cell class switching, and other inflammatory processes. The JAK1 / TYK2-JAK1 / JAK2 combination regulates signals associated with innate immune responses, such as IL-6 and type I interferons, which are involved in naive T cell differentiation, T cell homeostasis, granulopoiesis, and other inflammatory processes (Howell MD et al., Front. Immunol. 2019, 10, 2342).JAK2, often associated with itself (JAK2 / JAK2), regulates the signaling of various cytokines and growth factors, including 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 engineered mouse models and human diseases demonstrate the importance of the JAK / STAT pathway in immune fitness. In particular, overexpression or mutation of certain JAK isoforms and aberrant JAK / STAT signaling lead to hematopoietic and lymphoid malignancies and inflammatory disorders. Currently, several US Food and Drug Administration (FDA)- and / or EU-approved JAK inhibitors are in clinical use. Two small molecules (ruxolitinib and fedratinib) are used to treat hematologic disorders such as myelofibrosis and polycythemia vera; six JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, filgotinib, upadacitinib, and delgocitinib in Japan) are being used to treat immune-mediated disorders such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis, and acute graft-versus-host disease. Furthermore, some of these drugs and others are currently in Phase II and III clinical trials for indications ranging from autoimmune diseases (lupus, vitiligo, etc.), inflammatory bowel disease to non-Hodgkin's lymphoma and COVID-19 (Hu X. et al., Sig Transduct Target Ther 2021, 6: 402).

[0004] Small molecules targeting JAK / STAT also represent an attractive option for the treatment of fibrotic disorders. Indeed, inflammatory cytokines (e.g., IL-4, IL-3, IL-6, IL-11, IL-31) and growth factors (e.g., FGF, VEGF) involved in fibrotic processes activate the JAK / STAT pathway. Ruxolitinib, tested in a mouse model of bleomycin-induced fibrosis, attenuated pulmonary fibrotic lesions and reduced levels of fibrotic molecular markers (Zhang, Y et al., Ann. Rheum. Dis. 2017, 76, 1467-1475), while tofacitinib acted as a preventive agent in experimental skin and lung fibrosis (Wang, W et al., Scleroderma Relat. Disord. 2020, 5, 40-50). Several case studies have been published in patients. A case report confirmed the efficacy and safety of tofacitinib in combination with nintedanib in the management of aggressive interstitial lung disease with poor prognosis (Conca, W et al., Front. Pharmacol. 2020, 11, 5857619). Baricitinib was shown to be a safe immune modulator that reduced biomarker levels of pulmonary fibrosis and inflammation in RA patients, including the subgroup with interstitial lung disease (D'Alessandro m et al., Int. Immunopharmacol. 2020, 86, 106748).

[0005] Several JAK inhibitors, including tofacitinib, baricitinib, and ruxolitinib, are currently undergoing clinical trials for COVID-19. Baricitinib and ruxolitinib have been associated with reduced mortality risk, reduced the use of invasive mechanical ventilation, and had marginal effects on intensive care unit admission rates and the incidence of acute respiratory distress syndrome (ARDS) (Wijaya, I. et al. Clin. Epidemiol. Glob. Health 2021, 11, 100755). Also tested in COVID-19 patients was improved clinical symptoms and chest computed tomography findings (Cao Y. et al., J. Allergy Clin. Immunol. 2020 146, 137-146).

[0006] Asthma is one of many immune-mediated diseases whose pathogenesis is characterized by the essential role of JAK / STAT signaling. It is a chronic inflammatory disease of the airways caused by a complex interplay between immune responses, genetic susceptibility, and nonspecific external stimuli such as cold, allergens, and exercise, leading to hyperresponsiveness, airway remodeling, and ultimately contributing to airflow limitation. Severe asthma affects 5-15% of the population, including adults with asthma (3 billion people worldwide), and represents a public health problem associated with increased mortality, hospitalizations, significant symptom burden, medical costs, and work and school absences (Steve NG et al., J Allergy Clin Immunol 2021;148:953-63). Severe asthma represents a subset of asthma that is difficult to treat and occurs in patients whose disease remains uncontrolled with high-dose inhaled corticosteroids (ICS) in combination with long-acting beta-agonists or other control agents. To date, four types of biologics 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 alpha antibody). Despite their efficacy, many patients continue to experience exacerbations or loss of disease control, indicating the need for novel therapeutic agents (Israel E, Reddel HK. N Engl J Med 2017; 377:965-76).

[0007] In recent years, a better understanding of the pathogenesis of asthma has led to a shift from phenotypic classification to the introduction of the concept of "endotypes." According to the latter, classification is based on pathophysiological mechanisms and clinical biomarkers associated with a given patient (Wenzel SE et al., Am J Respir Crit Care Med 2021;203:809-21). There are two major 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 type 2 innate lymphoid cells (ILC2s); these include IL-4, IL-5, and IL-13, which cause airway inflammation by activating eosinophils, B cells, airway epithelial cells, and other cell types. Biomarkers of type 2 asthma include increased blood / sputum eosinophilia and elevated levels of exhaled nitric oxide (FENO) and IgE. The type 2-low pathway is characterized by the absence of type 2-high cytokines and biomarkers, manifested by increased neutrophil levels or a granulocyte-poor profile in the airways, with normal airway neutrophil and eosinophil levels. Type 2-low asthma is currently poorly understood and may encompass multiple distinct endotypes. Potential mediators and / or biomarkers for the T2-low endotype under investigation include IL-6, IL-17A / F, IL-23, type I interferons, CXCL10, TNF, and alarmins (Hinks TSC et al., ERJ 2021, 57 (1) 2000528).

[0008] Nearly all mediators mentioned above for both T2 and T2-low endotypes activate the JAK / STAT pathway, providing a rationale for the potential use of JAK inhibitors in severe asthma of both endotypes. Simultaneous targeting of several cytokines with JAK inhibitors, considering their administration in addition to ICS, may offer advantages over biologics (for non-responders) and standard therapy (for patients who remain uncontrolled).

[0009] Despite the strong rationale for JAK inhibitors in asthma, safety concerns may arise with systemic administration or limit administration to certain patients, such as children. Given that asthma is a pulmonary disorder, the inhaled route of administration of JAK inhibitors may offer the advantage 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 I clinical trials completed) and AZD-4604 (Phase I clinical trials ongoing); Theravance Biopharma has initiated a novel preclinical program with the inhaled JAK inhibitor TD-8236, and Kinaset / Vectura is developing VR588 (Phase I clinical trials ongoing) as an inhaled compound. Numerous preclinical studies supported by these companies have demonstrated the efficacy of JAK inhibitors in controlling asthma. In the preclinical phase of drug development, the orally administered JAK1 / 3 inhibitor R256 (now called AZD0449) was shown to be effective in reducing airway resistance, BAL eosinophilia, and mucus production, and, when administered during sensitization, also in reducing TH2 cytokine responses (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). Genentech's iJak-381, given as a dry powder, reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in OVA-challenged mice. Furthermore, it reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in a mouse model of chronic exposure to AAH allergen (Dengler HS et al., Sci Transl Med 2018;10:eaao2151). Furthermore, oral JAK inhibitors such as tofacitinib, formulated for administration as an aerosol, reduced eosinophil counts in a house dust mite mouse model of asthma (Younis US et al., AAPS PharmSci-Tech 2019;20:167).

[0010] Another respiratory disease that could benefit from lung-restricted JAK inhibition is chronic obstructive pulmonary disease (COPD), a pulmonary inflammatory disorder most commonly caused by cigarette smoke exposure and characterized by largely irreversible and progressive airflow limitation. Although proinflammatory cytokines drive chronic airway inflammation, some of which induce JAK / STAT activation (e.g., IL-6, IFN-γ, IL-2), the role of this pathway in COPD pathogenesis remains poorly characterized. We found that phosphorylated STAT4+ cells (Di Stefano A et al., Eur Respir J. 2004 Jul;24(1):78-85) are increased in COPD compared with non-smoking healthy subjects. In another study, the number of phospho-STAT3+ and phospho-STAT1+ cells was higher in lung biopsies from COPD patients than in non-smoker controls, but previous data on phospho-STAT4 molecules could not be replicated (Yew-Booth L et al., Eur Respir J 2015; 46(3):843-5). These data also suggest the therapeutic use of JAK inhibitors in COPD disease.

[0011] Regardless of inhaled administration, safety concerns may still arise due to the drug levels that reach the systemic circulation after inhalation of a JAKi. In addition to a profile that is well suited for inhalation, JAKi preferably have additional properties that may further limit systemic exposure after inhalation. Summary of the Invention [Problem to be solved by the invention]

[0012] There continues to be a strong need for JAK inhibitors, and in particular inhaled JAK inhibitors, that may provide compounds with improved safety.

[0013] In view of the many pathological responses mediated by JAK enzymes, there continues to be a need for JAK enzyme inhibitors that may be useful in the treatment of many disorders and particularly respiratory diseases.

[0014] Therefore, the discovery of novel, safe and potent JAK inhibitors suitable for local administration to the lung for the treatment of asthma and respiratory diseases remains an important need. [Means for solving the problem]

[0015] Overview of this project Thus, compounds of formula (I) are useful as JAK kinase inhibitors [ka] wherein n, K, V, Q and R1 are as defined in the detailed description of the invention. It is an object of the present invention to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] It is another object of the present invention to provide pharmaceutical compositions containing such compounds, methods of using such compounds in the treatment of respiratory disorders, and processes and intermediates useful in the preparation of such compounds.

[0017] In certain embodiments, the present invention provides a compound of formula (I) for use as a medicament. In certain embodiments, the present invention provides the use of a compound of the present invention for the manufacture of a medicament.

[0018] In a further aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of any disease associated with the JAK enzyme mechanism.

[0019] 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, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0020] In certain embodiments, the compounds of the present invention, alone or in combination with other active ingredients, may be administered for the prevention and / or treatment of pulmonary 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). DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention definition The term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) wherein the parent compound, if any free acid or basic group is present, is suitably modified to form the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0022] Thus, suitable examples of such salts may include inorganic or organic acid addition salts of basic residues such as amino groups and inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0023] Cations of inorganic bases which may be suitably used in preparing the salts of the present invention include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by reacting an inorganic or organic acid with a base-functioning compound to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0024] Many organic compounds can form complexes with the solvent in which they are reacted or precipitated or crystallized. These complexes are known as "solvates" and are also the subject of the present invention. Polymorphs and crystalline forms of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof are also the subject of the present invention.

[0025] The terms "halogen" or "halo-" or "halogen atom" include fluorine, chlorine, bromine, and iodine atoms, meaning fluoro, chloro, bromo, iodo as substituents.

[0026] The term "(C1-C6) alkyl" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Particular alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methylbutyl, and the like.

[0027] The expression "(C-C)haloalkyl" refers to a "(C-C)alkyl" group as defined above in which one or more hydrogen atoms have been replaced with one or more halogen atoms, which may be the same or different. Examples include halogenated, polyhalogenated, and fully halogenated alkyl groups (in which all of the hydrogen atoms have been replaced with halogen atoms, e.g., trifluoromethyl or difluoromethyl groups).

[0028] In a similar way, the term "(C1-C x ) hydroxyalkyl" or "(C1-C x "(C-C)aminoalkyl" refers to a "(C-C)aminoalkyl" as defined above, in which one or more hydrogen atoms have been replaced by one or more hydroxy (OH) or amino groups, respectively. x )alkyl" group and where x is an integer up to 10. Thus, "(C1-C6)hydroxyalkyl" or "(C1-C6)aminoalkyl" refers to such hydroxy- or amino-alkyl groups having in the range of 1 to 6 carbon atoms.

[0029] The definition of aminoalkyl includes alkyl groups substituted with one or more amino groups (-NR4R5) (i.e., "(C1-C6) alkyl" groups). Examples of aminoalkyl are R4R5N-(C1-C6) alkyl or -(CH2) m and mono-aminoalkyl groups such as NR4R5, where R4 and R5 and m are as defined in the detailed description of the invention.

[0030] With reference to the substituents R4 and R5 defined above, when either R4 or R5, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocyclic radical, at least one additional ring carbon atom in the heterocyclic radical can be replaced with at least one heteroatom or hetero-group (e.g., N, NH, S, or O) or can carry an -oxo (=O) substituent. The heterocyclic radical is optionally further substituted at an available point in the ring, i.e., a carbon atom or heteroatom or hetero-group available for substitution. Thus, examples of heterocyclic radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4-yl-2-one, and 4-methylpiperazin-1-yl.

[0031] The term “(C3-C 10 "(C-C)cycloalkyl," as well as "(C-C)cycloalkyl," refer to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and polycyclic ring systems such as adamantane-yl.

[0032] The term "aryl" refers to a mono-, bi-, or tricyclic carbocyclic ring system having 6 to 20, preferably 6 to 15, ring atoms in which at least one ring is aromatic. The term "heteroaryl" refers to a mono-, bi-, or tricyclic ring system having 5 to 20, preferably 5 to 15, ring atoms in which at least one ring is aromatic and at least one ring atom is a heteroatom (e.g., N, S, or O).

[0033] Examples of aryl or heteroaryl monocyclic ring systems include, for example, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl groups and the like.

[0034] Examples of aryl or heteroaryl bicyclic ring systems include naphthalenyl, biphenylenyl, purinyl, pteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzimidazol-yl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothiophenyl, benzodioxinyl, dihydrobenzodioxinyl, indenyl, dihydro-indenyl, dihydrobenzo[1,4]dioxinyl, benzothiazol-2-yl, dihydrobenzodioxepinyl, benzoxazinyl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 5,6,7,8-tetrahydro-1,7-naphthyridine radicals, and the like.

[0035] Examples of aryl or heteroaryl tricyclic ring systems include fluorenyl groups as well as benzo-fused derivatives of the above heteroaryl bicyclic ring systems.

[0036] The derived expression "(C3-C 10 "(C-C)heterocycloalkyl" and similarly "(C-C)heterocycloalkyl" refer to saturated or partially unsaturated mono-, bi-, or tricycloalkyl groups of the indicated number of carbon atoms in which at least one ring carbon atom is replaced with at least one heteroatom (e.g., N, NH, S, or O) and / or may have an -oxo (=O) substituent (e.g., C(=O), S(=O)). The heterocycloalkyl (i.e., heterocyclic radical or group) is optionally further substituted at any available point on the ring, i.e., at any carbon atom or heteroatom available for substitution.

[0037] Substitution of carbon atoms includes spirodisubstitution and substitution of two adjacent carbon atoms, thus forming a further fused 5- to 6-membered heterocyclic ring. Examples of (C3-C6)heterocycloalkyl are oxetanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one. -yl, dihydropyrrolyl, 5-oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, 1,1-dioxidethiomorpholino, octahydrocyclopenta[c]pyrrol-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl; 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, and the like.

[0038] Examples of such heterocyclic radicals are 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4-yl-2-one, 4-methylpiperazin-1-yl, 1-methylpiperidin-4-yl, 4-methylpiperazin-1-yl-2-one, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 2-methyl-2,9-diazaspiro[5.5]undecan-9-yl, 9-methyl-3,9-diazaspiro[5.5]undecan-3-yl, and (3aR,6aS)-5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl.

[0039] The term "aryl(C1-C6)alkyl" refers to an aryl ring linked to a straight or branched alkyl group having from 1 to 6 member carbon atoms, such as phenylmethyl (ie, benzyl), phenylethyl, or phenylpropyl.

[0040] Similarly, the term "heteroaryl(C1-C6)alkyl" refers to a heteroaryl ring linked to a straight or branched alkyl group having from 1 to 6 member carbon atoms, such as furanylmethyl.

[0041] The term "alkanoyl" refers to an HC(O)- or alkylcarbonyl group (e.g., (C1-C6)alkylC(O)-), where the group "alkyl" has the meaning defined above. Examples include formyl, acetyl, propanoyl, butanoyl.

[0042] The term “(C1-C 10 )alkoxy" or "(C1-C 10 "(C-C)alkoxyl," similarly "(C-C)alkoxy" or "(C-C)alkoxyl," etc., refer to a linear or branched hydrocarbon of the indicated number of carbon atoms attached to the remainder of the molecule through an oxygen bridge. "(C-C)alkylthio" refers to the above hydrocarbon attached through a sulfur bridge.

[0043] The derived expressions "(C-C)haloalkoxy" or "(C-C)haloalkoxyl" refer to a haloalkyl as defined above attached through an oxygen bridge. Examples of (C-C)haloalkoxy are difluoromethoxy, trifluoromethoxy.

[0044] Similarly derived expressions "(C3-C6)heterocycloalkyl-(C1-C6)alkyl" and "(C3-C6)cycloalkyl-(C1-C6)alkyl" refer to heterocycloalkyl and cycloalkyl groups as defined above attached to the remainder of the molecule via an alkyl group having the indicated number of carbon atoms, e.g., piperidin-4-yl-methyl, cyclohexylethyl.

[0045] The derived expression "(C1-C6)alkoxy(C1-C6)alkyl" refers to an alkoxy group as defined above, such as methoxymethyl, attached to the remainder of the molecule via an alkyl group having the indicated number of carbon atoms.

[0046] Similarly, "(C1-C6)haloalkoxy(C1-C6)alkyl" refers to a (C1-C6)haloalkoxy" group as defined above attached to the remainder of the molecule via an alkyl group of the indicated number of carbon atoms, e.g., difluoromethoxypropyl.

[0047] Similarly, "(C1-C6)alkoxycarbonyl" refers to an alkoxy group as defined above attached to the remainder of the molecule via a carbonyl group.

[0048] "(C1-C6) alkylthiocarbonyl-" refers to an alkylthio group as defined above attached to the remainder of the molecule via a carbonyl group (C=O).

[0049] "(C1-C6)alkoxycarbonyl-(C1-C6)alkyl" refers to an alkoxy group as defined above attached to the remainder of the molecule via a carbonyl group to which is attached an alkyl group of the further indicated number of carbon atoms, e.g., methoxycarbonylmethyl.

[0050] "(C1-C6)alkoxycarbonyl-(C1-C6)alkylthio" refers to the resulting linked groups such as methoxycarbonylmethylthio and the like.

[0051] Other derived expressions are self-explanatory, for example, "halo-((C1-C6)alkyl(C3-C8)heterocycloalkyl)" refers to linked groups such as 4-fluoro-1-methylpyrrolidin-3-yl, and the like.

[0052] An oxo moiety is represented by (O) instead of other common notations, such as (=O). Thus, in terms of general formulas, a carbonyl group is preferably represented herein by -C(O)- instead of other common notations such as -CO, -(CO)-, or -C(=O)-. Generally, groups in parentheses are side chain groups that are not included in a chain, and parentheses are used when considered useful to aid in the clarity of linear chemical formulas; for example, the sulfonyl group -SO- is also represented as -S(O)-, for example, to provide clarity relative to the sulfinic group -S(O)O-.

[0053] When an index is present, the statement (value) "p is zero..." or "p is 0" means that there is no substituent or group having p, e.g., Ip, present, i.e., there are no optional substituents other than H. Similarly, when an index is attached to a bridging divalent group (e.g., (CH2)m), the statement "m in each instance is zero..." or "m is 0" means that there is no bridging group, i.e., it is a bond.

[0054] When basic amino or quaternary ammonium is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate.Similarly, when an acidic group such as a COOH group is present, the corresponding physiological cation salts may also be present, for example, containing alkali or alkaline earth metal ions.

[0055] When the compounds of formula (I) contain one or more asymmetric centers, they can exist as optical stereoisomers.

[0056] When the compounds of the present invention have at least one asymmetric center, they can therefore exist as enantiomers. When the compounds of the present invention have two or more asymmetric centers, they can also exist as diastereoisomers. It should be understood that all such single enantiomers, diastereoisomers, and mixtures thereof in any ratio are within the scope of the present invention. The absolute configuration (R) or (S) about the carbon bearing the asymmetric center is assigned based on the Cahn-Ingold-Prelog nomenclature system, which is based on group priority.

[0057] When "single stereoisomer," "single diastereoisomer," or "single enantiomer" is listed near the chemical name of a compound, it means that the isomer has been isolated as a single diastereoisomer or enantiomer (e.g., by chiral chromatography), but the absolute configuration of the relevant asymmetric center has not been determined / assigned.

[0058] Atropisomers result from restricted rotation about a single bond, where the steric strain barrier for rotation is high enough to allow the isolation of conformers (Bringmann G et al, Angew. Chemie Int. Ed. 44 (34), 5384-5427, 2005. doi:10.1002 / anie.200462661).

[0059] Oki defined atropisomers as conformational isomers that interconvert with half-lives of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).

[0060] Atropisomers differ from other chiral compounds in that they can often be thermally equilibrated, whereas other forms of chiral isomerization are usually only possible chemically.

[0061] Separation of atropisomers is possible through chiral resolution methods such as selective crystallization. In atropo-enantioselective or atroposelective synthesis, one atropisomer is formed at the expense of the other. Atroposelective synthesis can be achieved through the use of chiral auxiliaries such as the proline-derived asymmetric catalyst Corey-Bakshi-Shibata (CBS) catalyst, or by approaches based on thermodynamic equilibration when the isomerization reaction favors one atropisomer over the other.

[0062] The racemates of the compounds of formula (I) as well as the individual atropisomers (substantially free of the corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are within the scope of the present invention.

[0063] The present invention further relates to the corresponding deuterated derivatives of the compounds of formula (I). In the context of this invention, a deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount greater than the natural abundance. Preferably, the percentage of deuterium at that position is at least 90%, more preferably at least 95%, and even more preferably 99%.

[0064] All preferred groups or embodiments described above and below for compounds of formula (I) can be applied mutatis mutandis in combination with one another.

[0065] As noted above, the present invention provides compounds of general formula (I) that act as JAK inhibitors, methods for their preparation, and pharmaceutical compositions comprising them alone or in combination with one or more active ingredients, in admixture with one or more pharmaceutically acceptable carriers.

[0066] In a first aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony R1 is selected from pyrazolo[1,5-a]pyrimidin-3-yl and (3-oxo-3,4-dihydropyrazin-2-yl)amino; Formula I-1 or I-2 [ka] [ka] It is represented in the diagram as a compound of Here, the substituent [ka] contains at least one ester or thioester moiety (i.e., by combining appropriate combinations of V, Q, R4 and R5); V is a divalent radical selected from C(O)O, C(O)N(R6), N(R6)C(O)O; Q is (C1-C6)alkoxycarbonyl, -(CH2) m NR4R5, (C3-C8)cycloalkyl, and (C3-C6)heterocycloalkyl; wherein said (C3-C8)cycloalkyl and (C3-C6)heterocycloalkyl are optionally selected from the group consisting of (C1-C6)alkoxycarbonyl (CH2) m , namely preferably (C1-C6)alkoxycarbonyl (when m is 0), (C3-C8)cycloalkyl-oxycarbonyl, N-C-(C1-C6)alkoxycarbonyl, (C1-C6)haloalkyl-oxycarbonyl, (C3-C8)heterocycloalkyl-oxycarbonyl, (C1-C6)alkyl(C3-C8)heterocycloalkyl-oxycarbonyl, (C3-C8)heterocycloalkyl-(C1-C6)alkoxycarbonyl, (C1-C6)alkyl-(C3-C8)heterocycloalkyl-(C1-C6)alkoxycarbonyl, (C1-C6)hydroxyalkyl-oxycarbonyl, (C1-C6)aminoalkyl-oxycarbonyl, (C1-C6)alkoxy-(C1-C6 )alkyl-oxycarbonyl, (C1-C6)alkylthiocarbonyl, NC-(C3-C8)cycloalkyl(C1-C6)alkoxycarbonyl, NC-(C3-C8)cycloalkyl-oxycarbonyl, (C1-C6)haloalkyl-(C3-C8)heterocycloalkyl-oxycarbonyl, halo-((C1-C6)alkyl(C3-C8)heterocycloalkyl)-oxycarbonyl, (C1-C6)haloalkyl-(C3-C8)heterocycloalkyl-(C1-C6)alkoxycarbonyl, (C1-C6)haloalkyl-(C3-C8)heterocycloalkyl-oxycarbonyl-(C1-C6)alkyl, (C1-C6)hydroxyalkyl-oxycarbonyl-(C1-C6)alkyl, (C1-C 10 ) substituted with one or more substituents selected from the group consisting of alkyl and halogen; K is selected from O, CH2, and S; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R4 and R5 are the same or different; -H, (C1-C6) alkyl, (C1-C6)haloalkyl, (C3-C6)heterocycloalkyl (C1-C6)alkyl-(C3-C8)heterocycloalkyl; (C1-C6)alkoxycarbonyl-methyl; (C1-C6)alkoxycarbonyl-phenyl-methyl; and (C1-C6)alkoxycarbonyl-(C1-C6)alkyl-phenyl-methyl selected from the group consisting of: R6, independently at each occurrence, is selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) hydroxyalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0067] In the above group, preferred are compounds of formula I-1, wherein K is O; Formula (Ia) [ka] [During the ceremony, V is C(O)N(R6), Q is a (C-C)heterocycloalkyl substituted with a group selected from (C-C)alkoxycarbonyl, (C-C)cycloalkyl-oxycarbonyl, N-C—(C-C)alkoxycarbonyl, (C-C)haloalkyl-oxycarbonyl, (C-C)alkyl(C-C)heterocycloalkyl-oxycarbonyl, (C-C)hydroxyalkyl-oxycarbonyl, (C-C)alkoxy(C-C)alkyl-oxycarbonyl and (C-C)alkylthiocarbonyl, preferably a piperidine moiety; n, independently at each occurrence, is 0 or an integer selected from 1, 2, 3, and 4; R6, independently at each occurrence, is selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) hydroxyalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0068] Particularly preferred compounds in this embodiment are: [Table 1]

[0069] Further preferred embodiments of the above group of compounds of formula (I) are the single enantiomers, diastereoisomers and mixtures thereof, wherein V is the divalent group C(O)O; Q is optionally (C1-C 10 ) (C1-C6) alkoxycarbonyl substituted with one or more groups selected from alkyl and halogen, —(CH2) m selected from the group consisting of NR4R5 and (C3-C6)heterocycloalkyl; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R4 and R5 may be the same or different, -H, (C1-C6) alkyl selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0070] Another preferred embodiment of the above group of compounds of formula (I) when K is S is the compound of formula (Ib) [ka] [During the ceremony, V is a divalent radical selected from N(R6)C(O)O; Q is selected from the group consisting of (C1-C6)alkoxycarbonyl; n is an integer selected from 1, 2, 3 and 4; R6, independently at each occurrence, is selected from the group consisting of H and (C1-C6) alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0071] Another preferred embodiment of the compound group of the above formula (I-2) is a compound of formula (Ic) in which K is O or S, and which is a single enantiomer, a diastereoisomer, or a mixture thereof. [ka] [During the ceremony, V is a divalent radical selected from C(O)N(R6); Q is one (C1-C6)alkoxycarbonyl (CH2) m is a (C3-C6)heterocycloalkyl substituted with; n is an integer selected from 1, 2, 3 and 4; R6, independently at each occurrence, is selected from the group consisting of H and (C1-C6) alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0072] In certain embodiments, the present invention provides compounds of Examples 1-59 listed in the table below, or pharmaceutically acceptable salts and solvates thereof. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0073] The compounds of the present invention exhibit high biochemical potency against JAK targets (JAK1, JAK2, JAK3 and Tyk2) and high potency in representative functional assays in cells (e.g., pSTAT6 inhibition in BEAS cells stimulated with IL-13).

[0074] Preferred compounds exhibited at least a 10-fold or greater decrease in the functional activity (e.g., pSTAT6 inhibition in IL-13-stimulated BEAS cells) of predicted carboxylic acid metabolites, with more preferred compounds exhibiting a greater than 100-fold, and even more preferably, a greater than 200-fold decrease.

[0075] Even more preferred are compounds of the present invention which, in addition to the above properties, exhibit high clearance in in vitro stability assays in representative human and / or mouse tissues, e.g., at least liver microsomes and / or hepatocytes and / or plasma, and have a half-life of 30 minutes or more in well-established and validated assays.

[0076] These assays were adapted from literature methods (Kevin J. Coe & Tatiana Koudriakova, Metabolic Stability Assessed by Liver Microsomes and Hepatocytes, Methods in Pharmacology and Toxicology, 2013; L Di, EH Kerns, Y Hong, H Chen, Development and application of high throughput plasma stability assay for drug discovery, International journal of pharmaceutics, 2005) and validated against accepted literature references (i.e., verapamil for human / mouse microsomes / hepatocytes and propantheline for plasma stability in human / mouse).

[0077] During lead optimization, high turnover in tissue stability studies is generally considered an indicator of high in vivo systemic clearance, which may further contribute to limited systemic exposure after inhalation, making these preferred compounds particularly suitable for inhalation administration.

[0078] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the methods and procedures described in the experimental section below, or by slightly modified procedures readily available to one of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Although optimal reaction conditions may vary depending on the particular reactants or solvents used, such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures. The preparations described below and in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0079] In some cases, known protecting groups (PGs) can be used to mask or protect sensitive or reactive moieties, requiring only one step according to general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0080] Here, and for clarity, the compounds of formula I-1 and I-2 described herein, including all compounds listed above, can generally be prepared according to the procedures shown in the following schemes. Where specific details or steps differ from the general schemes, they are detailed in the specific examples and / or additional schemes. [ka] [ka]

[0081] Compounds of formula (I-1) can be prepared according to Scheme 1, starting from intermediates of formula IIa (or IIb or IIc), by removing PG1 by means of procedures well known to those skilled in the art. A suitable protecting group for protecting the secondary amine of intermediate IIa (or IIb or IIc) can be a carbamate-type protecting group such as Boc (tert-butoxycarbonyl). The Boc group can be easily removed by treating the Boc-protected intermediate IIa (or IIb or IIc) with a strong organic or inorganic acid under acidic conditions. For example, the Boc group can be removed by treating the intermediate with neat trifluoroacetic acid or a mixture of an organic solvent such as DCM, DCE, THF, or the like, typically overnight at room temperature.

[0082] The group Q' present in the intermediate of formula IIa (or IIb or IIc) is a group of formula Q that can be subjected to one-step functional group interconversion to produce compounds of formula I-1. Examples 43, 44, and 45 were prepared from Examples 29, 30, and 9, respectively, by transesterification with an appropriate alcohol to provide the desired ester. The transesterification reaction can be carried out by heating the parent ester and an excess of the desired alcohol in the presence of a strong inorganic acid, such as sulfuric or hydrochloric acid, at elevated temperature or up to the boiling point of the alcohol.

[0083] When such a transformation is not required (Q' is already Q and / or PG1 is H), it is clear that any of the general approaches described below for the preparation of intermediate IIa (or IIb or IIc) will provide compounds of general formula I-1.

[0084] Intermediate IIa (or IIb or IIc) can be obtained by reaction of intermediate IIIa (or IIIb or IIIc, respectively) with intermediate VI, followed by direct introduction of the pyrazolo[1,5-a]pyrimidin-3-yl moiety via a metal / palladium-catalyzed cross-coupling reaction such as Suzuki coupling, Stille coupling, or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005). For example, a suitable palladium-catalyzed cross-coupling to introduce the pyrazolo[1,5-a]pyrimidin-3-yl moiety can be carried out by reacting intermediate IIIa (or IIIb or IIIc) with the corresponding boronic acid or boron pinacolate (intermediate VI, where A is dihydroxyboryl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) to XPhos-Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- This reaction can be carried out by reacting a palladacycle catalyst precursor such as [(biphenyl)]palladium(II) methanesulfonate] or a Pd catalyst such as tetrakistriphenylphosphinepalladium(0) or PdCl2(dppf)2 in an organic solvent such as THF, 1,4-dioxane, 1,2-dimethoxyethane, 2-propanol, or DMF with or without water in the presence of an inorganic base such as K3PO4 or Cs2CO3 under heating (typically in the range of 50-100°C) for several hours (typically 1-5 hours). Boronic acids and boronate pinacolates are generally commercially available or can be easily prepared by those skilled in the art starting from commercially available reagents.

[0085] Intermediates of formula IIIa can be obtained from intermediates IVa by means of amide coupling with the corresponding amine Va. The amide coupling can be carried out by reacting the amine with an acid in an organic solvent such as DMF, DCM, or THF in the presence of a coupling agent such as HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), or COMU ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium) and an organic base such as DIPEA, TEA, or pyridine.

[0086] Intermediates of formula IIIb can be obtained from intermediate IVa and alcohol intermediate Vb via a two-step / one-pot process involving 1) acyl azide formation and Curtius rearrangement to give the isocyanate intermediate and 2) a one-pot reaction of the isocyanate with alcohol Vb to form the corresponding carbamate. The corresponding acyl azide of intermediate IIIb can be prepared by reaction with an azide source such as azido(trimethyl)silane in the presence of a suitable coupling agent such as T3P and an organic base such as TEA or DIPEA in an organic solvent such as 2-methyl-THF, DMF, or toluene. Subsequent Curtius rearrangement is carried out by thermolysis of the solvent at reflux temperatures (typically 50°C to 100°C) for several hours (typically 1 to 3 hours) to give the corresponding isocyanate; after isocyanate formation, alcohol intermediate Vb is added and reflux is continued overnight to form the carbamate of formula IIIb. In some cases, the reaction of IVa with intermediate Vb can also lead to the formation of intermediate IIIc, which can be isolated from the same reaction along with intermediate IIIb. [ka]

[0087] In another approach, intermediate IIIb can be prepared from intermediates IVb and Vb in a two-step / one-pot process involving 1) isocyanate formation and 2) one-pot reaction with alcohol Vb to form the corresponding carbamate. Intermediate IVb is reacted with bis(trichloromethyl)carbonate in an organic solvent such as DCM or THF at low temperature, such as dry ice temperature (-78°C), in the presence of an organic base such as TEA or DIPEA for up to 1 or 2 hours to form the corresponding isocyanate; addition of intermediate Vb and reaction at room temperature can form the carbamate of formula IIIb.

[0088] In a different approach, intermediate IIa can be obtained from intermediate VIIa and intermediate Va by amide coupling using the same method as described above for intermediate IIIa from IVa and Va.

[0089] In a different approach, intermediate IIc can be obtained from intermediates VIIa and Vb by an esterification reaction promoted by a coupling agent such as EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) or DIC (N,N'-diisopropylcarbodiimide) in an organic solvent such as DCM or THF in the presence of an organic base such as DMAP or pyridine at room temperature for several hours (typically 2-4 hours). Intermediate VIIa can be obtained from intermediates IVa and VI by Suzuki coupling in a manner similar to that described above for the reaction of intermediate IIIa (or IIIb or IIIc, respectively) with intermediate VI.

[0090] Intermediate IVa (or IVb) can be prepared according to Scheme 2. Intermediate IVa (or IVb) can be prepared by N-arylation of intermediate VIIIa (or VIIIb) with the halide intermediate IX using a copper-catalyzed Ullmann-type reaction. The Ullmann reaction between the NH heteroaryl and aryl / heteroaryl halide (bromide or iodide) can be carried out in the presence of a suitable copper(I) catalyst / promoter such as CuI, CuO, or CuTC (copper thiophenecarboxylate), either ligand-free or in the presence of a suitable ligand such as N,N-dimethylglycine, proline, phenanthroline, or dimethylcyclohexane-1,2-diamine (DMCHA), in the presence of an inorganic base such as KCO or CsCO, in a polar organic solvent such as DMSO, DMF, or DMA, with heating overnight or longer (typically at 90-150°C).

[0091] [ka] Intermediate IX can be obtained from intermediate X in a two-step process involving the introduction of PG1 (Boc group introduction) and halogenation, or in the reverse order of steps. Insertion of the Boc group can be carried out by reacting the anilino intermediate with Boc2O in an organic solvent such as THF or DCM in the presence of an organic base such as DMAP or pyridine at room temperature for several hours up to overnight (typically 12 hours). The halogenation reaction can be carried out by reacting the aryl derivative with an electrophilic bromine or iodine source such as 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione, N-bromosuccinimide, or N-iodosuccinimide in an organic solvent such as ethyl acetate, DMF, or DCM at temperatures above about 0°C (up to 40°C).

[0092] [ka] In another approach, intermediate IVa, in which K is S and PG1 is H, can be obtained from intermediate VIIIa by means of a multi-step synthetic sequence as shown in Scheme 3. Intermediate VIIIa and intermediate XII undergo nucleophilic aromatic substitution (SNAr) to give intermediate XI, for example, by reacting them in an organic solvent such as DMF or 1,4-dioxane in the presence of an organic base such as DBU or DIPEA at RT for several hours (typically 4 hours); at the end of the SNAr reaction, a methyl halide such as MeI can be added, resulting in in situ methylation of the carboxylic acid and the formation of intermediate XI. Intermediate XI can be reacted with mercaptoethanol under Pd-catalyzed CS coupling conditions to give intermediate XII. C-S coupling can be achieved by reacting aryl bromide XI with mercaptoethanol in the presence of a suitable catalyst system such as Pd(dba) / Xantphos or other suitable palladium / phosphine source in an organic solvent such as 1,4-dioxane, toluene, or DMA in the presence of an organic base such as DIPEA or DBU at temperatures up to 100°C for several hours (typically 3-5 hours). Intermediate XII can be converted to intermediate XIII via a two-step process involving 1) nitro reduction and 2) chlorination. Nitro reduction can be achieved by treating intermediate XII with a reducing agent such as iron or zinc powder in an organic solvent such as methanol or ethanol in the presence of an aqueous solution of a weak inorganic salt such as ammonium chloride at temperatures up to 80°C for several hours (typically 4-5 hours). Subsequent conversion of the alcohol to the corresponding chloride can be achieved by reaction with neat thionyl chloride or oxalyl chloride at low temperatures (approximately 0°C). The chloride intermediate XIII can be cyclized to give intermediate XIV by heating (typically 80-100° C.) in a suitable organic solvent such as DMF or 1,4-dioxane in the presence of an inorganic base such as potassium carbonate or sodium carbonate and an additive such as sodium iodide.Finally, intermediate XIV can be converted to intermediate IVa (where K is S and PG1 is H) by ester hydrolysis by treating the methyl ester in a water-miscible organic solvent such as THF or methanol in the presence of an aqueous solution of an inorganic base such as lithium hydroxide or sodium hydroxide for several hours (typically 2-4 hours) at temperatures up to 40°C.

[0093] [ka] In another approach (Scheme 4), intermediate IIIa can be achieved from intermediate XV by displacement of Lg" by alkylation of the primary / secondary nitrogen present in the Q' moiety by treating amine Q' and halide XV in an organic solvent such as DMF or 1,4-dioxane in the presence of an organic base such as DIPEA or TEA at room temperature for several hours (typically 5-7 hours). Intermediate XV can be obtained from intermediates IVa and XVI by an amide coupling reaction using conditions similar to those described in Scheme 1 for the conversion of intermediates IVa and Va to intermediate IIIa.

[0094] In a different approach (Scheme 5), intermediate IIIa' (or IIIb') can be prepared by esterification with an alcohol of formula r-OH and the corresponding acid of formula XVIIa (or XVIIb) by using conditions similar to those described in Scheme 1 for the conversion of intermediates VIIa and Vb to IIc.

[0095] [ka] Intermediate XVIIa (or XVIIb) can be obtained from the corresponding intermediate IIIa (or IIIb), where Q' is a methyl ester (Q' is q-COOMe) or an ethyl ester (Q' is q-COOEt), by hydrolysis under basic conditions equivalent to those described in Scheme 4 for the conversion of intermediate XIV to intermediate IVa. The group Q'' present in the intermediate of formula IIIa' (or IIIb') is a group that can be subjected to one-step functional group interconversion and / or PG deprotection to obtain a group of formula Q. Intermediate IIIa' (or IIIb') can be converted to a compound of formula I-1 by using methods similar to those described in Scheme 1 for the conversion of intermediate IIIa (or IIIb) to a compound of formula I-1.

[0096] In a different approach (Scheme 6), when the group Q' in the intermediate of formula IIa contains a methyl or ethyl ester, IIa can be converted to IIa' by a two-step method that allows the conversion of the group Q' to Q''. In the first step, ester hydrolysis of Q' in IIa gives an acid intermediate, which can be esterified with a suitable alcohol (r-OH) to give intermediate IIa'. Methyl or ethyl ester hydrolysis can be carried out by reacting the ester derivative with LiOH, NaOH, or a suitable inorganic hydroxide in a mixture of water and THF, DMF, or a suitable polar organic solvent. The acid can be converted to an ester by activation of the acid with a suitable coupling agent such as 2,4,6-trichlorobenzoyl chloride or HATU, followed by reaction with the corresponding alcohol in an organic polar solvent such as DMF with an organic base such as TEA, DMAP, or DIEA. This procedure can also be applied to the preparation of thioesters by replacing the alcohol (r-OH) with a suitable thiol derivative (r-SH).

[0097] In another approach, compounds of formula I-1 when Q contains a terminal CN group can be prepared from the corresponding intermediate IIa, where Q′ contains a leaving group such as Br or Cl, by alkylation with an inorganic cyanide salt such as NaCN or KCN in an organic polar solvent such as DMF by heating at a temperature above 80°C.

change

[0098] Compounds of Formula I-2 can be prepared similarly to compounds of Formula I-1 using a similar synthetic sequence by incorporating a pyrazin-2(1H)-one-3-aminyl moiety instead of the pyrazol[1,5-a]pyrimidin-3-yl moiety. An example of such a modification is provided in Scheme 7. A suitable palladium-catalyzed cross-coupling for incorporating the pyrazin-2(1H)-one-3-aminyl moiety is the Buchwald-Hartwig coupling. For synthetic convenience, when PG2 is methyl (e.g., methoxyimino, -C(OMe)=N-), the lactam group of (3-oxo-3,4-dihydropyrazin-2-yl)amino must be protected as an alkoxyimino group, followed by deprotection at the end of the synthesis of intermediate XIX. Intermediate IVa and intermediate XVIII were reacted with an appropriate ligand palladium salt such as XPhos-Pd-G3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) or RuPhos-Pd-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate). Intermediate XIX can be obtained by reaction with a suitable phosphine ligand, such as a biphenylphosphine ligand type (RuPhos, X-Phos, or similar), in the presence of a strong organic base such as sodium tert-butoxide or an inorganic base such as CsCO, in an organic solvent such as 1,4-dioxane, THF, or toluene, at elevated temperatures (typically 80-120 °C) for a short period of time (typically overnight), in the presence of an alkane system or generally a suitable Pd source (e.g., Pd(dba) or Pd(OAc)). Deprotection of PG2 from intermediate XIX to give intermediate XX can be achieved by reacting the protected precursor with TMS-Cl (trimethylsilyl chloride) and sodium iodide in acetonitrile for 1-5 hours at 60-100 °C; under these conditions, PG1, when Boc, can also be deprotected.Finally, compounds of formula I-2 can be prepared by reaction of intermediate XX with intermediate Va under amide coupling conditions similar to those described in Scheme 1 for the preparation of IIIa from IVa and Va. [ka]

[0099] As detailed herein, the compounds of the present invention inhibit JAK kinase activity, particularly for the treatment of JAK-dependent diseases for which they are kinase activity inhibitors.

[0100] In one aspect, the present invention provides a compound of the present invention, i.e. a compound of formula (I) or a pharmaceutical composition thereof, for use as a medicament, preferably for respiratory and particularly pulmonary diseases.

[0101] In a further aspect, the present invention provides the use of Compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of disorders associated with the JAK mechanism, in particular for the treatment of disorders such as respiratory and pulmonary diseases.

[0102] In particular, the present invention provides a compound of formula (I) for use in the prevention and / or treatment of a pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF) acute lung injury and acute respiratory distress syndrome (ARDS).

[0103] Furthermore, the present invention provides a method for preventing and / or treating disorders associated with the JAK mechanism, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0104] In particular, the present invention provides methods for the prevention and / or treatment wherein the disorder is a respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

[0105] The use of the compounds of the invention for the prevention of the above-mentioned disorders is preferred.

[0106] The use of the compounds of the invention for the treatment of the above disorders is equally preferred.

[0107] Generally speaking, compounds that are JAK inhibitors may be useful in the treatment of many disorders associated with the JAK enzymatic mechanism.

[0108] In certain embodiments, the disorder that can be treated by the compounds of the present invention is selected from the group consisting of interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS).

[0109] In a further embodiment, the disorder is selected from asthma and chronic obstructive pulmonary disease (COPD).

[0110] The treatment method of the present invention comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, "effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means both a compound sufficient to treat the patient's condition but low enough to avoid significant side effects, which can nevertheless be routinely determined by one skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered once or according to a dosing regimen of multiple administrations at various intervals over a period of time. Typical daily dosages can vary depending on the particular route of administration selected.

[0111] The present invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0112] The present invention also relates to the use of the compounds of the present invention and pharmaceutical compositions thereof for various routes of administration.

[0113] Administration of the compounds of the present invention and pharmaceutical compositions thereof may be achieved, for example, by oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and infusion), inhalation, rectal, vaginal, topical, local, transdermal and ocular administration, depending on the needs of the patient.

[0114] A variety of solid oral dosage forms can be used to administer the compounds of the present invention, including solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known additives, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. Time-release capsules, tablets, and gels are also advantageous.

[0115] A variety of liquids, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs, can be used for administering the compounds of the present invention in oral dosage forms. Such dosage forms may contain suitable known inert diluents, such as water, and suitable known additives, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention can be formulated as an injectable composition, for example, for intravenous injection, in the form of an isotonic sterile solution. Other formulations are also possible.

[0116] Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylate and polyethylene glycol.

[0117] Formulations for vaginal administration are also known which may be in the form of creams, gels, pastes, foams or spray formulations which contain, in addition to the active ingredient, suitable carriers, etc.

[0118] For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, salve, lotion, emulsion, suspension, gel, solution, paste, powder, spray, and drops of liquid suitable for administration to the skin, eye, ear, or nose. Topical administration may also include transdermal administration by means of a transdermal patch or the like.

[0119] The compound of the present invention can show a profile suitable for oral administration.The optimization of a drug for oral delivery requires certain characteristics that enable the orally administered compound to be absorbed and hardly removed by the GI (gastrointestinal) tract, in order to obtain good bioavailability (F%), and therefore maintain sufficient concentration in plasma and target tissue for a suitable time to sustain pharmacological effect.In order to enhance oral bioavailability, it is necessary to optimize one or more properties of the compound, such as but not limited to maximizing membrane permeability and reducing metabolic hotspots (in vitro clearance optimization).

[0120] For the treatment of diseases of the respiratory tract, as noted above, it may also be preferable to administer the compounds of the invention by inhalation.

[0121] Certain preferred compounds of the invention exhibit a profile suitable for administration by the inhaled route.

[0122] Drugs optimized for inhalation delivery require specific characteristics that allow the compound, when administered to the lung, to maintain a sufficient local concentration (pulmonary retention) to exert a pharmacological effect for a desired period of time, minimize drug absorption in the GI tract for the swallowed fraction, and generally insignificant levels in undesired compartments (i.e., plasma).To this end, one or more properties of the compound are optimized, including, but not limited to, membrane permeability, dissolution rate, and basicity of the compound to enhance binding to phospholipid-rich lung tissue or via lysosomal trapping.In some embodiments, the compounds of the present invention exhibit one or more of the above properties within the range desired for an inhalation compound.Inhalation JAKi preferably have additional properties that can further limit systemic exposure after inhalation.

[0123] A method for limiting systemic exposure after local administration is soft drug design, which means the introduction of specific moieties, such as esters, in the present invention, that favor controlled and rapid systemic metabolism (in the liver and / or blood) to metabolites with reduced or negligible functional activity compared to the parent compound. To this end, one approach has been to optimize "appropriately designed ester derivatives" with corresponding predicted carboxylic acid metabolites that exhibit reduced functional activity (e.g., cell-based activity). Even more advantageously, such optimized esters can be substrates for liver and / or blood esterases, which may be beneficial in achieving enhanced clearance in vivo.

[0124] Thus, preferred compounds of the present invention exhibit one or more of the following properties: high biochemical activity on the target, strong functional activity (e.g., cell-based activity), rapid clearance in representative assays (stability in liver microsomes and / or hepatocytes, plasma stability), and reduced predicted functional activity of carboxylic acid metabolites, and may therefore potentially yield compounds with improved safety.

[0125] Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations, which may be administered via a suitable inhalation device which may be selected from a dry powder inhaler, a pressurized metered dose inhaler or a nebulizer, respectively.

[0126] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0127] A diluent or carrier, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the invention.

[0128] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the invention in solution or in dispersed form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and other additives as desired.

[0129] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media and may be nebulized using jet or ultrasonic nebulizers known from the prior art or by Respimat, a registered trademark of Boehringer Ingelheim Pharmaceuticals. (登録商標) It can be delivered by a soft mist nebulizer such as (Wachtel, H., Kattenbeck, s., Dunne, s. et al. Pulm Ther (2017) 3: 19).

[0130] Regardless of the route of administration, the compounds of the invention may be administered as single agents or in combination with other pharmaceutically active ingredients (i.e., as co-therapeutic agents administered as a fixed dose combination or in a combination therapy of separately formulated active ingredients).

[0131] The compounds of the present invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used to treat respiratory disorders and known to those skilled in the art, such as beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinase), 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 anti-inflammatory drugs (NSAIDs), and mucus control agents.

[0132] The present invention also relates to kits comprising a pharmaceutical composition comprising a compound of the invention, alone or in combination or admixture with one or more pharmaceutically acceptable carriers and / or excipients, and a device, which may be a single or multiple dose dry powder inhaler, a metered dose inhaler, or a nebulizer.

[0133] The dosage of the compounds of the invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, the frequency of administration intervals, the particular compound utilized, the efficacy, toxicological and pharmacokinetic profile of the compound.

[0134] Pharmaceutical compositions comprising the compounds of the present invention suitable for administration by inhalation are in various inhalable forms such as inhalable powders (DPIs), propellant-containing metered dose aerosols (PMDIs) or propellant-free inhalable formulations (e.g., UDVs).

[0135] The present invention also relates to devices containing pharmaceutical compositions comprising the compounds of the invention, which may be single or multiple dose dry powder inhalers, metered dose inhalers and nebulizers, especially soft mist nebulizers.

[0136] The following examples will further illustrate the invention.

[0137] The features of the present invention will become apparent as the following description of exemplary embodiments is read, which are given by way of illustration of the invention and are not intended to be limiting thereof.

[0138] Preparation of Intermediates and Example Compounds General Experiment Details Chemical names of compounds were generated using Structure To Name Enterprise 10.0 Cambridge Software or the latest version.

[0139] Purification by "chromatography" or "flash chromatography" refers to purification using a Biotage SP1 or Interchim puriFlash purification system or a Biotage Isolera Four purification system equipped with a Biotage Dalton 2000 mass detector, or equivalent MPLC using a pre-packed polypropylene column containing the stationary phase (cartridge). When the product was purified using a Si cartridge, this refers to an Interchim (or equivalent) pre-packed polypropylene column containing unbonded activated silica with spherical particles of 15 μm average particle size, or an Isolute® (or equivalent) pre-packed polypropylene column containing unbonded activated silica with irregularly shaped particles of 50 μm average particle size. Fractions containing the desired product (identified by TLC and / or LCMS analysis) were pooled and concentrated under reduced pressure. Purification by "reverse phase chromatography" or "reverse phase flash chromatography" refers to purification using a Biotage Sfar C 18 This refers to purification on an MPLC instrument equipped with a C18-functionalized silica cartridge, such as a HPLC-MS / ...

[0140] NMR method NMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probehead), a Bruker DRX 500, a Bruker Avance AV 400 (5 mm RT direct probehead), or a Bruker DPX 300 spectrometer using standard Bruker pulse sequences. Alternatively, NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400 MHz or a Varian Unity Inova 400 spectrometer with a 5 mm inverse-detection triple resonance probe operating at 400 MHz. DMSO-d6 or CDCl3 was used as the solvent. Chemical shifts are reported relative to the internal standard tetramethylsilane or solvent residual peaks. All experiments were recorded at 298 K unless otherwise noted. Coupling constants (J values) are given in Hertz (Hz) and multiplicities are noted using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, nd = undetermined.

[0141] LCMS method Method 1 Acquity UPLC coupled to SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; [Table 8] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0142] Method 2 Acquity UPLC coupled to SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; [Table 9] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0143] Method 3 Agilent LC 1260 Infinity with SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; column: Acquity UPLC BEH C 18 (100 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; [Table 10] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1500AMU.

[0144] Method 4 Agilent LC 1260 Infinity with SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; column: Acquity UPLC BEH C 18 (100 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.05% aqueous ammonia, mobile phase B: acetonitrile; [Table 11] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0145] Method 5 Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer;Column:Acquity UPLC BEH C 18 (100 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; [Table 12] Column temperature: 25°C; UV detection: 215 nm and 254 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0146] Method 6 Acquity UPLC coupled with a QDA mass detector; column: Acquity UPLC CSH C18 (50 mm × 2.1 mm id, 1.7 μm packed diameter); mobile phase A: 0.05% (v / v) formic acid in water / MeCN 95 / 5; mobile phase B: 0.05% (v / v) formic acid in acetonitrile / water 95 / 5; [Table 13] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0147] HPLC-MDAP Method 1 Agilent 1290 Infinity II Purification System; Column: Waters XBridge® (C18, 100 mm × 19 mm id, 5 μm), Mobile Phase A: 0.1% (v / v) formic acid in water, Mobile Phase B: acetonitrile; [Table 14]

[0148] Abbreviations used: Boc2O = di-tert-butyl dicarbonate; aq. = aqueous; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; 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; EDC.HCl = ethyl-N,N-dimethylaminoethyl-carbodiimide hydrochloride; EtOAc = ethyl acetate; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); LCMS = liquid chromatography-mass spectrometry; 1 H-NMR = proton nuclear magnetic resonance; RM = reaction mixture; Rt = retention time; RT = room temperature; Saturated = saturated; T3P (登録商標)= Propylphosphonic anhydride; TEA = Triethylamine; TFA = Trifluoroacetic acid; THF = Tetrahydrofuran; XPhos-Pd-G3-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0149] In the following procedures, some of the starting materials are identified through "Intermediate" or "Example" numbers followed by step numbers, which are provided solely as an aid to those skilled in the art of chemistry.

[0150] "Similar" or "equivalent" procedures means that such procedures may include minor variations, such as reaction temperatures, amounts of reagents / solvents, reaction conditions, work-up conditions, and / or chromatographic purification conditions.

[0151] The stereochemistry of example compounds, when indicated, has been assigned with the assumption that any resolved stereocenters in the starting materials will be maintained throughout all subsequent reaction conditions.

[0152] Unless otherwise stated, when the absolute configuration (R) or (S) is stated in the compound name, the ee% should be considered to be 90% or greater.

[0153] Intermediate production Intermediate 1 Process 1 [ka] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)piperidine-4-carboxylate (Intermediate 1-1) A suspension of tert-butyl N-(2-bromoethyl)carbamate (3 g, 13.0 mmol), ethyl piperidine-4-carboxylate (2.1 mL, 13.0 mmol), and K2CO3 (3.7 g, 27 mmol) in DMF (30.0 mL) was stirred at 65 °C for 24 h. After cooling to RT, the RM was diluted with water (80 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (80 mL) and saturated aqueous NaCl (50 mL). The organic solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM:MeOH (93:7) in DCM to give the title product (3.24 g). LCMS (Method 2): Rt = 1.05 min, ES + m / z 301.3 [M+H] + .

[0154] Process 2 [ka] Ethyl 1-(2-aminoethyl)piperidine-4-carboxylate (Intermediate 1) A solution of intermediate 1-1 (1.77 g, 5.9 mmol) and TFA (8.8 mL, 118 mmol) in DCM (14 mL) was stirred at RT overnight. The volatiles were removed under reduced pressure, and the crude product was passed through an SCX cartridge, washed with EtOH (500 mL), and eluted with 15% aqueous NH in EtOH (100 mL) to give the title product (1.16 g). 1 H-NMR (300 MHz, CDCl3) δ: 4.13 (q, J = 6.9 Hz, 2H), 2.84-2.88 (m, 2H), 2.78 (t, J = 6.2 Hz, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.24-230 (m, 1H), 2.02 (t, J = 11.5 Hz, 2H), 1.87-1.91 (m, 2H), 1.71-1.79 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H).

[0155] Intermediate 2a Process 1 [ka] 1-Methoxy-2-methylpropan-2-yl 1-benzylpiperidine-4-carboxylate (Intermediate 2a-1) A solution of 1-benzylpiperidine-4-carboxylic acid (500 mg, 2.26 mmol) in DCM (15.0 mL) was treated with oxalyl dichloride (1.94 mL, 22.6 mmol) and DMF (52.2 μL, 0.68 mmol). The RM was stirred at RT for 2 h, then the volatiles were evaporated under reduced pressure. The residue was dissolved in DCM (5.0 mL) and cooled to 10 °C, followed by the addition of 1-methoxy-2-methyl-propan-2-ol (1.32 mL, 11.3 mmol) and DIPEA (2.52 mL, 18.1 mmol). The RM was stirred at RT for 16 h. The RM was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were passed through a phase separator, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH (20:1) in DCM to give the desired product (242 mg). LCMS (Method 1): Rt = 0.64 min, ES + m / z 306.2 [M+H] + .

[0156] Process 2 [ka] 1-Methoxy-2-methylpropan-2-ylpiperidine-4-carboxylate (Intermediate 2a) A solution of intermediate 2a-1 (242 mg, 0.27 mmol) in MeOH (6 mL) was added to Pd / C (10%, 77.8 mg, 0.07 mmol) and maintained under a hydrogen atmosphere at 1 bar (balloon pressure) for 16 h. The RM was passed through a bed of diatomaceous earth and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:15:1.5) in DCM to give the title product (113 mg). 1H-NMR (300 MHz, CDCl3) δ: 3.48 (s, 2H), 3.34 (s, 3H), 3.05 (dt, J = 12.5, 3.9 Hz, 2H), 2.60 (td, J = 12.0, 2.6 Hz, 2H), 2.33 (tt, J = 11.0, 3.8 Hz, 1H), 1.79-1.87 (m, 2H), 1.49-1.62 (m, 2H), 1.40 (s, 6H).

[0157] Intermediate 2b Process 1 [ka] 1-Benzyl 4-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-1,4-dicarboxylate (Intermediate 2b-1) 1-Phenylmethoxycarbonylpiperidine-4-carboxylic acid (300 mg, 1.14 mmol) was suspended in a 5 / 2 mixture of MeCN / DMF (7.0 ml), then 4-(bromomethyl)tetrahydro-2H-pyran and cesium carbonate were added, and the mixture was stirred at 40° C. for 18 hours. The mixture was filtered, and the crude was purified by chromatography on a Si cartridge eluting with a hexane / EtOAc gradient to give the desired product (300 mg). LCMS (Method 6): Rt = 1.09 min, ES + m / z 362.2 [M+H] +

[0158] Process 2 [ka] (Tetrahydro-2H-pyran-4-yl)methylpiperidine-4-carboxylate (Intermediate 2b) A solution of intermediate 2b-1 (300 mg, 0.83 mmol) in EtOH (6 mL) was added with Pd / C (5%, 50 mg) and the pH was adjusted to below 2 with 2 M aqueous HBr. The RM was kept under a hydrogen atmosphere for 3 h, then filtered through a pad of silica gel and concentrated to dryness to give the title product (188 mg). LCMS (Method 6): Rt = 0.23 min, ES +228.28 m / z [M+H] +

[0159] Intermediate 2c Process 1 [ka] 1-Benzyl 4-(1-methylpiperidin-4-yl)piperidine-1,4-dicarboxylate (Intermediate 2c-1) 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid (350 mg, 1.33 mmol, 82) was suspended in 5 mL of dry DCM, and one drop of dry DMF was added, followed by the dropwise addition of oxalyl chloride (233 μL, 2.66 mmol). After 1 h, the RM was concentrated to dryness, dissolved in dry DCM (10 mL), and the solution was added dropwise to a dry DCM solution of a mixture of 1-methylpiperidin-4-ol (230 mg, 1.994 mmol) and DIPEA (697 μL, 3.99 mmol). After 1 h, the RM was quenched by the addition of aqueous saturated NaHCO (20 mL), and the organic layer was separated, dried over NaSO, and concentrated to dryness. The crude material was purified by chromatography on a Si cartridge using 0–20% MeOH in DCM to give the title product (391 mg). LCMS (Method 6): Rt = 0.55 min, ES + 361.3 m / z [M+H] +

[0160] Process 2 [ka] 1-Methylpiperidin-4-ylpiperidine-4-carboxylate (Intermediate 2c) To a solution of intermediate 2c-1 (400 mg, 1.110 mmol) in EtOH (6 mL) was added Pd / C 5% (50 mg) and the pH was adjusted to below 2 with 2 M aqueous HCl. The RM was kept under a hydrogen atmosphere for 3 h, then filtered through a pad of silica gel and concentrated to dryness to give the desired compound (230 mg). LCMS (Method 6): Rt = 0.17 min, ES + 227.3 m / z [M+H] +

[0161] Intermediate 3 Process 1 [ka] 7-Bromo-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 3-1) A solution of 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (3.0 g, 18.20 mmol) in EtOAc (30.0 mL) was cooled to 0 °C. 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (2.6 g, 9.08 mmol) was added portionwise over 15 min. The RM was stirred for an additional 30 min at 0 °C and quenched with aqueous KCO (10% w / w; 60 mL). The organic layer was separated, washed with saturated aqueous NaCl, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–30% EtOAc in cyclohexane to give the title product (3.5 g). LCMS (Method 1): Rt = 0.97 min, ES + m / z 243.9 / 245.9 [M+H] + .

[0162] Process 2 [ka] tert-Butyl 7-bromo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 3) THF (15 mL) was added to a mixture of intermediate 3-1 (1.4 g, 5.74 mmol), DMAP (840.9 mg, 6.88 mmol), and BocO (2.80 g, 13.19 mmol), and the RM was then stirred at RT overnight. The RM was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was washed with 2 M aqueous citric acid (2 × 20 mL), saturated aqueous NaCl (20 mL), and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in cyclohexane to give the title compound (1.26 g). LCMS (Method 1): Rt = 1.27 min 1H-NMR (300 MHz, CDCl3) δ: 7.56 (brs, 1H), 7.05 (s, 1H), 4.14-4.18 (m, 2H), 3.82 (s, 3H), 3.78-3.82 (m, 2H), 1.53 (s, 9H).

[0163] Intermediate 4 Process 1 [ka] tert-Butyl 7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 4-1) A solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (500 mg, 3.06 mmol), DMAP (449 mg, 3.68 mmol), and BocO (1.54 g, 7.05 mmol) in THF (10 mL) was stirred at RT overnight. Additional BocO was added, and stirring continued at RT. The RM was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was washed with 2 M aqueous citric acid (2 × 15 mL), saturated aqueous NaCl (20 mL), and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in cyclohexane to give the title product (228 mg). LCMS (Method 1): Rt = 1.35 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.18 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.57 (dd, J = 8.5, 2.6 Hz, 1H), 3.69 (s, 3H), 3.56-3.60 (m, 2H), 2.63 (t, J = 6.46 Hz, 2H), 1.74-1.82 (m, 2H), 1.45 (s, 9H).

[0164] Process 2 [ka] tert-Butyl 6-bromo-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 4) A solution of intermediate 4-1 (228 mg, 0.86 mmol) in EtOAc (10 mL) was cooled to 0 °C. 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (124 mg, 43.3 mmol) was added portionwise over 15 min. The RM was stirred at 0 °C for 20 min and then quenched with 10% (w / w) aqueous K2CO3 (20 mL). The organic layer was separated, washed with saturated aqueous NaCl (20 mL), and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–15% EtOAc in cyclohexane to give the title product (240 mg). LCMS (Method 1): Rt = 1.46 min, ES + m / z 285.9 / 287.9 ​​[M+H] + .

[0165] Intermediate 5 Process 1 [ka] tert-Butyl 6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 5-1) The title compound was prepared in a manner analogous to Intermediate 4-Step 1, starting from 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine. LCMS (Method 5): Rt = 2.5 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.47 - 7.38 (m, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 8.9, 3.0 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.80 - 3.72 (m, 2H), 3.68 (s, 3H), 1.50 (s, 9H).

[0166] Process 2 [ka] tert-Butyl 7-iodo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 5) Intermediate 5 - Step 1 (5.9 g, 22.1 mmol) was dissolved in DMF (60 mL), then N-iodohydroxysuccinimide (12.7 g, 111 mmol) was added and the RM was stirred at 40 °C overnight. The RM was quenched with cold water and extracted with EtOAc. The combined organic layers were evaporated to dryness and the residue was purified by silica gel chromatography with a gradient elution of 1:1 to 3:2 DCM-hexane to give the title compound (7.38 g). LCMS (Method 1): Rt = 2.8 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.50 (s, 1H), 7.24 (s, 1H), 4.14 (dd, J = 5.3, 3.8 Hz, 2H), 3.80 - 3.75 (m, 2H), 3.74 (s, 3H), 1.51 (s, 9H).

[0167] Intermediate 6 Process 1 [ka] Methyl 1-(5-bromo-2-methoxy-4-nitrophenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 6-1) 6-Chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (3.00 g, 15.2 mmol) was added to a solution of 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (3.80 g, 20.2 mmol) and DBU (5.88 mL, 45.6 mmol) in DMF (48 mL). The RM was stirred at RT for 4 h. Iodomethane (3.78 mL, 60.7 mmol) was added, and the RM was stirred at RT overnight. The RM was quenched with water (200 mL), and the formed precipitate was collected by filtration and dried. The crude material was triturated with EtOAc and washed with EtOAc to give the title product (5.83 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.08 min, ES + m / z 426.9 / 428.9 / 430.9 [M+H] + .

[0168] Process 2 [ka] Methyl 6-chloro-1-(5-((2-hydroxyethyl)thio)-2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 6-2) A degassed mixture of intermediate 6-1 (5.0 g, 11 mmol), 2-sulfanylethanol (1.13 mL, 12 mmol), DIPEA (5.91 mL, 20 mmol), Xantphos (820 mg, 1.4 mmol), and Pd(dba) (330 mg, 0.57 mmol) in 1,4-dioxane (100 mL) was stirred at 100 °C under argon for 3 h. After cooling to RT, the reaction was quenched with water. The formed precipitate was collected by filtration, washed with a small amount of EtOAc, and dried to give the title compound (5.3 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.08 min, ES + m / z 439.0 / 441.0 [M+H] + .

[0169] Process 3 [ka] Methyl 1-(4-amino-5-((2-hydroxyethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 6-3) A solution of intermediate 6-2 (5.3 g, 12 mmol) in MeOH (200 mL) was stirred at 80 °C, followed by the addition of a solution of NH4Cl (6.5 g, 121 mmol) in water (20 mL) and iron powder (6.7 g, 121 mmol). The RM was stirred at 80 °C for 4.5 h, then filtered while hot, and the filtrate was concentrated under reduced pressure. The crude material was diluted with saturated aqueous NaHCO3, the resulting suspension was sonicated, and the solid was collected by filtration. The solid was washed several times with water and dried to give the title product (3.13 g). LCMS (Method 1): Rt = 0.92 min, ES + m / z 409.1 / 411.1 [M+H] + .

[0170] Process 4 [ka] Methyl 1-(4-amino-5-((2-chloroethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 6-4) Intermediate 6-3 (4.4 g, 11 mmol) was mixed with thionyl chloride (12 mL, 165 mmol) at 0 °C. The RM was warmed to RT and stirred for 2 h, then the volatiles were removed under reduced pressure and the residue was dissolved in saturated aqueous NaHCO3. The formed slurry was sonicated, and the solid was collected by filtration, washed with water, and dried. The resulting crude was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in DCM to give the title product (2.7 g). LCMS (Method 1): Rt = 1.24 min, ES + m / z 427.0 / 429.0 / 431.0 [M+H] + .

[0171] Process 5 [ka] Methyl 6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 6-5) A solution of intermediate 6-4 (2.70 g, 6.32 mmol), K2CO3 (2.62 g, 19 mmol), and NaI (189 mg, 1.26 mmol) in DMF (80 mL) was stirred at 90 °C overnight. After cooling to RT, the RM was diluted with water (200 mL). The formed precipitate was filtered, washed several times with water, and dried. The resulting material was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / acetonitrile (9:1) in DCM to give the title product (730 mg). LCMS (Method 1): Rt = 1.13 min, ES + m / z 391.1 / 393.1 [M+H] + .

[0172] Process 6 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 6) Intermediate 6-5 (730 mg, 1.87 mmol) was suspended in THF (15 mL) and LiOH solution (1.0 M aqueous solution, 9 mL, 9 mmol) was added. The RM was stirred at 40 °C for 2.5 h. The organic solvent was removed under reduced pressure and the residue was diluted with water. The pH was adjusted to 2.5 using 1 M aqueous HCl. The formed precipitate was filtered, washed several times with water, and dried to give the title compound (698 mg). LCMS (Method 1): Rt = 0.95 min, ES + m / z 377.1 / 379.0 [M+H] + .

[0173] Intermediate 7 [ka] 1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 7) Method 1 A solution of degassed 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (400 mg, 2.02 mmol), Intermediate 3 (733 mg, 2.13 mmol), CsCO (2.31 g, 7.09 mmol), and thiophene-2-carbonyloxycopper (278 mg, 1.46 mmol) in anhydrous DMSO (7 mL) was stirred under nitrogen at 110 °C overnight. After cooling to RT, the RM was filtered. The filtrate was diluted with MeCN (50 mL), and the precipitate thus formed was collected by filtration and triturated with MeOH. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–100% MeOH in EtOAc to give the title product (150 mg).

[0174] Method 2 A mixture of degassed 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (9.4 g, 47.5 mmol), Intermediate 5 (18.6 g, 47.5 mmol), CsCO (54 g, 166.3 mmol), and thiophene-2-carbonyloxycopper (9 g, 47.5 mmol) in DMSO (100 mL) was stirred under argon at 110 °C for 24 h. The RM was quenched with water and extracted with DCM. The combined organic layers were washed with 10% w / w aqueous citric acid, saturated aqueous NaCl, and evaporated to dryness. The residue was purified by silica gel chromatography eluting with DCM to give MeOH + 1% AcOH (v / v). The material thus obtained was triturated with ethyl ether to give the title compound (3.14 g). LCMS (Method 1): Rt = 1.22 min, ES + m / z 461.2 / 463.2 [M+H] + .

[0175] Intermediate 8 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 8) Intermediate 8 was prepared in a manner similar to Intermediate 7 (Method 1) starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (200 mg, 1.0 mmol) and Intermediate 3-1 (371 mg, 1.5 mmol). LCMS (Method 1): Rt = 0.86 min, ES + m / z 360.9 / 362.8 [M+H] + .

[0176] Intermediate 9 [ka] 1-(1-(tert-butoxycarbonyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 9) A mixture of intermediate 4 (1.04 g, 3.04 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (300 mg, 1.52 mmol), thiophene-2-carbonyloxycopper (290 mg, 1.52 mmol), and CsCO (1.48 g, 4.56 mmol) in DMSO (7 mL) was stirred for 72 h at 100 °C under nitrogen. After cooling to RT, the RM was added dropwise to stirring water. The pH was adjusted to 4 (with 1 M aqueous HCl), and the formed precipitate was filtered, washed with water, and dried. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM:MeOH:HC0H (90:10:0.3) in DCM to give the title product (330 mg). LCMS (Method 1): Rt = 1.24 min, ES + m / z 458.9 / 460.9 [M+H] + .

[0177] Intermediate 10 [ka] tert-Butyl 7-(3-amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 10) A degassed mixture of Intermediate 3 (408 mg, 1.19 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridin-3-amine (200 mg, 1.19 mmol), CsCO (980 mg, 3.01 mmol), DMCHDA (93.5 μL, 0.59 mmol), and CuI (113 mg, 0.59 mmol) in DMSO (4.9 mL) was stirred overnight at 110 °C under argon. After cooling to RT, the RM was quenched with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (282 mg). LCMS (Method 1): Rt = 1.15 min, ES + m / z 431.9 / 433.9 [M+H]+ .

[0178] Intermediate 11a [ka] tert-Butyl 7-(6-chloro-3-((2-(4-(ethoxycarbonyl)piperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 11a) A mixture of Intermediate 7 (700.0 mg, 1.52 mmol), Intermediate 1 (369 mg, 1.82 mmol), DIPEA (1.06 mL, 6.08 mmol), HATU (693 mg, 1.82 mmol), and DMF (12 mL) was stirred at RT for 2.5 h. The RM was diluted with water (40 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–60% DCM / EtOH / NH4OH (90:5:0.5) in DCM to give the title product (866 mg). LCMS (Method 1): Rt = 1.02 min, ES + m / z 643.4 / 645.4 [M+H] + .

[0179] Intermediates 11b~11e The following intermediates were prepared in a manner analogous to intermediate 11a from the starting materials shown. [Table 15]

[0180] Intermediate 12 [ka] 1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 12) To a solution of intermediate 11a (1.0 g, 1.48 mmol) in THF (10 mL) was added 1 M aqueous LiOH (10.6 mL, 11.8 mmol) at RT. The RM was stirred at RT for 16 h. The volatiles were removed under reduced pressure and the residue was diluted with water. The pH was adjusted to 6.5 using 1 M aqueous HCl and the RM was extracted with DCM (3 × 10 mL). The combined organic layers were evaporated to dryness to give the title product (756 mg). LCMS (Method 1): Rt = 0.99 min, ES + m / z 615.1 / 617.1 [M+H] +

[0181] Intermediate 13a [ka] tert-Butyl 7-(6-chloro-3-((2-(4-((cyclopentyloxy)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 13a ) A solution of intermediate 12 (80.0 mg, 0.13 mmol), cyclopentanol (102 μL, 0.77 mmol), EDC*HCl (24.7 mg, 0.13 mmol), and DMAP (6.29 mg, 0.05 mmol) in dry DCM (3 mL) was stirred under nitrogen at RT for 3 h. The RM was diluted with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–90% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (55 mg). LCMS (Method 2), Rt = 1.54, ES + m / z 683.4 / 685.4.

[0182] Intermediate 13b~13o The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 13a. [Table 16] [Table 17] [Table 18]

[0183] Intermediate 13r [ka] tert-Butyl 7-(6-chloro-3-((2-(3-(ethoxycarbonyl)piperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 13r ) A solution of intermediate 11d (60 mg, 0.10 mmol), ethyl piperidine-3-carboxylate (16 mg, 0.10 mmol), and DIPEA (71 μL, 0.41 mmol) in DMF (1 mL) was stirred at RT for 6 h. Ethyl piperidine-3-carboxylate (16 mg, 0.10 mmol) was added, and the RM was stirred at RT overnight. The RM was diluted with EtOAc (10 mL) and washed with water (3 × 10 mL) and saturated aqueous NaCl (10 mL). The organic layer was evaporated to dryness, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / EtOH / NH4OH (90:5:0.5) in DCM to give the title product (30.1 mg). LCMS (Method 1), Rt = 1.05, ES + m / z 643.3 / 645.4.

[0184] intermediate 13s-13aa The following intermediates were prepared from the starting materials indicated in a manner analogous to intermediate 13r. If base, solvent, additives or temperature were varied, this is further described. [Table 19] [Table 20]

[0185] Intermediate 13ab Process 1 [ka] tert-Butyl 7-(6-chloro-3-((2-((3-(2-methoxy-2-oxoethyl)benzyl)amino)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 13ab-1) The title compound was prepared in an analogous manner to intermediate 13r, starting from intermediate 11d and methyl 2-[3-(aminomethyl)phenyl]acetate hydrochloride. LCMS (Method 1): Rt = 1.06 min, ES + m / z 665.3 / 667.3 [M+H] +

[0186] Process 2 [ka] tert-Butyl 7-(6-chloro-3-((2-((3-(2-methoxy-2-oxoethyl)benzyl)(methyl)amino)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 13ab) A solution of intermediate 13ab-1 (64 mg, 0.10 mmol) in MeOH (1 mL) was treated with formic acid (145 μL, 3.8 mmol) and 37% aqueous formaldehyde (287 μL, 3.8 mmol). The RM was stirred at RT for 60 h. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–45% DCM / MeOH / NH OH (90:4:1) in DCM to give the title product (28 mg). LCMS (Method 2), Rt = 1.46, ES + m / z 679.2 / 681.2.

[0187] intermediate 13ac Process 1 [ka] N-(2-Bromoethyl)-6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 13ac-1) A solution of intermediate 11d (100.0 mg, 0.17 mmol) and TFA (642.0 μL, 8.64 mmol) in DCM (1.0 mL) was stirred at RT for 16 h and then evaporated to dryness. The residue was dissolved in MeOH (0.5 mL), passed through an SCX cartridge, washed with MeOH (20 mL), and eluted with 1 M methanolic ammonia (20 mL) to give the desired product (81.9 mg). LCMS (Method 1): Rt = 1.07, ES + m / z 466.1 / 468.1.

[0188] Process 2 [ka] 1-Methoxy-2-methylpropan-2-yl 1-(2-(6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Intermediate 13ac) The title compound was prepared in a similar manner to intermediate 13r, starting from intermediate 13ac-1 and intermediate 2a. LCMS (Method 1): Rt = 0.85 min, ES + m / z 601.4 / 603.4 [M+H] +

[0189] Intermediate 13ad [ka] Propyl N-(2-(6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)-N-methylglycinate (Intermediate 13ad) A solution of Intermediate 11d (100 mg, 0.20 mmol), propyl 2-(methylamino)acetate (80.0 mg, 0.61 mmol), and Na2CO3 (43.0 mg, 0.41 mmol) in acetone (2.0 mL) was stirred at 40 °C for 16 h and at 65 °C for 1 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL), and the aqueous layer was further extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2 × 10 mL), saturated aqueous NaCl (10 mL), and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–60% DCM / MeOH (20:1) in DCM to give the title product (51.7 mg). LCMS (Method 2): Rt = 1.11 min, ES + m / z 517.2 / 519.2 [M+H] +

[0190] Intermediate 13ae [ka] 3-(Dimethylamino)propyl 6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 13ae) Intermediate 6 (50.0 mg, 0.13 mmol), T3P (登録商標) A mixture of (50.0% solution in DMF, 155 μL, 0.26 mmol), azido(trimethyl)silane (35.2 μL, 0.26 mmol), TEA (55.5 μL, 0.4 mmol), and 3-(dimethylamino)propan-1-ol (31.4 μL, 0.26 mmol) in THF (1 mL) was refluxed for 3 h. The reaction mixture was refluxed for 3 h, diluted with EtOAc (25 mL), and washed with saturated aqueous NaHCO (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–35% DCM / MeOH / NH OH (90:15:1.5) in DCM to give the desired product. LCMS (Method 1): Rt = 0.83 min, ES + m / z 462.1 / 464.2 [M+H] +

[0191] Intermediate 13af [ka] 3-(4-Methylpiperazin-1-yl)propyl 6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 13af) The title product was prepared in a manner analogous to Intermediate 13ae from Intermediate 6 (60 mg, 0.16 mmol) and 3-(4-methylpiperazin-1-yl)propan-1-ol (50 mg, 0.32 mmol). LCMS (Method 1): Rt = 0.81 min, ES + m / z 517.1 / 519.1 [M+H] +

[0192] Intermediate 13ag~13ai The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 13r. [Table 21]

[0193] Intermediate 14a [ka] tert-Butyl 7-(6-chloro-3-(((2-ethoxy-2-oxoethoxy)carbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 14a) A solution of intermediate 10 (90.0 mg, 0.21 mmol) in DCM (5 mL) was cooled to -78 °C, followed by the addition of TEA (87.1 μL, 0.63 mmol) and bis(trichloromethyl)carbonate (61.8 mg, 0.21 mmol). The RM was stirred at ~78 °C for 1 h. Ethyl 2-hydroxyacetate (79 μL, 0.83 mmol) and TEA (58.1 μL, 0.42 mmol) were added, and the RM was stirred overnight, allowing it to reach RT. The RM was quenched with saturated aqueous NaHCO3 and water, then extracted with DCM (4 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–40% EtOAc in DCM to give the title product (92 mg). LCMS (Method 1): Rt = 1.29, ES + m / z 562.1 / 564.1.

[0194] Intermediate 14b~14c The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 14a. [Table 22]

[0195] Intermediate 14d [ka] Ethyl (1s,3s)-3-(((6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)cyclobutane-1-carboxylate (Intermediate 14d) To a solution of intermediate 6 (50.0 mg, 0.13 mmol) in 2-Me-THF (1.0 mL), (登録商標)(50.0% solution in EtOAc, 119 μL, 0.26 mmol), azido(trimethyl)silane (35.2 μL, 0.26 mmol), and TEA (55.5 μL, 0.40 mmol) were added. The RM was refluxed for 1 h, after which a solution of ethyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (38.3 mg, 0.26 mmol) and TEA (55.5 μL) in 2-Me-THF (150 μL) was added. The RM was stirred at RT and refluxed overnight. After cooling to RT, the RM was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-50% EtOAc in cyclohexane to give the title product (27 mg). LCMS (Method 1): Rt = 1.08, ES + m / z 518.0 / 520.1.

[0196] Intermediate 14e~14f The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 14d. [Table 23]

[0197] Intermediate 15 [ka] (3S,4S)-4-Fluoro-1-methylpyrrolidin-3-ol (Intermediate 15) A mixture of (3S,4S)-4-fluoropyrrolidin-3-ol hydrochloride (50 mg, 0.35 mmol), iodomethane (22.0 μL, 0.35 mmol), and NaCO (75 mg, 0.71 mmol) in MeCN (1.0 mL) was stirred at 80 °C for 18 h. The RM was cooled to RT, filtered, and the collected solid was washed with DCM (10 mL), and the combined organics were evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM:MeOH:NHOH (90:15:0.5) in DCM to give the title product (8 mg). 1 H NMR(500 MHz, CDCl3) δ / ppm: 4.85-5.06(m, 1H), 4.38(m, 1H), 3.12-3.30(m, 1H), 2.97(br dd, J = 9.9, 4.4 Hz, 1H), 2.67-2.79(m, 2H), 2.47(s, 3H).

[0198] Intermediate 16 [ka] (R)-1-(2-fluoroethyl)pyrrolidin-3-ol (Intermediate 16) A solution of (3R)-pyrrolidin-3-ol (200 mg, 2.3 mmol), KCO (577 mg, 4.2 mmol), and 1-bromo-2-fluoroethane (321 mg, 2.5 mmol) in MeCN (3.8 mL) was stirred at 70 °C overnight. After cooling to RT, the RM was filtered through a plug of diatomaceous earth and washed with MeCN. The solvent was removed under reduced pressure to give the title product (282 mg), which was used in the next synthetic step without further purification. 1H-NMR (300 MHz, CDCl3) δ: 4.54 (dt, J = 47.6, 5.0 Hz, 2H), 4.31-4.37 (m, 1H), 2.91-2.98 (m, 1H), 2.78 (dt, J = 28.0, 5.0 Hz, 2H), 2.71-2.76 (m, 1H), 2.60 (dd, J = 10.2, 5.2 Hz, 1H), 2.37 (td, J = 8.7, 6.5 Hz, 1H), 2.12-2.24 (m, 1H), 1.68-1.78 (m, 1H).

[0199] Intermediate 17 Process 1 [ka] Methyl (R)-1-(2-(((benzyloxy)carbonyl)amino)ethyl)pyrrolidine-3-carboxylate (Intermediate 17-1) A mixture of N-(2-bromoethyl)carbamate (250 mg, 0.97 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (176 mg, 1.1 mmol), and K2CO3 (402 mg, 2.9 mmol) in MeCN (2 mL) was stirred at 70 °C overnight. After cooling to RT, the RM was diluted with water and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with water (3 × 15 mL) and passed through a phase separator. The solvent was removed to give the product (282 mg), which was used in the next step without further purification. 1 H-NMR (500 MHz, CDCl3) δ: 7.36-7.38 (m, 4H), 7.30-7.34 (m, 1H), 5.29 (bs, 1H), 5.11 (s, 2H), 3.69 (s, 3H), 3.29-3.35 (m, 2H), 2.98-3.04 (m, 1H), 2.85 (t, J = 8.6 Hz, 1H), 2.70-2.73 (m, 1H), 2.53-2.68 (m, 4H), 2.06-2.10 (m, 2H).

[0200] Process 2 [ka] (R)-1-(2-(((benzyloxy)carbonyl)amino)ethyl)pyrrolidine-3-carboxylic acid (Intermediate 17-2) A solution of intermediate 17-1 (140 mg, 0.46 mmol) in ethanol (1.2 mL) was treated with NaOH (2.0 M aqueous solution, 560 μL, 1.1 mmol). The RM was stirred at RT for 1 h. The RM was quenched with 2 N aqueous HCl (560 μL) and then stirred at RT for 15 min. The ethanol was partially removed by evaporation, followed by the addition of acetone. The RM was stirred at RT for 15 min, then filtered through a pad of diatomaceous earth and washed thoroughly with acetone. The filtrate was evaporated to dryness to give the title product (138 mg), which was used in the next synthetic step without further purification. 1 H-NMR (500 MHz, CDCl3) δ: 7.54 (bs, 1H), 7.35-7.31 (m, 4H), 7.27-7.30 (m, 1H), 5.12 (m, 1H), 5.08 (s, 2H), 3.93 (m, 1H), 3.40-3.61 (m, 3H), 2.88-3.15 (m, 5H), 2.37-2.43 (m, 1H), 2.15-2.22 (m, 1H).

[0201] Process 3 [ka] (R)-1-(2-Fluoroethyl)pyrrolidin-3-yl (R)-1-(2-(((benzyloxy)carbonyl)amino)ethyl)pyrrolidine-3-carboxylate (Intermediate 17) To a solution of intermediate 17-2 (135 mg, 0.46 mmol), intermediate 16 (73.8 mg, 0.55 mmol), and 2,4,6-trichlorobenzoyl chloride (86.6 μL, 0.55 mmol) in dry THF (3 mL), TEA (129 μL, 0.92 mmol) and DMAP (14.1 mg, 0.25 mmol) were added, and the RM was stirred at RT overnight. The RM was poured into a mixture of EtOAc and water (10 mL each), and the pH was adjusted from 5.5 to 3.5 using 1.0 M aqueous HCl. The aqueous layer was basified to pH 9.5 with 2 M NaOH and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2 ×), saturated aqueous NaCl, dried over Na2SO4, and the solvent was removed under reduced pressure to give the title product (162 mg). 1 H-NMR (500 MHz, CDCl3) δ: 7.35-7.31 (m, 4H), 7.27-7.30 (m, 1H), 5.37 (bs, 1H), 5.18-5.22 (m, 1H), 5.11 (s, 2H), 4.56 (dt, J = 47.4, 4.9 Hz, 2H), 3.32 (m, 2H), 2.71-3.03 (m, 8H), 2.57-2.67 (m, 4H), 2.48-2.52 (m, 1H), 2.24-2.31 (m, 1H), 2.05-2.09 (m, 2H), 2.81-2.88 (m, 1H).

[0202] Intermediate 19 [ka] (S)-1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylic acid (Intermediate 19) Aqueous LiOH (1.0 M, 0.65 mL, 0.65 mmol) was added to a solution of intermediate 13u (80.0 mg, 0.13 mmol) in THF (1.0 mL), aqueous LiOH (1.0 M, 0.65 mL, 0.65 mmol) was added, and the RM was stirred at RT for 30 h. THF was removed under reduced pressure, followed by the addition of water, and the pH was adjusted to 6.5. The aqueous mixture was extracted with DCM / i-PrOH (3 × 10 mL), and the combined organic layers were passed through a phase separator and the solvent was removed under reduced pressure to give the title compound (68 mg). LCMS (Method 1): Rt = 0.94 min, ES + m / z 601.3 / 603.2 [M+H] +

[0203] Intermediate 20a [ka] tert-Butyl 7-(6-chloro-3-((2-((S)-3-((((R)-1-methylpyrrolidin-3-yl)oxy)carbonyl)pyridin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 20a) To a solution of intermediate 19 (40.0 mg, 66.6 μmol), 2,4,6-trichlorobenzoyl chloride (10.4 μL, 66.6 μmol), and (R)-1-methylpyrrolidin-3-ol (6.44 μL, 66.6 μmol) in dry THF (1 mL) was added TEA (18.6 μL, 0.13 mmol) and DMAP (2.03 mg, 16.6 μmol), and the RM was stirred at RT for 1 h. The RM was diluted with EtOAc (15 mL) and washed with saturated aqueous NaHCO (3 × 10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH (9:1) in DCM to give the desired product (42 mg). LCMS (Method 2): Rt = 1.27 min, ES + m / z 684.3 / 686.3 [M+H] +

[0204] Intermediate 20b [ka] tert-Butyl 7-(6-chloro-3-((2-(4-(((1-isopropylazetidin-3-yl)oxy)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 20b) The title compound was prepared in a manner analogous to Intermediate 20a, starting from Intermediate 12 (80 mg, 0.13 mmol) and 1 equivalent of 1-isopropylazetidin-3-ol. LCMS (Method 2): Rt = 1.36 min, ES + m / z 712.3 / 715.4 [M+H] +

[0205] Preparation of Example Compounds Example 1 [ka] Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Example 1) A degassed mixture of Intermediate 11c (80.0 mg, 0.14 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (49 mg, 0.200 mmol), XPhos Pd G3 (6 mg, 7 μmol), and KPO (0.5 M, 572 μL, 0.29 mmol) in THF / water (1 / 1, 4.57 mL) was heated at 65 °C for 3.5 h. Additional 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine and XPhos Pd G3 were added, and the RM was heated at 100 °C for an additional 1 h. After cooling to RT, the RM was diluted with water and extracted with DCM (3 × 15 mL). The combined organic layers were passed through a phase separator and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-90% DCM / EtOH (90:1) in DCM to give the desired product (62 mg). LCMS (Method 3): Rt = 4.42 min, ES + m / z 642.3 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.45 (d, J = 1.2 Hz, 1H), 9.23 (dd, J = 7.1, 1.7 Hz, 1H), 8.90 (s, 1H), 8.73 (dd, J = 4.0, 1.7 Hz, 1H), 8.46 (br t, J = 5.8 Hz, 1H), 8.23 ​​(d, J = 1.0 Hz, 1H), 7.16 (dd, J = 7.0, 4.2 Hz, 1H), 7.08 (s, 1H), 6.63-6.68 (m, 1H), 6.44 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 3.54-3.62 (m, 2H), 3.36-3.50 (m, 2H), 2.94-3.04 (m, 2H), 2.79-2.91 (m, 2H), 2.42-2.53 (m, 2H), 2.19-2.35 (m, 1H), 2.03 (br t, J = 10.3 Hz, 2H), 1.69-1.86 (m, 2H), 1.45-1.65 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H).

[0206] Examples 2 to 8 The following example compounds were prepared from the indicated intermediates in a manner analogous to Example 1. If base, solvent, temperature, ligand and / or palladium source were varied, this is further noted. [Table 24] [Table 25] [Table 26] [Table 27]

[0207] Example 9 Process 1 [ka] tert-Butyl 7-(3-((2-(4-(ethoxycarbonyl)piperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 9 - Intermediate 1) A degassed mixture of Intermediate 11a (500 mg, 0.78 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (286 mg, 1.17 mmol), KPO (330 mg, 1.55 mmol), and XPhos PdG (66 mg, 78 μmol) in water (4.5 mL) / THF (9 mL) was stirred at 65 °C for 1 h under nitrogen. After cooling to RT, the RM was diluted with water (40 mL) and extracted with EtOAc (40 mL and 2 × 15 mL). The combined organic layers were washed with water, saturated aqueous NaCl (40 mL each), dried over NaSO, and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-65% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the product (483 mg). LCMS (Method 1), Rt = 0.91, ES + m / z 726.4.

[0208] Process 2 [ka] Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Example 9) Example 9 - To a solution of Intermediate 1 (480 mg, 0.66 mmol) in DCM (10 mL) was added TFA (2.06 mL, 27.8 mmol) and the RM was stirred at RT overnight. The RM was evaporated under reduced pressure and the residue was loaded onto an SCX cartridge, washed with ethanol, and eluted with 15% aqueous ammonia in ethanol. The crude material thus obtained was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (246 mg). LCMS (Method 3), Rt = 4.13 min, ES + m / z 626.3 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.46 (s, 1H), 9.23 (br d, J = 6.7 Hz, 1H), 8.91 (s, 1H), 8.76-8.72 (m, 1H), 8.45 (br s, 1H), 8.24 (s, 1H), 7.20-7.15 (m, 1H), 6.89 (s, 1H), 6.49 (s, 1H), 6.38 (br s, 1H), 4.14 (br s, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.63 (s, 3H), 3.48-3.36 (m, 5H), 2.86 (br d, J = 10.7 Hz, 2H), 2.47-2.44 (overlapping with DMSO, 1H), 2.28 (br s, 1H), 2.04 (br t, J = 10.7 Hz, 2H), 1.79 (br d, J = 11.6 Hz, 2H), 1.56 (br d, J = 9.8 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H)

[0209] Examples 10 to 42 The following example compounds were prepared from the starting materials indicated by a two-step procedure similar to that of Example 9. If base, solvent, temperature, ligand and / or palladium source were varied, as further noted. [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47

[0210] Example 43

change

[0211] Examples 44-45 The following example compounds were prepared in a manner analogous to Example 43 from the starting materials indicated. [Table 48]

[0212] Example 46 Process 1 [ka] 1-(6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example 46 - Intermediate 1) A degassed mixture of Intermediate 8 (50 mg, 0.14 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (47.6 mg, 0.19 mmol), KPO (58.8 mg, 0.28 mmol), and XPhos PdG (5.9 mg, 7 μmol) in 1 / 1 water / THF (5 mL) was stirred under nitrogen at 70 °C for 1.5 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was suspended in 1 M aqueous HCl to form a precipitate, which was collected by filtration and subsequently washed with water. The filtrate was further extracted with EtOAc (3 × 20 mL), DCM (2 × 10 mL), and DCM:i-PrOH (1:1, 2 × 20 mL). The combined organic layers were dried over NaSO, and the solvent was removed under reduced pressure. The combined crude material was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / AcOH (90:9:1.5) in DCM to give the title product (37.9 mg). LCMS (Method 3), Rt = 3.79 min, ES + m / z 444.1 [M+H] +

[0213] Process 2 [ka] (4-Methylmorpholin-2-yl)methyl 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Example 46) Example 46—A solution of Intermediate 1 (20.0 mg, 0.04 mmol), (4-methylmorpholin-2-yl)methanol (18.5 mg, 0.14 mmol), EDC*HCl (13.5 mg, 0.07 mmol), and DMAP (4.3 mg, 35 μmol) in DMF (1 mL) was stirred at RT overnight. The RM was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with saturated aqueous NaCl (5 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–20% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (6.6 mg). LCMS (Method 3), Rt = 4.21 min, ES + m / z 557.2 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.26-9.22 (m, 1H), 8.92 (s, 1H), 8.76-8.73 (m, 1H), 8.28 (s, 1H), 7.18 (dd, J = 4.3, 7.0 Hz, 1H), 6.87 (s, 1H), 6.51 (s, 1H), 6.43 (s, 1H), 4.46-4.41 (m, 2H), 4.15 (t, J = 4.1 Hz, 2H), 3.92-3.83 (m, 2H), 3.63 (s, 3H), 3.61-3.56 (m, 1H), 3.40 (br d, J = 1.5 Hz, 2H), 2.80 (br d, J = 11.3 Hz, 1H), 2.62 (br d, J = 11.9 Hz, 1H), 2.21 (s, 3H), 2.09-2.03 (m, 1H), 1.93 (t, J = 10.7 Hz, 1H)

[0214] Example 47 Process 1 [ka] 1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylic acid (Example 47 - Intermediate 1) Example 9 - A mixture of Intermediate 1 (1.0 g, 1.38 mmol) and LiOH (1.0 M aqueous solution, 6.9 mL, 6.9 mmol) in THF (15 mL) was stirred at RT overnight. The RM was diluted with water and washed with EtOAc. The aqueous layer was acidified to pH 5 using 1.0 M aqueous HCl, and after cooling on ice for 30 min, the formed precipitate was filtered, washed several times with water, and dried to give the title compound (842 mg). LCMS (Method 1), Rt = 0.82 min, ES + m / z 698.3 [M+H] +

[0215] Process 2 [ka] tert-Butyl 7-(3-((2-(4-((3-cyanocyclobutoxy)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 47 - Intermediate 2) Example 47—To a solution of a mixture of Intermediate 1 (70.0 mg, 0.10 mmol), 2,4,6-trichlorobenzoyl chloride (39 μL, 0.25 mmol), and 3-hydroxycyclobutanecarbonitrile (21.4 μL, 0.25 mmol) in dry DMF (1 mL) was added TEA (70 μL, 0.50 mmol) and DMAP (3 mg, 25 μmol), and the RM was stirred at RT overnight. The RM was diluted with EtOAc (15 mL) and washed with saturated aqueous NaHCO (3 × 10 mL), saturated aqueous NH (15 mL), and saturated aqueous NaCl (10 mL). The organic layer was dried over Na SO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH (95:5) in DCM to give the title product (47 mg). LCMS (Method 2): Rt = 1.21 min, ES + m / z 777.4 [M+H] +

[0216] Process 3 [ka] 3-Cyanocyclobutyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Example 47) Example 47—An ice-cold mixture of Intermediate 2 (45.0 mg, 57.9 μmol) in dry DCM (1 mL) was treated with TFA (222 μL, 2.90 mmol). The RM was stirred for 2 h at RT, then diluted with DCM, cooled to 0° C., neutralized with aqueous saturated NaHCO3, and extracted with DCM (3 × 10 mL). The combined organic layers were passed through a phase separator and the solvent removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH (9:1) in DCM to give the title product (31 mg). LCMS (Method 3): Rt = 4.26 min, ES + m / z 677.5 [M+H] + 1 H-NMR (600 MHz, DMSO-d6) δ: 9.46 (d, J = 1.1 Hz, 1H), 9.24 (dd, J = 7.0, 1.7 Hz, 1H), 8.91 (s, 1H), 8.74 (dd, J = 4.1, 1.7 Hz, 1H), 8.45 (t, J = 5.9 Hz, 1H), 8.24 (d, J = 1.1 Hz, 1H), 7.17 (dd, J = 7.0, 4.0 Hz, 1H), 6.89 (s, 1H), 6.49 (s, 1H), 6.37-6.40 (m, 1H), 4.87 (quin, J = 7.3 Hz, 1H), 4.14 (t, J = 4.4 Hz, 2H), 3.63 (s, 3H), 3.44 (q, J = 6.5 Hz, 2H), 3.37-3.41 (m, 2H), 3.03-3.12 (m, 1H), 2.82-2.90 (m, 2H), 2.70-2.78 (m, 2H), 2.51-2.53 (m, 2H), 2.26-2.34 (m, 3H), 2.01-2.08 (m, 2H), 1.77-1.85 (m, 2H), 1.51-1.61 (m, 2H).

[0217] Example 48 - Intermediate 1 and Example 49 - Intermediate 1 The following intermediates were prepared in a manner analogous to Example 47 - Intermediate 1 from the starting materials indicated. [Table 49]

[0218] Examples 48 to 53 The following example compounds were prepared from the starting materials indicated, respectively, in a two-step procedure (Steps 1 and 2) similar to Example 47 - Steps 2 and 3. If the base, solvent, temperature, or coupling agent was changed, it is further noted. [Table 50] [Table 51] [Table 52] [Table 53]

[0219] Example 54 Process 1 [ka] tert-Butyl 7-(3-((2-(4-((3-bromopropoxy)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 54 - Intermediate 1) The title product was prepared in a manner analogous to Example 47-Intermediate 2, starting from Example 47-Intermediate 1 and 3-bromopropan-1-ol. LCMS (Method 2): Rt = 1.33 min, ES + m / z 818.3 / 820.2 [M+H] +

[0220] Process 2 [ka] tert-Butyl 7-(3-((2-(4-((3-cyanopropoxy)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 54 - Intermediate 2) Example 54—A solution of a mixture of Intermediate 1 (32.0 mg, 0.04 mmol) and NaCN (10.0 mg, 0.20 mmol) in DMF (1.0 mL) was stirred at 80° C. for 1.5 h. The RM was diluted with EtOAc (15 mL) and washed with saturated aqueous NaHCO (3×10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–70% DCM / MeOH (9:1) in DCM to give the title product (28 mg). LCMS (Method 2): Rt = 1.18 min, ES + m / z 765.4 [M+H] +

[0221] Process 3 [ka] 3-Cyanopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Example 54) The title compound was prepared in a manner analogous to Step 3 of Example 47, starting from Example 54 - Intermediate 2. LCMS (Method 3): Rt = 4.12 min, ES + m / z 665.4 [M+H] + 11H-NMR (500, DMSO-d6) δ: 9.45 (d, J = 1.1 Hz, 1H), 9.23 (dd, J = 7.0, 1.5 Hz, 1H), 8.91 (s, 1H), 8.73 (dd, J = 4.3, 1.5 Hz, 1H), 8.45 (t, J = 5.8 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.17 (dd, J = 7.0, 4.0 Hz, 1H), 6.89 (s, 1H), 6.49 (s, 1H), 6.35 - 6.41 (m, 1H), 4.14 (t, J = 4.3 Hz, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.63 (s, 3H), 3.44 (q, J = 6.9 Hz, 2H), 3.36 - 3.41 (m, 2H), 2.80 - 2.93 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.49 - 2.52 (m, 2H), 2.28 - 2.35 (m, 1H), 2.04 (br t, J = 10.5 Hz, 2H), 1.88 (quin, J = 6.6 Hz, 2H), 1.78 - 1.85 (m, 2H), 1.51 - 1.64 (m, 2H).

[0222] Example 55 <s> Process 1

Chem.

[0223] Process 2 [ka] tert-Butyl 7-(3-((2-((R)-3-((((R)-1-(2-fluoroethyl)pyrrolidin-3-yl)oxy)carbonyl)pyrrolidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 55 - Intermediate 2) A solution of Intermediate 17 (140 mg, 0.34 mmol) in concentrated HCl (1.5 mL) was stirred overnight at RT. The solvent was removed under reduced pressure, and the residue was dried in a vacuum oven at 40 °C for 72 h. To the residue dissolved in dry DMF (2 mL) was added Example 55-Intermediate 1 (171 mg, 0.32 mmol), DIPEA (507 μL, 2.96 mmol), and HATU (169 mg, 0.44 mmol), and the RM was stirred at RT for 1 h. A second portion of HATU was added, and the RM was stirred at RT for an additional 1 h. The RM was quenched with saturated aqueous NH4Cl, and the formed precipitate was collected by filtration and washed several times with water. The resulting solid was purified by flash chromatography on a Si cartridge eluting with 0–40% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (10 mg). LCMS (Method 2): Rt = 1.18 min, ES + m / z 799.4 [M+H] +

[0224] Process 2 [ka] (R)-1-(2-Fluoroethyl)pyrrolidin-3-yl (R)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate (Example 55) The title compound was prepared in a manner analogous to Step 3 of Example 47, starting from Example 55 - Intermediate 2. LCMS (Method 3): Rt = 3.44 min, ES + m / z 699.3 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.46 (d, J = 1.2 Hz, 1H), 9.23 (dd, J = 7.0, 1.5 Hz, 1H), 8.91 (s, 1H), 8.73 (dd, J = 4.1, 1.7 Hz, 1H), 8.45 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.17 (dd, J = 7.0, 4.0 Hz, 1H), 6.88 (s, 1H), 6.49 (s, 1H), 6.37-6.40 (m, 1H), 5.02-5.08 (m, 1H), 4.48 (dt, J = 48.0, 4.7 Hz, 2H), 4.14 (t, J = 4.3 Hz, 2H), 3.63 (s, 3H), 3.43 (q, J = 6.4 Hz, 2H), 3.37-3.41 (m, 2H), 2.94-3.03 (m, 1H), 2.83 (t, J = 8.7 Hz, 1H), 2.56-2.75 (m, 9H), 2.51-2.55 (m, 1H), 2.33-2.40 (m, 1H), 2.08-2.20 (m, 1H), 1.88-2.03 (m, 2H), 1.61-1.71 (m, 1H).

[0225] Examples 56-57 The compounds of the following examples, the substances shown in the examples, and the substances in Example 9 were manufactured by the same engineering method as 2. Table 54

[0226] Example 58 Process 1

change

[0227] Process 2 [ka] 1-(6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example 58 - Intermediate 2) Example 58 - A solution of a mixture of Intermediate 1 (84 mg, 0.15), sodium iodide (92 mg, 0.61 mmol), and TMS-Cl (78 μL, 0.61 mmol) in acetonitrile (2.0 mL) was stirred at 85 °C for 3 h. The RM was cooled to RT and quenched with water (50 μL). Toluene (5 mL) was added and the solvent was removed under reduced pressure to give the title compound (290 mg), which was used in the next synthetic step without further purification. LCMS (Method 2): Rt = 0.49 min, ES + m / z 436.2 [M+H] +

[0228] Process 3 [ka] Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate (Example 58) The title compound was prepared in a manner analogous to Intermediate 11a, starting from Example 58 - Intermediate 2 and Intermediate 1. LCMS (Method 3): Rt = 4.10 min, ES + m / z 618.3 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ: 9.15 (d, J = 0.5 Hz, 1H), 8.81 (s, 1H), 8.39 (t, J = 5.3 Hz, 1H), 8.14 (d, J = 0.7 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 4.4 Hz, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 6.35 (bs, 1H), 4.12 (d, J = 3.9 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.63 (s, 3H), 3.41 (q, J = 6.7 Hz, 2H), 3.30 (m, 2H, overlaps with HDO), 2.83-2.86 (m, 2H), 2.48 (t, J = 6.7 Hz, 2H), 2.27 (tt, J = 6.7 Hz, 1H), 2.00-2.05 (m, 2H), 1.76-1.80 (m, 2H), 1.51-1.58 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H)

[0229] Example 59 Process 1 [ka] tert-Butyl 7-(3-((2-(4-((ethylthio)carbonyl)piperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 59 - Intermediate 1) The title product was prepared in a manner analogous to Example 47, Step 2, starting from Example 47-Intermediate 1 and ethanethiol. LCMS (Method 1): Rt = 1.00 min, ES + m / z 742.4 [M+H] +

[0230] Process 2

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[0231] Production of Comparative Examples A1 to A12 Example A1

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[0232] Examples A2 to A12 The following example compounds were prepared from the starting materials indicated in a manner analogous to Example A1. [Table 55] [Table 56] [Table 57] [Table 58]

[0233] Example A9 (or Example 46 - Intermediate 1) [ka] 1-(6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example A9) Example 46 - See procedure for preparation of Intermediate 1. LCMS (Method 1), Rt = 3.79 min, ES + m / z 444.1 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ: 9.47 (s, 1H), 9.19 (dd, J = 7.0, 1.6, 1H), 8.88 (s, 1H), 8.71 (dd, J = 3.9, 1.5 Hz, 1H), 8.15 (d, J = 0.6 Hz, 1H), 7.13 (dd, J = 6.9, 3.9 Hz, 1H), 6,78 (s, 1H), 6.48 (s, 1H), 6.27 (bs, 1H), 4.14 (t, J = 4.2, 2.0 Hz), 3,63 (s, 3H), 3.25-3.41 (m, 2H)

[0234] Example A10 [ka] 2-(((1-(6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)acetic acid (Example A10) The title compound was obtained as a secondary product during the preparation of Example 3. LCMS (Method 1), Rt = 4.20 min, ES + m / z 533.1 [M+H] + 110.76 (br s, 1H); 9.20-9.29 (m, 2H); 8.90 (s, 1H); 8.74 (dd, J = 4.0, 1.5 Hz, 1H); 8.10 7.17 (dd, J = 6.9, 4.1 Hz, 1H); 6.96 (s, 1H); 6.56-6.65 (m, 1H); 6.43 (s, 1H); 4.70 (s, 2H); 3.64 (s, 3H); 3.54-3.61 (m, 2H); 2.95-3.02 (m, 2H).

[0235] Example A11 The following example compounds were prepared from the starting materials indicated in a manner analogous to Example A1. [Table 59]

[0236] Example A12 [ka] 2-(1-(2-(1-(6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidin-4-yl)acetic acid (Example A12) The title compound was prepared in a manner analogous to Step 3 of Example 47, starting from Example 48-Intermediate 1. LCMS (Method 3), Rt = 3.77 min, ES + m / z 612.2 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 12.03 (br s, 1H); 9.46 (d, J = 1.2 Hz, 1H); 9.23 (dd, J = 7.0, 1.5 Hz, 1H); 8.91 (s, 1H); 8.74 (dd, J = 4.1, 1.7 Hz, 1H); 8.42 (t, J = 5.8 Hz, 1H); 8.24 (d, J = 0.9 Hz, 1H); 7.17 (dd, J = 6.9, 4.1 Hz, 1H); 6.89 (s, 1H); 6.49 (s, 1H); 6.37-6.40 (m, 1H); 4.14 (t, J = 4.1 Hz, 2H); 3.63 (s, 3H); 3.41-3.46 (m, 2H); 3.37-3.41 (m, 2H); 2.86-2.92 (m, 2H); 2.44-2.52 (m, 2H, DMSO and repeat); 2.12 (d, J = 6.4 Hz, 2H); 1.95 (br t, J = 11.0 Hz, 2H); 1.59-1.67 (m, 3H); 1.13-1.24 (m, 2H).

[0237] The pharmacological activity of the present compound (1-59) Biochemical potency against JAK1, JAK2, JAK3 and Tyk2 アッセイ principle 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 JAK1, JAK2, JAK3, and TYK2 were performed using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. This involves measuring light emission from two labeled binding partners, detected by energy transfer from an excited donor to an acceptor dye. The LANCE Ultra kinase assay was used. In the presence of JAK1, JAK2, JAK3, and TYK2 kinases and ATP (corresponding to Km), a ULight peptide substrate (LANCE Ulight-JAK-1 (Tyr1023) Peptide, Perkin Elmer, TRF0121) was phosphorylated. It was then captured by a Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 Anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), which brings the Eu-chelated donor and ULight acceptor into close proximity. Upon excitation at 320 nm, the Eu chelate transfers its energy to the ULight dye, resulting in fluorescent emission at 665 nm.

[0238] Compound Testing Serial dilutions of compounds in pure DMSO were prepared from a 10 mM DMSO stock solution. Compounds were tested in 11 serial 5-fold dilutions (20 μM to 2 pM) starting from a 20 μM top concentration in a 384-well plate. 200 nL of compound was transferred from the mother plate to the test plate using Mosquito (TTP Labtech). Assays were performed in a 384-well Perkin Elmer test plate with a 20 μL assay volume (kinase reaction) and a 40 μL total volume (stop reagent and antibody detection reagent). 30 / 50 / 20 / 10 nM peptide and 20 / 0.7 / 0.2 / 12 μM ATP in 10 μL of substrate solution (peptide + ATP) were added for JAK1, JAK2, JAK3, and TYK2, respectively. Ten μL of enzyme solution was added to the kinase reaction at concentrations of 0.15 / 0.083 / 0.025 / 0.144 ng / μL for JAK1, JAK2, JAK3, and TYK2, respectively. After shaking and incubation at room temperature for 1.5 hours, 20 μL of stop (10 μL EDTA) and detection mix (10 μL europium-antiphospho-antibody, final: 0.5 nM) were added. After 1 hour of incubation, readings were performed on an EnVision 2104 reader (Perkin Elmer).

[0239] I C 50 Data calculations, curve and QC analysis were performed using Excel tools and GraphPadPrism software, v9. Briefly, individual concentration-effect curves are generated by plotting the logarithm of the test concentration of the test compound (X) versus the corresponding percent inhibition value (Y) using a least-squares (normal) fit. The best-fit IC 50 Values ​​are calculated using the log(inhibitor) normalized response-variable slope equation, where Y=100 / (1+10^((LogIC 50 QC criteria parameters (Z', S:B, R2, HillSlope) are calculated using the formula: (-X)*HillSlope). 50 The curve was confirmed. IC 50Data calculations, curves, and QC analysis were performed using Excel tools and GraphPadPrism software. QC criteria parameters: Z' ≥ 0.5, Hill slope range 0.5-5, S:B > 2.

[0240] The compounds of the present invention exhibit a pIC corresponding to an inhibitory concentration of ≦1 μM. 50 Most of the compounds exhibited inhibitory activity against at least JAK1 of greater than 7.3, and even more preferably greater than 8.3, corresponding to inhibitory concentrations of ≦50 nM, and even more preferably ≦5 nM.

[0241] The data for compounds 1 to 46 are shown in the table below. [Table 60] [Table 61] The compounds are classified in the above table in terms of potency for inhibitory activity against JAK1, JAK2, JAK3 and Tyk2 isoforms according to the following classification criteria: +++:pIC 50 ≧8.3 ++:8.3>pIC 50 ≧7.3 +:pIC 50 <7.3

[0242] Inhibition of IL-13-induced pSTAT6 in BEAS BEAS-2B human cell line was 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 determined using the Fastscan phospho-STAT6 (Tyr641) ELISA kit (Cell Signaling). Inhibitors were tested in duplicate at 11 serial 5-fold dilutions (10 μM to 40 pM) starting at 10 μM. IC 50 Data calculations, curves, and QC analysis were performed using Excel tools and GraphPadPrism software. QC criteria parameters were: Z' ≥ 0.35, Hill slope range 0.5-5, S:B > 2.

[0243] The compounds of the present invention are pIC 50 In terms of (BEAS), it showed a measurable value higher than 7.3.

[0244] Predicted acid metabolites are pIC 50 In terms of (BEAS), it showed measurable values ​​higher than 5. [Table 62] [Table 63] Compounds are classified in the above table in terms of potency for functional activity in the BEAS according to the following classification criteria: §§§§:pIC 50 ≧8.3 §§§:8.3>pIC 50 ≧7.3 §§:7.3>pIC 50 ≧6.3 §:pIC 50 <6.3 and the corresponding predicted acid metabolite vs. parent ester IC 50 Difference ratio (ratio = IC 50 Predicted acid metabolites / IC50 From the perspective of Ester kkkk:ratio≧200 kkk:200>ratio≧100 kk:100>ratio≧10 k:ratio<10

[0245] When a numerical limit or range is given herein, the endpoints are included. Also, unless expressly stated, all values ​​and subranges within the numerical limit or range are specifically included.

[0246] As used herein, the term "a" or "an" means "one or more."

[0247] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.

Claims

1. The single enantiomers, diastereoisomers and mixtures thereof in any ratio of the formula I-1 or I-2 【Chemical 1】 【Chemistry 2】 [During the ceremony, substituent 【Chemistry 3】 comprises at least one ester or thioester moiety; V is C(O)O, C(O)N(R ６ ), N(R ６ )C(O)O; Q is (C １ -C ６ ) alkoxycarbonyl, -(CH ２ ) ｍ NR ４ R ５ , (C ３ -C ８ ) cycloalkyl and (C ３ -C ６ )heterocycloalkyl; wherein said (C ３ -C ８ ) cycloalkyl and (C ３ -C ６ )Heterocycloalkyl is optionally (C １ -C ６ ) alkoxycarbonyl (CH ２ ) ｍ , (C ３ -C ８ ) cycloalkyl-oxycarbonyl, NC—(C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) haloalkyl-oxycarbonyl, (C ３ -C ８ ) heterocycloalkyl-oxycarbonyl, (C １ -C ６ ) alkyl(C ３ -C ８ ) heterocycloalkyl-oxycarbonyl, (C ３ -C ８ ) heterocycloalkyl-(C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkyl-(C ３ -C ８ ) heterocycloalkyl-(C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) hydroxyalkyl-oxycarbonyl, (C １ -C ６ ) aminoalkyl-oxycarbonyl, (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkyl-oxycarbonyl, (C １ -C ６ ) alkylthiocarbonyl, NC—(C ３ -C ８ ) cycloalkyl(C １ -C ６ ) alkoxycarbonyl, NC—(C ３ -C ８ ) cycloalkyl-oxycarbonyl, (C １ -C ６ ) haloalkyl-(C ３ -C ８ ) heterocycloalkyl-oxycarbonyl, halo-((C １ -C ６ ) alkyl(C ３ -C ８ )heterocycloalkyl)-oxycarbonyl, (C １ -C ６ ) haloalkyl-(C ３ -C ８ ) heterocycloalkyl-(C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) haloalkyl-(C ３ -C ８ ) heterocycloalkyl-oxycarbonyl-(C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl-oxycarbonyl-(C １ -C ６ ) alkyl, (C １ -C １０ ) substituted with one or more substituents selected from the group consisting of alkyl and halogen; K is O, CH ２ , S; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R ４ and R ５ are the same or different, H. (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ６ ) heterocycloalkyl and (C １ -C ６ ) alkyl-(C ３ -C ８ ) heterocycloalkyl; (C １ -C ６ ) alkoxycarbonyl-methyl; (C １ -C ６ ) alkoxycarbonyl-phenyl-methyl; (C １ -C ６ ) alkoxycarbonyl-(C １ -C ６ ) alkyl-phenyl-methyl selected from the group consisting of: R ６ are, in each case independently, H, (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl. or a pharmaceutically acceptable salt or solvate thereof.

2. K is O; single enantiomers, diastereoisomers and mixtures thereof of formula (Ia) 【Chemistry 4】 [During the ceremony, V is C(O)N(R ６ ) and Q is (C １ -C ６ ) alkoxycarbonyl, (C ３ -C ８ ) cycloalkyl-oxycarbonyl, NC—(C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) haloalkyl-oxycarbonyl, (C １ -C ６ ) alkyl(C ３ -C ８ ) heterocycloalkyl-oxycarbonyl, (C １ -C ６ ) hydroxyalkyl-oxycarbonyl and (C １ -C ６ )Alkoxy(C １ -C ６ ) alkyl-oxycarbonyl and (C １ -C ６ ) alkylthiocarbonyl (C ３ -C ６ ) heterocycloalkyl; n, independently at each occurrence, is 0 or an integer selected from 1, 2, 3, and 4; R ６ are, in each case independently, H, (C １ -C ６ ) alkyl and (C １ -C ６ ) hydroxyalkyl.

2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt or solvate thereof.

3. 10. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, of single enantiomers, diastereoisomers and mixtures thereof, selected from the following list: Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Isopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Cyclopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-cyano-2-methylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2,2,2-trifluoroethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 1-methylazetidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 3-hydroxy-2,2-dimethylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-hydroxy-2-methylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 1-Methoxy-2-methylpropan-2-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (R)-1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; S-Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carbothioate.

4. V is a divalent radical selected from C(O)O; Q is optionally (C １ -C １０ ) substituted with one or more groups selected from alkyl and halogen (C １ -C ６ ) alkoxycarbonyl, -(CH ２ ) ｍ NR ４ R ５ and (C ３ -C ６ ) heterocycloalkyl; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R ４ and R ５ are the same or different, H. (C １ -C ６ ) alkyl 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in single enantiomers, diastereoisomers and mixtures thereof, selected from the group consisting of:

5. wherein K is S, single enantiomers, diastereoisomers and mixtures thereof of formula (Ib) 【Chemistry 5】 [During the ceremony, V is N(R ６ )C(O)O; Q is (C １ -C ６ ) alkoxycarbonyl; n is an integer selected from 1, 2, 3 and 4; R ６ is independent in each case H, (C １ -C ６ ) alkyl is selected from the group consisting of 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

6. 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in single enantiomers, diastereoisomers and mixtures thereof, selected from the following list: Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; ethyl (1s,3s)-3-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)cyclobutane-1-carboxylate; Ethyl 2-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)acetate; Ethyl 1-(2-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)ethyl)piperidine-4-carboxylate; 1-Methoxy-2-methylpropan-2-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Propyl N-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)-N-methylglycinate; 3-(Dimethylamino)propyl 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate; 3-(4-methylpiperazin-1-yl)propyl 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate; Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; sec-butyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Cyclopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Cyclopentyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2,2,2-trifluoroethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-hydroxy-2-methylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 3-hydroxy-2,2-dimethylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-Methoxyethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; tetrahydro-2H-pyran-4-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (tetrahydro-2H-pyran-4-yl)methyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (4-methylmorpholin-2-yl)methyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-(dimethylamino)-2-methylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 1-methylazetidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (R)-1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (S)-1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-cyano-2-methylpropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 1-methylpiperidin-4-yl 1-(3-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)propyl)piperidine-4-carboxylate; Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-3-carboxylate; Ethyl 4-fluoro-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Methyl (R)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; Methyl (S)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)azetidine-3-carboxylate; Ethyl (3aR,5r,6aS)-2-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate; ethyl (1R,5S,6r)-3-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxylate; Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)-4-methylpiperidine-4-carboxylate; Ethyl 2-(1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidin-4-yl)acetate; Ethyl 4-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)-1-methylpiperazine-2-carboxylate; Methyl 2-(3-(((2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)(methyl)amino)methyl)phenyl)acetate; Ethyl 1-(2-(1-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Ethyl 2-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)acetate; ethyl (1s,3s)-3-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)cyclobutane-1-carboxylate; Ethyl 1-(2-(((1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamoyl)oxy)ethyl)piperidine-4-carboxylate; 1-methylpiperidin-4-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Ethyl (R)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; Ethyl (S)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; Isopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (4-methylmorpholin-2-yl)methyl 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate; 3-cyanocyclobutyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 2-hydroxy-2-methylpropyl 2-(1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidin-4-yl)acetate; 2-cyano-2-methylpropyl (R)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; (3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (3R*,4R*)-4-fluoro-1-methylpyrrolidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (R)-1-(2-fluoroethyl)pyrrolidin-3-yl 2-(1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidin-4-yl)acetate; (1-cyanocyclopropyl)methyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; 3-cyanopropyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; (R)-1-(2-fluoroethyl)pyrrolidin-3-yl (R)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; (R)-1-methylpyrrolidin-3-yl (S)-1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylate; 1-Isopropylazetidin-3-yl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate; S-Ethyl 1-(2-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carbothioate.

7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carriers or excipients.

8. 8. A pharmaceutical composition according to claim 7 suitable for administration by inhalation selected from inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations.

9. 10. A device comprising the pharmaceutical composition of claim 8, which can be a single or multi-dose dry powder inhaler, a metered dose inhaler or a soft mist nebulizer.

10. A compound or pharmaceutical composition according to any one of claims 1 to 8 for use as a medicament.

11. 11. The compound or pharmaceutical composition of claim 10 for use in the prevention and / or treatment of a pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

12. 10. A combination of a compound of any of claims 1 to 6 with one or more active ingredients selected from classes currently used in the treatment of respiratory disorders and known to those skilled in the art, such as beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinase), 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 anti-inflammatory drugs (NSAIDs) and mucus control agents.

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