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), processes for preparing such compounds, pharmaceutical compositions containing them, and their therapeutic uses. The compounds of the present invention may be useful in treating diseases or conditions associated with dysregulation of the JAK family of non-receptor kinases, in particular in treating various inflammatory diseases, including asthma, COPD, and other respiratory diseases.

Description

[Technical Field]

[0001] The present invention relates to compounds, derivatives of which are 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] The JAK family consists of non-receptor tyrosine protein kinases and has four major members: JAK1, JAK2, JAK3, and TYK2. More than 50 cytokines and growth factors bind to type I and type II receptors, non-covalently associated with various combinations of JAK kinases. Ligand-induced signaling 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 into the nucleus to regulate specific genes. JAKs contain seven homology domains (JAK homology domains, JH). Starting from the carboxyl terminus, JH1 is the first JH, also 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 almost all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26; 6(1): 402). Many cellular processes, including hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis, are downstream of JAK / STAT signaling. Various biological responses are regulated by specific pairings of JAK isoforms. The JAK1 / JAK3 combination mediates the signaling of IL-2, -4, -7, -9, -15, and -21, which are involved in lymphoid cell growth / maturation, T cell / NK cell differentiation / homeostasis, B cell class switching, and other inflammatory processes. The JAK1 / TYK2-JAK1 / JAK2 combination regulates signaling associated with innate immune responses, such as IL-6 and type I interferons, which are associated with naive T cell differentiation, T cell homeostasis, granulopoiesis, and other inflammatory processes (Howell MD et al., Front. Immunol. 2019, 10, 2342).JAK2 frequently binds to itself (JAK2 / JAK2) and regulates the signaling of various cytokines and growth factors, such as IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Hodge et al., Clin Exp Rheumatol 2016; 34(2): 318-28).

[0003] Genetically modified mouse experiments and human diseases demonstrate the importance of the JAK / STAT pathway in immune fitness. In particular, overexpression or mutations involving several JAK isoforms, as well as aberrant JAK / STAT signaling, lead to hematopoietic or lymphoid malignancies and inflammatory disorders. Currently, several 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, upadicitinib, and delgocitinib in Japan) are used for immune-mediated disorders such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis, and acute graft-versus-host disease. Furthermore, several of these drugs, as well as 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 are also attractive options for the treatment of fibrotic disorders. In fact, inflammatory cytokines (IL-4, IL-3, IL-6, IL-11, IL-31, etc.) and growth factors (FGF, VEGF, etc.) involved in the fibrotic process activate the JAK / STAT pathway. Ruxolitinib, tested in a bleomycin-induced fibrosis mouse model, improved pulmonary fibrosis and reduced the 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 reports have been studied in patients. A case report confirmed the efficacy and safety of tofacitinib in combination with nintedanib in the management of poor-prognosis malignant interstitial lung disease (Conca, W et al., Front. Pharmacol. 2020, 11, 5857619). Baricitinib has proven to be a safe immunomodulatory agent that reduces levels of pulmonary fibrosis and inflammatory biomarkers in patients with RA, including subgroups of interstitial lung disease (D'Alessandro M et al., Int. Immunopharmacol. 2020, 86, 106748).

[0005] Several JAK inhibitors are undergoing clinical trials for COVID-19: tofacitinib, baricitinib, and ruxolitinib. Baricitinib and ruxolitinib have been associated with a reduced risk of death. They have reduced the use of invasive mechanical ventilation, with a borderline impact 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). Ruxolitinib has also been tested in COVID-19 patients and improved clinical signs and chest computed tomography scans (Cao Y. et al., J. Allergy Clin. Immunol. 2020, 146, 137-146).

[0006] Asthma is one of numerous immune-mediated diseases whose pathogenesis is characterized by the essential role of JAK / STAT signaling. It is a chronic inflammatory disease of the airways resulting from a complex interplay between immune responses, genetic susceptibility, and nonspecific external stimuli such as colds, allergens, and exercise, which leads to hyperresponsiveness, airway remodeling, and ultimately airflow limitation. Severe asthma affects 5% to 15% of the adult asthma population (300 million people worldwide) and represents a public health problem associated with increased mortality, hospitalizations, significant symptom burden, medical costs, and loss of work and education (Steve NG et al., J Allergy Clin Immunol 2021;148:953-63). Severe asthma represents a subgroup of difficult-to-treat asthma and occurs in patients whose disease remains uncontrolled despite the use of 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 uncontrolled disease, indicating the need for novel therapeutic agents (Israel E, Reddel HK. N Engl J Med 2017;377:965-76).

[0007] In recent years, improved understanding of asthma pathogenesis has led to a shift from phenotypic classification systems to the introduction of the concept of "endotypes." According to the latter, classification is based on the 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 group 2 innate lymphoid cells (ILC2s); these include IL-4, IL-5, and IL-13, which initiate airway inflammation by activating eosinophils, B cells, airway epithelial cells, and other cell types. Biomarkers of type 2 asthma include blood / sputum eosinophils 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, as manifested either by elevated airway neutrophil levels or a granulocyte-reduced profile 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 Type 2-low endotype under investigation include IL-6, IL-17A / F, IL-23, type I interferons, CXCL10, TNF, alarmins (TSLP, IL-25, IL-33), IL-1β, IL-8, and IFN-γ (Hinks TSC et al., ERJ 2021, 57(1) 2000528).

[0008] In both T2 and T2-low endotypes, nearly all of the mediators mentioned above activate the JAK / STAT pathway, providing a rationale for the potential use of JAK inhibitors in both endotypes of severe asthma. Targeting several cytokines simultaneously with JAK inhibitors may offer advantages over biologics (in unresponsive patients) and standard therapy (in uncontrolled patients), given their administration in addition to ICS.

[0009] Despite the strong rationale for using JAK inhibitors in asthma, systemic administration of inhibitors can raise safety concerns and limit their use in certain asthmatic subjects, such as children. Given that asthma is a lung-limited disease, the inhaled route of administration of JAK inhibitors may offer therapeutic benefits 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 (completed Phase I clinical trials) and AZD-4604 (ongoing Phase I clinical trials); Theravance Biopharm has initiated a new preclinical program for the inhaled JAK inhibitor TD-8236, and Kinaset / Vectura is developing an inhaled compound, VR588 (ongoing Phase I clinical trials). Numerous preclinical studies sponsored by these companies have demonstrated the efficacy of JAK inhibitors in the management of asthma. In the preclinical phase of drug development, oral administration of the JAK1 / 3 inhibitor R256 (now called AZD0449) was shown to reduce airway resistance, BAL eosinophilia, and mucus production, and even TH2 cytokine responses when administered during sensitization (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). iJak-381, available as a dry powder from Genentech, reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in mice challenged with OVA. Furthermore, it reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in mice chronically exposed to AAH allergen (Dengler HS et al., Sci Transl Med 2018;10:eaao2151). Furthermore, an oral JAK inhibitor, tofacitinib, formulated to be administered as an aerosol, reduced eosinophil numbers 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 restricting JAK inhibition to the lung is chronic obstructive pulmonary disease (COPD), an inflammatory lung condition most commonly caused by cigarette smoke exposure and characterized by largely irreversible, progressive airflow limitation. Although proinflammatory cytokines are drivers of chronic airway inflammation, and several of these (e.g., IL-6, IFN-γ, and IL-2) induce JAK / STAT activation, the role of this pathway in COPD pathogenesis is poorly characterized. Phosphorylated STAT4+ cells (Di Stefano A et al., Eur Respir J. 2004 Jul;24(1):78-85) have been found to be increased in COPD compared with healthy nonsmoker controls. In another study, the number of phosphorylated STAT3+ and phosphorylated STAT1+ cells was higher in samples from COPD patients than in non-smoker controls, whereas previous data on phosphorylated STAT4 molecules could not be replicated (Yew-Booth L et al., Eur Respir J 2015;46(3):843-5). These data may also suggest the therapeutic use of JAK inhibitors in COPD disease.

[0011] In view of the many pathological responses mediated by JAK enzymes, there is a continuing need for inhibitors of JAK enzymes that may be useful in the treatment of numerous disorders, particularly respiratory diseases. Thus, there remains a significant need to find novel, potent JAK inhibitors suitable for local administration to the lung for the treatment of asthma and respiratory diseases. Summary of the Invention

[0012] Thus, compounds of formula (I): [ka] wherein W, X1, X2, X3, X4, R1, R2, and R3 are as defined in the detailed description of the invention. It is an object of the present invention to provide a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0013] 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 making such compounds.

[0014] In one aspect, the present invention provides a compound of formula (I) for use as a medicament. In one aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament.

[0015] In a further aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of any disease associated with the mechanism of action of a JAK enzyme.

[0016] In another aspect, the present invention provides a method for preventing and / or treating any disease associated with the mechanism of action of the JAK enzymes 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.

[0017] In certain embodiments, the compounds of the present invention, used 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

[0018] definition The term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) wherein the parent compound, if any, is suitably modified by converting any of its free acidic or basic groups, if any, into the corresponding addition salts with any base or acid that is conventionally pharmaceutically acceptable.

[0019] Suitable examples of such salts may thus include inorganic or organic acid addition salts of basic residues such as amino groups, as well as inorganic or organic base addition salts of acidic residues such as carboxyl groups.

[0020] Cations of inorganic bases which may suitably be used to prepare the salts of the present invention include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Salts formed by reacting primary compounds which function as bases with inorganic or organic acids 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.

[0021] Many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates," which are a further object of the present invention. Polymorphs and crystalline forms of the compound of formula (I), or its pharmaceutically acceptable salts, or solvates, are a further object of the present invention.

[0022] The term "halogen" or "halogen atom" includes fluorine, chlorine, bromine, and iodine atoms; it refers to fluoro, chloro, bromo, and iodo as substituents. 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.

[0023] The expression "(C-C)haloalkyl" refers to a "(C-C)alkyl" group as defined above, in which one or more hydrogen atoms are replaced with one or more halogen atoms, which may be the same or different from one another. Examples include halogenated, polyhalogenated, and fully halogenated alkyl groups in which all hydrogen atoms are replaced with halogen atoms, such as trifluoromethyl or difluoromethyl groups.

[0024] Similarly, "(C1-C x ) hydroxyalkyl" or "(C1-C x The term "(C-C)aminoalkyl" refers to the above-mentioned "(C-C x )alkyl" groups in which one or more hydrogen atoms are respectively replaced by one or more hydroxy (OH) or amino groups.

[0025] The definition of aminoalkyl includes alkyl groups substituted with one or more amino groups (-NR4R5) (i.e., "(C1-C6) alkyl" groups). An example of an aminoalkyl is 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 present invention.

[0026] With respect to the substituents R and R defined above, it is further noted that when either R or R, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group, at least one additional ring carbon atom of the heterocyclic group may be substituted with at least one heteroatom or heterogroup (e.g., N, NH, S, or O), or may have an -oxo (=O) substituent. The heterocyclic group may be optionally further substituted at an available point of the ring, i.e., at an available carbon atom for substitution, or at a heteroatom or heterogroup. Thus, examples of the heterocyclic group include 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4-yl-2-one, and 4-methylpiperazin-1-yl.

[0027] "(C3-C 10The term "(C-C)cycloalkyl" as well as "(C-C)cycloalkyl" refer to a saturated cyclic hydrocarbon group containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, as well as polycyclic ring systems such as adamantanyl.

[0028] 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).

[0029] Examples of aryl or heteroaryl monocyclic ring systems include, for example, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinylnyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl groups and the like.

[0030] Examples of aryl or heteroaryl bicyclic ring systems include naphthalenyl, biphenylenyl, purinyl, phteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzimidazol-yl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothiopheneyl, 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 groups, and the like.

[0031] Examples of aryl or heteroaryl tricyclic ring systems include fluorenyl groups, as well as benzo-fused derivatives of the heteroaryl bicyclic ring systems discussed above.

[0032] "(C3-C 10 The derived expressions "(C-C)heterocycloalkyl" as well as "(C-C)heterocycloalkyl" refer to saturated or partially unsaturated mono-, di-, or tri-cycloalkyl groups of the indicated number of carbons, where at least one ring carbon atom is replaced with at least one heteroatom (e.g., N, NH, S, or O) and / or optionally has an -oxo (=O) substituent (e.g., C(=O), S(=O)). The heterocycloalkyl (i.e., heterocyclic group) may be optionally further substituted at available points on the ring, i.e., on carbon atoms available for substitution or on heteroatoms. Examples of heterocycloalkyl are oxetanyl, tetrahydro-furanyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydro-furanyl, dihydroisoxazolyl, pyridin-2-one-yl, and the like. aryl, 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, or the like.

[0033] 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, for example, phenylmethyl (i.e., benzyl), phenylethyl, or phenylpropyl.

[0034] 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, for example, furanylmethyl.

[0035] The term "alkanoyl" refers to an HC(O)- or alkylcarbonyl group (e.g., (C1-C6)alkylC(O)-), where the "alkyl" group is defined above. Examples include formyl, acetyl, propanoyl, and butanoyl.

[0036] "(C1-C 10 )alkoxy" or "(C1-C 10 "(C-C)alkoxy" or "(C-C)alkoxyl" and like terms refer to a straight or branched chain hydrocarbon of the indicated number of carbons connected to the remainder of the molecule through an oxygen bridge, as well as "(C-C)alkoxyl." "(C-C)alkylthio" refers to the above hydrocarbons connected through a sulfur bond.

[0037] 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 and trifluoromethoxy.

[0038] The similarly derived expressions "(C3-C6)heterocycloalkyl-(C1-C6)alkyl" and "(C3-C6)cycloalkyl-(C1-C6)alkyl" refer to the above-described heterocycloalkyl and cycloalkyl groups linked to the remainder of the molecule via an alkyl group of the indicated number of carbons, e.g., piperidin-4-yl-methyl, cyclohexylethyl.

[0039] The derived expression "(C1-C6)alkoxy(C1-C6)alkyl" refers to an alkoxy group as defined above linked to the remainder of the molecule via an alkyl group of the indicated number of carbons, e.g., methoxymethyl.

[0040] Similarly, "(C1-C6)haloalkoxy(C1-C6)alkyl" refers to a (C1-C6)haloalkoxy as defined above linked to the remainder of the molecule via an alkyl group of the indicated number of carbons, e.g., difluoromethoxypropyl. Similarly, "(C1-C6)alkoxycarbonyl" refers to an alkoxy group as defined above linked to the remainder of the molecule via a carbonyl group.

[0041] And, "(C1-C6)alkoxycarbonyl-(C1-C6)alkyl" refers to an alkoxy group as defined above linked to the remainder of the molecule via a carbonyl group further linked by an alkyl group of the indicated number of carbons, e.g., methoxycarbonylmethyl. And, "(C1-C6)alkoxycarbonyl-(C1-C6)alkylthio" refers to a linked group, such as methoxycarbonylmethylthio, as a result.

[0042] An oxo moiety is represented by (O) as an alternative to other common representations, such as (=O). Thus, with respect to general formulas, carbonyl groups are preferably represented herein as -C(O)- as an alternative to other common representations such as -CO-, -(CO)-, or -C(=O). In general, groups shown in parentheses are side groups that are not included in the backbone, and parentheses are used where deemed useful to help disambiguate linear chemical formulas; for example, the sulfonyl group -SO- may also be represented as -S(O)- to disambiguate, for example, with respect to the sulfinic group -S(O)O-.

[0043] When presented with a numerical index, the statement "p is zero" or "p is 0" (numerical value) means that the substituent or group with index p (e.g., Ip) is absent, i.e., when required, there are no substituents other than H. Similarly, when the index is a bridging divalent group (e.g., (CH) n), the statement "n is 0 in each occurrence" or "n is 0" means that the bridging group is absent, i.e., a bond.

[0044] Whenever a basic amino group or a quaternary ammonium group is present in the compounds of formula (I), a physiologically acceptable anion selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalenedisulfonate may be present. Similarly, in the presence of an acidic group, such as a COOH group, the corresponding physiological cationic salts may also be present, including, for example, alkali or alkaline earth metal ions.

[0045] Compounds of formula (I), if they contain one or more stereoisomeric centers, may exist as optical stereoisomers.

[0046] When the compound of the present invention has at least one stereoisomeric center, the compound may exist as an enantiomer, depending on the circumstances. When the compound of the present invention has two or more stereoisomeric centers, the compound may additionally exist as a diastereomer. It should be understood that all such single enantiomers, diastereomers, and mixtures thereof in any proportion are included within the scope of the present invention. The absolute configuration (R) or (S) of the carbon having a stereoisomeric center is assigned based on the Cahn-Ingold-Prelog naming rules, which are based on group preference.

[0047] "Single stereoisomer," "single diastereomer," or "single enantiomer," when reported near the chemical name of a compound, indicates that the isomer has been isolated (e.g., via chiral chromatography) as a single diastereomer or enantiomer, but the absolute configuration at the relevant stereoisomeric center has not been determined / assigned.

[0048] Atropisomers can result from hindered rotation around a single bond when the steric strain barrier to rotation is high enough to isolate the conformers (Bringmann G et al., Angew. Chemie Int. Ed. 44(34), 5384-5427, 2005. doi: 10. 1002 / anie. 200462661).

[0049] Oki defined atropisomers as conformers that interconvert with half-lives of 1000 seconds or more at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).

[0050] Atropisomers differ from other chiral compounds in that in many cases they can be thermally equilibrated, whereas in other forms of chirality isomerization is usually only possible chemically.

[0051] Separation of atropisomers is possible by chiral resolution methods such as selective crystallization. In atropo-enantioselective or atroposelective synthesis, one atropisomer is formed at the expense of another. Atroposelective synthesis may be achieved using chiral auxiliaries such as the Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by thermodynamic equilibrium-based solutions where the isomerization reaction favors one atropisomer over the other.

[0052] The racemic forms of the compounds of formula (I) as well as the individual atropisomers (substantially free of their corresponding enantiomers) and stereoisomerically enriched atropisomer mixtures are within the scope of the present invention.

[0053] The present invention further relates to the corresponding deuterated derivatives of the compounds of formula (I). In the context of the present invention, a deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount greater than or equal to its natural abundance. Preferably, the proportion of deuterium at that position is at least 90%, more preferably at least 95%, and even more preferably 99%.

[0054] All preferred aspects or embodiments mentioned above and hereinafter for compounds of formula (I) may be combined with one another and apply mutatis mutandis as well.

[0055] 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 either alone or in combination with one or more active ingredients in admixture with one or more pharmaceutically acceptable carriers.

[0056] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, X1 and X2 are alternately N or CH; X3 and X4 are alternately N or CH, and the two dashed lines indicate alternating double bonds such as between X3=N or between N=X4; W is heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-b]pyridazin-3-yl, and (3-oxo-3,4-dihydropyrazin-2-yl)amino; R1 is selected from the group pyridinyl, piperidinyl, phenyl or benzyl, which is halogens, preferably Cl and F; -OH, -CN, -NO2, -(CH2) mNR4R5, preferably -NH2, (C1-C6) alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, preferably methoxy; (C1-C6) alkylthio-, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, preferably difluoromethoxy; optionally substituted with one or more, preferably two or three, further independently selected groups; R1 particularly preferably has the formula K when it is phenyl: [ka] optionally substituted with at least one further group of the formula: L is absent or a divalent radical selected from O, S, S(O)2, (CO), C(O)O, O(O)C, C(O)N(R6), N(R6)C(O), NHCONH, N(R6)S(O)2, S(O)2N(R6); Z is H, -OH, -CN, -NO2, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) alkoxy(C1-C6) alkyl, (C1-C6) alkoxycarbonyl, -(CH2) m selected from the group consisting of NR4R5, -C(O)NH(R6), (C3-C8)cycloalkyl, aryl, heteroaryl, and (C3-C6)heterocycloalkyl; wherein the (C3-C8)cycloalkyl, aryl, heteroaryl and (C3-C6)heterocycloalkyl are further defined as (C1-C 10 ) optionally substituted by one or more substituents selected from the group consisting of alkyl, alkanoyl, (C1-C6)alkoxycarbonyl, oxo, —C(O)NH(R6), (C1-C6)alkoxy(C1-C6)alkyl; R2 and R3, when present, are selected from H, (C1-C6) alkyl, preferably methyl, and a group of formula J: [ka] (In the formula, V is absent or O, S, S(O)2, C(O), C(O)O, O(O)C, C(O)N(R6), N(R6)C(O); N(R6)-(CH2) m -N(R6), -N(R6)- is a divalent group selected from; Q is H, -CN, -OH, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) alkoxycarbonyl, hydroxycarbonyl, -(CH2) m selected from the group consisting of NR4R5, -C(O)NR4R5, -N(R6)C(O)R6, -CH(CN)NR4R5, (C3-C8)cycloalkyl, aryl, heteroaryl, and (C3-C6)heterocycloalkyl; wherein the (C3-C8)cycloalkyl, aryl, heteroaryl and (C3-C6)heterocycloalkyl are selected from the group consisting of -OH, oxo, (C1-C 10 ) alkyl, (C1-C 10 ) alkyl-S(O)2-O-, alkanoyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy(C1-C6) alkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkoxycarbonyl-NH-, -N(R6)(CH2) m optionally further substituted with one or more substituents selected from the group consisting of C(O)NR4R5, —NR4R5, (C3-C6)heterocycloalkyl; wherein 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, (C1-C6)hydroxyalkyl, Alkanoyl, (C1-C6)alkoxycarbonyl, and (C3-C6)heterocycloalkyl selected from the group consisting of: R6, at each occurrence, is independently selected from the group consisting of H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, and alkanoyl; R7, at each occurrence, is independently selected from the group consisting of H, (C1-C6) alkyl, and -NR4R5. and independently selected from the group consisting of: The present invention provides a series of derivatives of the compound represented by the formula: or a pharmaceutically acceptable salt or solvate thereof.

[0057] The compounds according to the invention are preferably 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[4,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives.

[0058] Particularly preferred is a compound of a 1H-pyrazolo[4,3-c]pyridine derivative represented by formula (I) (wherein X1 is CR3 (meaning CH substituted with R3), X2 is N, X3 is CR2 (meaning CH substituted with R2), and X4 is N), which is represented by formula (Io): [ka] [In the formula, W is heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-b]pyridazin-3-yl, and (3-oxo-3,4-dihydropyrazin-2-yl)amino; All other variables are as above.] or pharmaceutically acceptable salts and solvates thereof.

[0059] In a preferred embodiment, the present invention provides a compound of formula (Ia): [ka] [In the formula, R8 is (C1-C6)alkoxy, (C1-C6) haloalkoxy selected from the group consisting of: L is N(R6)S(O)2, S(O)2N(R6); Z is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) alkoxycarbonyl, -(CH2) m is selected from the group consisting of NR4R5, -C(O)NH(R6), (C3-C8)cycloalkyl, aryl, heteroaryl, and (C3-C6)heterocycloalkyl, wherein the (C3-C8)cycloalkyl, aryl, heteroaryl, and (C3-C6)heterocycloalkyl are selected from the group consisting of (C1-C 10 ) optionally substituted by one or more substituents selected from the group consisting of alkyl, alkanoyl, (C1-C6)alkoxycarbonyl, oxo, —C(O)NH(R6), (C1-C6)alkoxy(C1-C6)alkyl; V is absent or selected from the divalent radical -N(R6)-; Q is H, (C1-C6) alkyl, -(CH2) m and (C-C)heterocycloalkyl, wherein the (C-C)heterocycloalkyl is selected from the group consisting of (C-C 10 ) alkyl; wherein n and m, in each occurrence, are independently 0 or an integer from 1 to 4; R4 and R5 are the same or different; -H, (C1-C6) alkyl selected from the group consisting of: R6, at each occurrence, is independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) hydroxyalkyl; R7, at each occurrence, is independently selected from the group consisting of H, (C1-C6) alkyl. or pharmaceutically acceptable salts and solvates thereof, wherein R3 is H, R2 is a J group, and R1 is a substituted phenyl, as shown in

[0060] In this final embodiment, a compound of formula (Ia): During the ceremony, R8 is (C1-C6)alkoxy, preferably methoxy; L is -N(R6)S(O)2-; Z is H, (C1-C6) alkyl (preferably selected from methyl, ethyl and propyl), and (C3-C8)cycloalkyl (preferably cyclopropyl) selected from the group consisting of: V is absent or -N(R6)-; Q is -CN, (C1-C6) alkyl, preferably methyl; -(CH2) m NR4R5, preferably dimethylaminoethyl, and (C3-C6)heterocycloalkyl (preferably selected from piperidin-1-yl and morpholin-yl) selected from the group consisting of: wherein in the group K, n is 0 and m is 0 or 1; in the group J, n is 0, 1 or 2 and m is 0 or 1; R4 and R5 are the same or different; -H, (C1-C6) alkyl, preferably methyl selected from the group consisting of: R6 is H, R7 is H Particularly preferred is a compound of the formula: or a pharmaceutically acceptable salt or solvate thereof.

[0061] In this embodiment, one particularly preferred group of compounds is: [Table 1]

[0062] It is clear that the compounds of the invention in this final preferred embodiment exhibit increased potency (at least 1 log increase, or up to 2 logs increase against JAK1) when compared to Example C31, which has a sulfonamidic meta-substitution instead of a para-substitution when R1 is phenyl. With regard to inhibitory concentrations, preferred compounds exhibit values ​​of less than 50 nM, preferably less than 5 nM, against at least JAK1. The preferred compounds exhibit a balanced profile for the inhalation route of administration.

[0063] Another particularly preferred embodiment is a compound of formula (I): [ka] [In the formula, X1 and X2 are alternately N or CH; and X3 and X4 are alternately N or CH, and the two dashed lines indicate alternating double bonds such as between X3=N or between N=X4; W is heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-b]pyridazin-3-yl; R1 is selected from piperidinyl, phenyl, or benzyl groups (optionally substituted with one or more groups selected from cyanomethylcarbonyl, difluoromethoxy, Cl, and F); R2 is methyl or selected from hydroxycarbonylmethyl, methoxycarbonylmethyl, dimethylaminocarbonylmethyl, hydroxymethyl. or a pharmaceutically acceptable salt or solvate thereof.

[0064] According to certain embodiments, the present invention provides Examples 1a-10a (according to the last preferred embodiment described herein above), and further compounds of Examples 1 to 92 listed in the table below, and pharmaceutically acceptable salts and solvates thereof.

[0065] [Table 2] [Table 3] [Table 4] [Table 5]

[0066] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0067] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the general methods and procedures described in the experimental description below, or by slight modifications of methods readily available to those of ordinary skill in the art. While specific embodiments of the present invention are described or illustrated herein, those of ordinary skill in the art will understand that all embodiments or aspects of the present invention can be prepared using the methods described herein or by using other known methods, reagents, and starting materials. 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. Optimum reaction conditions will vary with the particular reactants or solvents used; such conditions can be readily determined by one of ordinary skill in the art by routine optimization. General schemes and detailed procedures are described below in the "Preparation of Intermediates and Examples" section.

[0068] As described in detail herein, the compounds of the present invention are inhibitors of kinase activity, and in particular inhibit JAK kinase activity to treat JAK-dependent diseases. In one aspect, the present invention provides a compound according to the invention, i.e. a compound of formula (I) or a pharmaceutical composition thereof, for use as a medicament, preferably for use in the prevention and / or treatment of respiratory diseases, particularly pulmonary diseases.

[0069] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder associated with a JAK mechanism of action, particularly for the treatment of disorders such as respiratory and pulmonary diseases. In particular, the present invention provides compounds 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).

[0070] Moreover, the present invention provides a method for preventing and / or treating disorders associated with a JAK mechanism of action, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention. In particular, the present invention provides methods for the prevention and / or treatment of respiratory diseases wherein the disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS).

[0071] The compounds of the invention are preferably used to prevent the disorders mentioned above. The use of the compounds of the invention to treat the disorders mentioned above is also preferred. Generally speaking, compounds that are JAK inhibitors may be useful in treating many disorders associated with the mechanism of action of JAK enzymes.

[0072] In one embodiment, the disorder that may be treated by the compounds of the invention is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS). In a further embodiment, the disorder is selected from asthma and chronic obstructive pulmonary disease (COPD).

[0073] The therapeutic method of the present invention involves 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, an "effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or other pharmaceutically active agent, means an amount of the compound sufficient to treat the patient's symptoms, yet low enough to avoid serious side effects, which amount can still be routinely determined by one of ordinary skill in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a single dose or according to a dosing regimen comprising multiple doses administered at various intervals over a predetermined period of time. Typical daily doses may vary depending on the particular route of administration selected.

[0074] The present invention also provides pharmaceutical compositions of a compound 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. The present invention is also directed to the use of the compounds of the present invention and pharmaceutical compositions thereof suitable for various routes of administration.

[0075] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be achieved, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally, and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and ocularly, depending on the needs of the patient.

[0076] 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 known excipients, including various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.), and suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc.Time-release capsules, tablets, and gels are also advantageous.

[0077] A variety of liquid oral dosage forms can also be used to administer the compound of the present invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs.Such dosage forms can also contain suitable known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compound of the present invention.The compound of the present invention can also be formulated as an injectable composition, for example, in the form of an isotonic sterile solution to be injected intravenously.Other formulations are also possible.

[0078] 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. Preparations for vaginal administration may be in the form of cream, gel, paste, foam, or spray formulation containing, in addition to the active ingredient, suitable carriers, as are known in the art.

[0079] For topical administration, the pharmaceutical compositions may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eyes, ears or nose. Topical administration also includes transdermal administration via means such as transdermal patches.

[0080] For treating diseases of the respiratory tract, the compounds of the invention described above may be administered by inhalation. Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations, which may be individually administered via a suitable inhalation device selected from a dry powder inhaler, a pressurized metered dose inhaler, or a nebulizer.

[0081] When administered as a dry powder, single or multi-dose inhalers known in the art may be utilized, in which case the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs, or into a reservoir. A diluent or carrier, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compounds of the invention.

[0082] Inhalation aerosols containing propellants such as hydrofluoroalkanes may contain the compounds of the present invention either in solution or in dispersed form. Formulations using propellants may also contain other ingredients such as cosolvents, stabilizers, and optionally other excipients.

[0083] Propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles and may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft mist nebulizers such as Respimat (©), a registered trademark of Boehringer Ingelheim Pharmaceuticals (Wachtel, H., Kattenbeck, S., Dunne, S. et al., Pulm Ther (2017) 3: 19).

[0084] The compounds of the present invention, regardless of route of administration, can be administered as the sole active agent or in combination with other pharmaceutically active ingredients (i.e., as co-therapeutic agents administered in fixed-dose combinations or in combination therapies of separately formulated active ingredients).

[0085] The compounds of the present invention may be administered as the sole active ingredient or in combination with other pharmaceutical ingredients, including active ingredients currently used in the treatment of respiratory disorders and known to those of skill in the art, such as beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta inhibitors (IKK2), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modifiers, nonsteroidal anti-inflammatory drugs (NSAIDs), and mucosal modifiers.

[0086] The present invention is also directed to kits containing pharmaceutical compositions of the compounds of the invention, alone or in combination or admixture with one or more pharmaceutically acceptable carriers and / or excipients, and to devices which may be single or multi-dose dry powder inhalers, metered dose inhalers or nebulizers.

[0087] 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 symptoms, the route of administration, the frequency of administration intervals, the particular compound utilized, the efficacy, toxicity profile, and pharmacokinetic profile of the compound.

[0088] Pharmaceutical compositions comprising compounds of the invention suitable for administration by inhalation are in a variety of respirable forms, such as inhalable powders (DPIs), propellant-containing metered dose aerosols (PMDIs) or propellant-free inhalable formulations (e.g., UDVs). The present invention is also directed to a device comprising a pharmaceutical composition comprising a compound of the present invention, which may be a single or multiple dose dry powder inhaler, a metered dose inhaler or a nebulizer, particularly a soft mist nebulizer.

[0089] The present invention will be described in more detail below with reference to examples. Features of the present invention will become apparent in the course of the following description of exemplary embodiments, which are set forth to illustrate the invention and are not intended to limit the scope of the invention.

[0090] Preparation of Intermediates and Examples 1a-10a The following compounds, Examples 1a-10a, reported in Table 1 below, were prepared and characterized as follows:

[0091] Table 1 [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0092] The compound of Example 1a was prepared according to the following scheme: [ka]

[0093] Process 1 Intermediate 1A: (6-Bromo-1-[5-chloro-2-(difluoromethoxy)phenyl]-3-methyl-pyrazolo[4,3-b]pyridine) A round-bottom flask was charged with 1-(5-bromo-3-fluoro-2-pyridyl)ethanone (2.00 g, 9.2 mmol), [5-chloro-2-(difluoromethoxy)phenyl]hydrazine hydrochloride (2.47 g, 10 mmol), and potassium carbonate (3.80 g, 28 mmol) in dimethylformamide (16 mL). The reaction mixture was stirred at 85° C. for 1.5 hours and then at 120° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL), washed with saturated aqueous NaCl (3×30 mL), and the organic layer was dried over NaSO. The solvent was partially removed under reduced pressure, and the crude product was allowed to stand at room temperature to form a solid. The solid was filtered, washed with petroleum ether, and then dried to give the title product (1.797 g). ES + m / z 388.0 / 390.0 / 392.0 [MH] +

[0094] Process 2 Intermediate 2A: (6-bromo-3-(bromomethyl)-1-[5-chloro-2-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridine) In a round-bottom flask under nitrogen, intermediate 1A (200 mg, 0.51 mmol) and 1,2-dichloroethane (4.0 mL) were added, followed by N-bromosuccinimide (110 mg, 0.62 mmol) and AIBN (2,2'-azobis(2-methylpropionitrile) (17 mg, 0.1 mmol). The reaction mixture was heated at 80 °C for 2 h, then cooled to room temperature and quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 5 mL), and the organics were combined, washed with saturated aqueous NaCl (10 mL), and dried over NaSO. After evaporation under reduced pressure, the crude material was purified by SPE (solid phase extraction) on silica gel to give the title compound (134 mg). + m / z 465.9 / 467.9 / 469.9 / 491.9 [MH] +

[0095] Process 3 Intermediate 3A: ([6-bromo-1-[5-chloro-2-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-3-yl]methyl acetate) A vial charged with Intermediate 2A (140 mg, 0.30 mmol), dimethylformamide (1.5 mL), and potassium acetate (103 mg, 1.0 mmol) was heated at 60 °C for 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 5 mL). The organics were combined, washed with saturated aqueous NaCl (2 x 5 mL), dried over NaSO, and evaporated to dryness. The crude product was used in the next synthetic step without further purification. ES + m / z 446.0 / 448.0 / 450.0 [MH] +

[0096] Process 4 Intermediate 4A: ([1-[5-chloro-2-(difluoromethoxy)phenyl]-6-pyrazolo[1,5-a]pyrimidin-3-yl-pyrazolo[4,3-b]pyridin-3-yl]methyl acetate) Intermediate 3A (83 mg, 0.16 mmol) in THF (1 mL) and aqueous tribasic potassium phosphate (0.50 M, 0.65 mL, 0.33 mmol) were degassed with nitrogen for 10 minutes, followed by the addition of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (44 mg, 0.18 mmol) and XPhos-Pd-G3 ((2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) (6.9 mg, 0.0082 mmol). The reaction mixture was heated at 55°C for 1.5 hours, cooled to room temperature, and diluted with dichloromethane (10 mL) and water (10 mL). The aqueous layer was extracted with dichloromethane (4 x 5 mL), then the organic layers were combined, washed with water (10 mL), and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude residue was purified by SPE (solid phase extraction) on silica gel to give the title compound (66 mg). ES + m / z 485.1.1 / 487.1 [MH] +

[0097] Process 5 Example 1a: ([1-[5-chloro-2-(difluoromethoxy)phenyl]-6-pyrazolo[1,5-a]pyrimidin-3-yl-pyrazolo[4,3-b]pyridin-3-yl]methanol) Intermediate 4A (95%, 48 mg, 0.094 mmol) and methanol (5 mL) were charged in a round-bottom flask, followed by the addition of KCO (0.039 g, 0.28 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude residue was purified by SPE (solid phase extraction) on silica gel to give the title compound (30 mg). + m / z 443.1 / 445.1 [MH] +

[0098] The compounds of Examples 2a-10a were prepared in a manner similar to that of Example 1a, following the same synthetic sequence; modifications of the reaction conditions, reactants, or solvents used can be readily determined by one skilled in the art by routine optimization procedures.

[0099] Pharmacological activity of compounds (1a-10a) of the present invention Biochemical potency JAK1 (data presented as pIC50 in Table 1) The purpose of this study was to evaluate the activity of novel JAK inhibitors by measuring their ability to inhibit JAK1 kinase activity in a biochemical time-resolved fluorescence resonance energy transfer (TR-FRET) LANCE (LANCE) assay. In the LANCE Ultra kinase assay, a ULight peptide substrate (LANCE Ulight-JAK-1 (Tyr1023) peptide, Perkin Elmer, TRF0121) was phosphorylated in the presence of JAK1 kinase and ATP (equivalent to Km). It was then captured by a Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), bringing the Eu-chelate donor and ULight acceptor dyes into close proximity. Upon excitation at 320 nm, the Eu-chelate transferred its energy to the ULight dye, resulting in fluorescence emission at 665 nm. Inhibitors were tested in duplicate at eleven 5-fold serial dilutions (30 μM to 3 pM) starting from 30 μM. IC50 data 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

[0100] In addition to enzymatic efficacy, the effect of inhibitors on JAK1 / JAK3 activity was characterized in a cellular assay against the level of IL-2-induced STAT5 phosphorylation in human peripheral blood mononuclear cells (PBMCs).

[0101] Cell-based PBMC assay (IL-2 stimulated pSTAT5) (data presented as pIC50 in the table) PBMCs were isolated from healthy human volunteers. Cells were seeded into wells and treated with compound and rhIL-2. After 30 minutes of incubation, cells were lysed and pSTAT5 was measured by PathScan Phospho-Stat 5 (Tyr694) ELISA (Cell Signaling). Inhibitors were tested in duplicate at 11 5-fold serial dilutions (30 μM to 3 pM) starting at 30 μM. IC50 data calculations, curves, and QC analysis were performed using Excel Tools and GraphPad Prism software. QC criteria parameter: Z' > 0.35, Hill Slope range 0.5~5, S:B>2

[0102] NMR spectra NMR spectra were recorded on a Bruker Avance III 600 (5 mm RT inverse sprue head), a Bruker DRX500, a Bruker Avance AV400 (5 mm RT direct probe head), and a Bruker DPX300 spectrometer using standard Bruker pulse sequences. DMSO-d6 or CDCl3 was used as the solvent, and TMS was used as the internal standard; in the latter case, the residual solvent peak was used. All experiments were recorded at 25 °C unless otherwise noted.

[0103] LC-MS spectra were recorded on an Acquity UPLC coupled to an SQD mass spectrometer. Chromatography column: Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter) or Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter). Column temperature: 40 °C. Mobile phase: A = 0.1% v / v formic acid solution in water, B = 0.1% v / v formic acid solution in acetonitrile, or A = 10 mM aqueous NH4HCO3 (adjusted to pH 10 with ammonia) and B = acetonitrile. Analytical samples were dissolved in a 1:1 mixture of water:acetonitrile. If necessary, approximately 10% DMSO was used to improve solubility.

[0104] Preparation of Intermediates and Examples 1-92 The preparative methods described below and reported in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention. Those skilled in the art will recognize that all embodiments or aspects of the present invention (including Examples 1a-10a) can be prepared using the methods described herein or can be readily adapted using other known methods, reagents, and starting materials.

[0105] In some cases, steps are required to mask or protect functional or reactive moieties, and commonly known protecting groups (PG) can be used in accordance with general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0106] Compounds of formula (Io), which are reported herein again for clarity, including all compounds listed herein above, may generally be prepared according to the procedures shown in the following schemes: Where specific details or steps differ from the general schemes, these are detailed in the specific examples and / or additional schemes. [ka]

[0107] Compounds of formula (Io) can be prepared according to Scheme 1. Compound IV is an intermediate in which the general groups r1, r2, r3, and w can be converted to R1, R2, R3, and W, respectively, by procedures well known to those skilled in the art, such as deprotection of protecting groups and / or functional group transformations, which may involve more than one step. The procedures can be applied to one or more of these groups (r1, r2, r3, and w) to convert intermediate IV to compounds of general formula Io, as detailed in the experimental sections for specific examples. It is clear that when such a transformation is not required (when r1, r2, r3, and w correspond to R1, R2, R3, and W, respectively), any of the general solutions shown below for the preparation of intermediate IV will provide compounds of general formula (Io).

[0108] Compounds of formula (Io) (or intermediate IV) can be obtained by reacting intermediate II with intermediate III to directly introduce W via metal / palladium-catalyzed cross-coupling reactions such as Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, etc. (Strategic Applications of Named Reactions in Organic Synthesis, L. Kurti, B. Czako, eds. 2005).

[0109] Scheme 1 [ka]

[0110] For example, a suitable palladium-catalyzed cross-coupling for introducing W, when it is a pyrazolo[1,5-a]pyrimidin-3-yl, is the Suzuki coupling. The Suzuki coupling involves the reaction of intermediate II with the corresponding boronic acid or pinacolatoboronate (intermediate III, where w is pyrazolo[1,5-a]pyrimidin-3-yl and A is dihydroxyboronyl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) using tetrakistriphenylphosphinepalladium(0), PdCl(dppf), or XPhos-Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1']biphenyl]. This reaction can be carried out in the presence of a Pd catalyst, such as a ligand-palladacycle catalyst precursor, e.g., [(-biphenyl)]palladium(II) methanesulfonate, in an organic solvent, such as 1,4-dioxane, THF, 1,2-dimethoxyethane, 2-propanol, or DMF, with or without water, in the presence of an inorganic base, such as an alkali carbonate (e.g., CsCO or KCO) or an inorganic phosphate (e.g., KPO), with heating (typically in the range of 50–100 °C) for several hours (typically 1–3 hours). Boronic acids and boronate pinacolate esters are generally commercially available or can be easily prepared by those skilled in the art starting from commercially available reagents. For synthetic convenience, primary / secondary amines and / or acidic NH groups (e.g., those derived from sulfonamides, amides, ureas, and carbamates) that may be present in Suzuki coupling intermediates should be protected with appropriate protecting groups. Suitable protecting groups for protecting acidic NH groups (such as NH groups derived from sulfonamides, amides, ureas, and carbamates) can be DMB (2,4-dimethoxybenzyl) or PMB (paramethoxybenzyl) groups. The DMB group can be easily removed by treating the corresponding DMB-protected intermediate IV with a strong organic or inorganic acid under acidic conditions. For example, DMB can be deprotected by treating the intermediate with trifluoroacetic acid alone or in a mixture with an organic solvent such as DCM, THF, etc., typically at room temperature for several hours (typically 1 to 3 hours).Suitable protecting groups for protecting the primary and secondary amines ultimately present in the r1 / r2 / r3 groups can be carbamate-type protecting groups such as Boc (tert-butoxycarbonyl). The Boc group can be easily removed by treating the Boc-protected intermediate IV with a strong organic or inorganic acid under acidic conditions. For example, the Boc group can be cleaved by treating the intermediate with trifluoroacetic acid alone or in a mixture with an organic solvent such as DCM, DCE, THF, etc., typically at room temperature for several hours (typically 1 to 3 hours).

[0111] A suitable palladium-catalyzed cross-coupling for introducing W, if it is an imidazo[1,2-b]pyridazin-3-yl, is a Stille coupling, which can be carried out by reacting intermediate II with its corresponding stannane (intermediate III, where w is imidazo[1,2-b]pyridazin-3-yl and A is tributylstannyl or trimethylstannyl) in the presence of a suitable palladium catalyst (such as Pd(PPh3)2Cl2) in a polar organic solvent (e.g., DMF or 1,4-dioxane) with or without an additive (such as a base or lithium salt). Stannanes are generally commercially available or can be easily prepared by those skilled in the art starting from commercially available reagents.

[0112] A suitable palladium-catalyzed cross-coupling to introduce W is the Buchwald-Hartwig coupling in the case of (3-oxo-3,4-dihydropyrazin-2-yl)amino. For synthetic convenience, the carbonyl group of (3-oxo-3,4-dihydropyrazin-2-yl)amino can be masked as an alkoxy group (e.g., methoxy) and deprotected from intermediate IV at the end of the synthesis. Intermediate II and intermediate III (where w is 3-methoxypyrazine-2-aminyl and A is H) can be reacted with a suitable ligand, 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) In the presence of a palladacycle system, or generally a suitable Pd source (e.g., Pd(dba) or Pd(OAc)) with a suitable biphenylphosphine ligand type (e.g., RuPhos, X-Phos, etc.), 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, heating at elevated temperatures (typically 80-120 °C) for several hours (typically 1-5 hours) can provide intermediate IV, where w is 3-methoxypyrazine-2-aminyl. The methoxy group of intermediate IV can be demethylated by treatment with TMS-Cl (trimethylsilyl chloride) and sodium iodide in acetonitrile at 60-100 °C for 1-5 hours to provide intermediate (Io), where W is (3-oxo-3,4-dihydropyrazin-2-yl)amino.

[0113] The above method may provide at least one non-limiting synthetic route for producing Examples 1-62, Examples 76-77, Examples 80 and 83-92, and Intermediate IV (wherein r1, r2, r3, and / or w are independently precursors of R1, R2, R3, and / or W).

[0114] Intermediate II, reported as intermediate IIa (when r1 is phenyl substituted with R8 and K'), can be obtained according to Scheme 2. K' and r2 denote groups from which K and R2, respectively, can be obtained by further manipulations well known to those skilled in the art, such as removal of protecting groups and / or functional group transformations, which may involve more than one step.

[0115] Intermediate IIa can be obtained from intermediate V by stepwise or simultaneous conversion of the ewg and r1 groups by generally accepted methods and in accordance with principles of chemistry.

[0116] Intermediate V can be obtained by aromatic nucleophilic substitution of intermediate VII with intermediate VI. The aromatic nucleophilic substitution can be carried out by heating (typically 80-130°C) a nucleophile and an aromatic electrophile (Lg is generally fluorine) in the presence of an inorganic base (such as K2CO3 or Cs2CO3) or an organic base (such as TEA, DBU, or DIPEA) in a polar organic solvent (e.g., DMF, DMA, or 1,4-dioxane).

[0117] In a more general method, intermediate V can be prepared from intermediates VI and VII by N-arylation. N-arylation can be carried out using a copper-catalyzed Ullmann-type reaction. The Ullmann reaction between an NH heteroaryl and an aryl / heteroaryl halide (chloride, bromide, or iodide) can be carried out without a ligand or with a suitable ligand such as N,N-dimethylglycine, proline, or dimethylcyclohexane-1,2-diamine (DMCHA) in the presence of an inorganic base such as K2CO3 or Cs2CO3, in the presence of a suitable copper(I) catalyst / promoter such as CuI, Cu2O, or CuTC (copper thiophene carboxylate), in a polar organic solvent such as DMSO, DMF, or DMA (typically at 90-150 °C) for several hours or longer (typically 3-12 hours).

[0118] Scheme 2 [ka]

[0119] The following schemes detail the most general methods that can be used to obtain particular intermediates IIa, which have been labeled with additional letters / numbers for clarity.

[0120] Intermediate IIa-A can be prepared from intermediate Va in a two-step process according to Scheme 3. In the first step, the nitro group of intermediate Va can be reduced to the corresponding aniline, for example, by treating such intermediate with a metal powder such as iron or zinc in the presence of an acid such as acetic acid or ammonium chloride, with or without water, in an alcoholic solvent such as ethanol or methanol at room temperature (or at elevated temperatures up to 80° C.). Another method for reducing the nitro compound can be carried out by catalytic hydrogenation using a platinum catalyst such as Pt / C (platinum on carbon) sulfide in the presence of a hydrogen source as ammonium chloride in an alcoholic solvent such as ethanol at temperatures up to 70° C.

[0121] Scheme 3 [ka]

[0122] In the second step, the aniline can be converted to L (where L is -NHS(O)-, -NHC(O)-, -NHC(O)NH-, or -NHC(O)O-, respectively) by sulfamidation, amidation, carbonylation, or carbamoylation. The sulfamidation reaction can be carried out by reacting the aniline with an appropriate sulfonyl chloride in an organic solvent such as DCM in the presence of an organic base such as pyridine or TEA, typically at a temperature between 0°C and room temperature. The acylation, carbonylation, or carbamoylation can be carried out by reacting the aniline intermediate with an acyl chloride, chloroformate, or carbamoyl chloride, respectively, in the presence of a base such as pyridine or TEA in an organic solvent such as DCM or THF.

[0123] In some cases, the L group, when L is -NHS(O)2, can be further elaborated to -NR6S(O)2 by introducing an R6 group, for example, by treating the corresponding sulfonamide with an appropriate alkylating agent and base. In other cases, the group Z' can be converted to Z by specific functional group manipulation. For example, if Z' is an ester, it can be converted to an amide in a two-step process involving ester hydrolysis and amidation.

[0124] Scheme 4 [ka]

[0125] Intermediate IIa-B can be prepared from intermediate Vb in a two-step process according to Scheme 4. In the first step, intermediate Vb can be reacted with an ammonia source such as p-methoxybenzylamine, HN-PG, in an organic solvent such as DCM or THF in the presence of a carboxylic acid such as acetic acid to form the corresponding imine / enamine, which can be reduced by adding an appropriate borohydride such as STAB (sodium triacetoxyborohydride) or NaBHCN. In some cases, typically when R7 is a group other than H, the formation of the imine / enamine can be promoted by using a Lewis acid instead of a carboxylic acid in the presence of an organic base such as TEA or DIPEA. Sulfamidation or acylation / carbonylation or carbamoylation can be carried out using conditions similar to those already described in Scheme 3.

[0126] Scheme 5 [ka]

[0127] In another solution reported in Scheme 5, intermediates of formula IIa-C can be obtained from intermediate Ve by a two-step process. In the first step, the ester of PG1 (PG1 is tert-butyl) can be deprotected by acidic treatment, for example with TEA or concentrated HCl in an organic solvent such as DCM or 1,4-dioxane. In the second step, the acid is converted to a compound of formula HNR6(CH2). nThe amine of -Z' can be reacted with an acid by an amide coupling reaction. 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), in the presence of an organic base such as TEA, DIEA, or pyridine.

[0128] Scheme 6 [ka]

[0129] In a different approach reported in Scheme 6, intermediates of formula IIa-D can be obtained from intermediate Vd in a three-step process involving 1) CN coupling, 2) nitro group reduction, and 3) sulfamidation (or acylation / carbonylation / carbamoylation). In a slightly different approach, the order of events can be reversed, first 1) nitro reduction, then 2) sulfamidation (or acylation / carbonylation / carbamoylation), and finally step 3) CN coupling. Intermediate Vd and HNR6(CH2) nC-N coupling between -Q' can be carried out by heating (typically to 60-100 °C) the heteroaromatic iodide with the amine in an organic solvent such as DMSO in the presence of a copper(I) catalyst / promoter such as CuI, CuO, or CuTC (copper thiophenecarboxylate), either without a ligand or with a suitable ligand such as proline, N,N-dimethylglycine, dimethylcyclohexane-1,2-diamine (DMCHA), or an inorganic base such as KCO or CsCO. Nitro group reduction and sulfamidation (or acylation / carbonylation / carbamoylation) can be carried out according to the conditions previously described in Scheme 3.

[0130] In a slightly different solution, the group r2 (-NR6C(O)(CH2) n -Q') can be constructed using a stepwise methodology starting with a protected ammonia source (such as 2,4-dimethylbenzylamine-DMB-NH) instead of iodine, followed by deprotection to give the primary amino group, which can be further manipulated by amide coupling or acylation to give -N(CO)R(CH)-Q'. In other cases, for example, the group -NRC(O)(CH) n -Q' can be further manipulated by converting the secondary amine of Q' to the respective tertiary amine. This conversion can be carried out by alkylating the secondary amine with a suitable alkylating agent. If, for synthetic convenience in the previous step, the secondary amine is Boc-protected, this group must be cleaved by a commonly accepted method.

[0131] In an alternative solution, intermediate IIa-E can be synthesized from intermediate Ve by subjecting it to a C—N coupling in the same manner as already described above for intermediate Vd.

[0132] In another approach, intermediate Vd can be used to prepare intermediates of formula IIa where r2 is -CH2CN in a two-step process. In the first step, the 4-isoxazolyl group is inserted as a masked precursor to -CH2CN by Suzuki coupling with the corresponding boron pinacolate, followed by cleavage to the desired moiety with KF.

[0133] In a different method described in Scheme 7, the intermediate of Formula IIa-F can be prepared by: 1) reacting an amine, HNR(CH) n -Z), 2) nitro group reduction, and 3) sulfamidation (or acylation / carbonylation / carbamoylation), using similar conditions as already described in Schemes 3 and 5 for the same reaction type. Alternatively, intermediate IIa-F can be prepared from intermediate Vf (when PG1 is H) by a three-step process involving 1) nitro group reduction, 2) sulfamidation (or acylation / carbonylation / carbamoylation), and 3) HNR6(CH2). n Intermediate Vf (when PG1 is methyl or ethyl) can be obtained by a three-step process involving amidation at -Z, which can be carried out by heating the ester and amine in an organic solvent such as THF or dioxane in the presence of a Lewis acid such as DABAL-Me3 (bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct) or AlMe3 (typically at 100-150 °C).

[0134] Scheme 7 [ka]

[0135] In another solution reported in Scheme 8, intermediate IIa-G can be prepared by 1) bromination of the methyl group, 2) the amine of the benzylic bromide, HNR(CH). nIntermediate Vg can be obtained by a four-step process involving nucleophilic substitution at -Z', 3) nitro group reduction, and 4) sulfamidation (or acylation / carbonylation / carbamoylation). Bromination is selectively carried out by reaction with NBS (N-bromosuccinimide) in the presence of a radical initiator such as AIBN (azobisisobutyronitrile) in a suitable inert organic solvent such as trifluorotoluene or tetrachloromethane at a temperature of about 80-90°C to give the corresponding benzylic bromide, which can be reacted with an excess (up to 30 equivalents) of an amine in THF or DMF.

[0136] Scheme 8 [ka]

[0137] Scheme 9 [ka]

[0138] In another solution reported in Scheme 9, intermediate IIa-H can be prepared starting from intermediate Vh' by C-N coupling with the corresponding amine, similarly as described in Scheme 6. Intermediate Vh' can be obtained from intermediate Vh using a method similar to that described in Scheme 4.

[0139] In another approach reported in Scheme 9, intermediate IIa-L can be prepared by 1) carbonylation of a heteroaryl iodide with a carboxylic acid derivative, followed by 2) condensation of the amine HNR(CH). nIntermediate Vh' can be obtained from Vh' by a two-step process involving amide coupling with -Z'. The carbonylation reaction can be carried out by reacting the iodide in the presence of a CO donor system such as formic acid / DCC (dicyclohexylcarbodiimide) or formic acid / acetic anhydride, in the presence of a palladium(II) source / ligand system such as Pd(OAc)2 / Xanphos or Pd(PPh3)2Cl2, in an organic solvent such as THF or 1,4-dioxane, by heating (typically at 50-80°C). Subsequent amide coupling can be carried out as described above in Scheme 5.

[0140] In a similar manner, all synthetic routes reported in the above schemes (Scheme 2 to Scheme 9) can also be applied to prepare intermediates of formula II when r1 is a further substituted phenyl or when r1 is pyridine.

[0141] In another solution, compounds of formula (Io) can be further manipulated by subjecting specific functional groups present at r1, r2, r3 of intermediate IV (prepared according to Scheme 1) to functional group transformations reported in Table 1, which provide at least one non-limiting synthetic route for the preparation of the examples reported in said table.

[0142] Table 1 [Table 16] [Table 17]

[0143] The starting intermediates reported in all schemes described above are either commercially available or can be readily prepared by one skilled in the art starting from commercially available reagents using generally accepted methods, unless their preparation is described in detail herein and / or in the experimental section.

[0144] General Experimental Details Chemical names of compounds were assigned using Structure To Name Enterprise 10.0 Cambridge Software or its latest version.

[0145] Purification by "chromatography" or "flash chromatography" refers to purification using a Biotage SP1 or Interchim puriFlash purification system, or equivalent MPLC system using a prepacked polypropylene column containing the stationary phase (cartridge). When the product was purified using a Si cartridge, this refers to an Interchim prepacked polypropylene column (or equivalent) containing unbonded activated silica with spherical particles of 15 μm average particle size or an Isolute® prepacked polypropylene column (or equivalent) containing unbonded activated silica with irregular particles of 50 μm average particle size. Fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and concentrated under vacuum. When an SCX-2 cartridge was used, "SCX-2 cartridge" refers to a Bond Elut® prepacked polypropylene column (or equivalent) containing a non-end-capped propylsulfonic acid-functionalized silica strong cation exchange sorbent.

[0146] NMR method NMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probe head), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probe head), or Bruker DPX 300 spectrometer using standard Bruker pulse sequences. DMSO-d6 or CDCl3 was used as the solvent, and tetramethylsilane was used as the internal solvent. In the latter case, the residual solvent peak was used. Unless otherwise specified, all experiments were recorded at 298 K. Chemical shifts are reported in ppm as δ values ​​relative to tetramethylsilane. Coupling constants (J values) are given in hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and nd = not determined.

[0147] LCMS method Method 1 Coupling of Acquity UPLC with SQD mass spectrometer; Column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm), Mobile phase A: 0.1% (v / v) formic acid in water, Mobile phase B: 0.1% (v / v) formic acid in acetonitrile;

[0148] [Table 18]

[0149] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1000 AMU

[0150] Method 2 Acquity UPLC coupled to an SQD mass spectrometer; column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm); mobile phase A: 10 mM ammonium bicarbonate aqueous solution (adjusted to pH 10 with ammonia); mobile phase B: acetonitrile

[0151] [Table 19]

[0152] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1000 AMU

[0153] Method 3 Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm); Mobile phase A: 0.1% (v / v) formic acid in water; Mobile phase B: 0.1% (v / v) formic acid in acetonitrile

[0154] [Table 20]

[0155] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1500 AMU

[0156] Method 4 Acquity UPLC coupled to an SQD mass spectrometer; column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm); mobile phase A: 10 mM ammonium bicarbonate aqueous solution (adjusted to pH 10 with ammonia); mobile phase B: acetonitrile

[0157] [Table 21]

[0158] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1500 AMU

[0159] Method 5 Acquity UPLC coupled to an SQD mass spectrometer; Column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm); Mobile phase A: 0.1% (v / v) formic acid in water; Mobile phase B: 0.1% (v / v) formic acid in acetonitrile

[0160] [Table 22]

[0161] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1500 AMU

[0162] Method 6 Acquity UPLC coupled to an SQD mass spectrometer; column: Acquity BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm); mobile phase A: 10 mM ammonium bicarbonate aqueous solution (adjusted to pH 10 with ammonia); mobile phase B: acetonitrile

[0163] [Table 23]

[0164] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1500 AMU

[0165] Method 7 Agilent LC 1260 Infinity + SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; column: Acquity BEH C18 (100 mm x 2.1 mm i.d., 1.7 μm); mobile phase A: 0.1% (v / v) formic acid in water; mobile phase B: 0.1% (v / v) formic acid in acetonitrile

[0166] [Table 24]

[0167] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1500 AMU

[0168] Method 8 Agilent LC 1260 Infinity+SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; column: Acquity UPLC BEH C18 (100 mm x 2.1 mm i.d., 1.7 μm); mobile phase A: 0.05% (v / v) aqueous ammonia; mobile phase B: acetonitrile

[0169] [Table 25]

[0170] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate-scan positive and negative electrospray (ES+ / ES-), scan range: 100 to 1000 AMU

[0171] In the procedures that follow, some of the starting materials are identified through "Intermediate" or "Example" numbers and step names, which are provided solely to assist those skilled in the art. When reference is made to the use of "similar" or "analogous" procedures, such procedures may involve minor variations, such as, for example, reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions, or chromatographic purification conditions, as would be understood by one of ordinary skill in the art.

[0172] The stereochemistry of the compounds in the examples is assigned with the assumption that, where indicated, the absolute configuration at the resolved stereocenter in the starting material is maintained throughout any subsequent reaction conditions.

[0173] Unless otherwise stated, when absolute configuration (R) or (S) is reported in the compound name, the ee% should be assumed to be 90% or greater. All solvents and commercially available reagents were used as received. Where the preparation of starting materials is not described, they are either commercially available, known in the literature, or readily accessible by one skilled in the art using standard procedures.

[0174] Abbreviation: AIBN = azobisisobutyronitrile; Boc2O = di-tert-butyl dicarbonate; DABAL-Me3 = bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC = dicyclohexylcarbodiimine; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EEDQ = 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; EtOAc = ethyl acetate; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide) hexafluorophosphate), HBTU = (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; LCMS = liquid chromatography-mass spectrometry; LiHMDS = lithium bis(trimethylsilyl)amide; MW = microwave; NBS = N-bromosuccinimide; 1 H-NMR = proton nuclear magnetic resonance; RM = reaction mixture; Rt = retention time; RT = room temperature; 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

[0175] Intermediate production Intermediate 1 [ka]

[0176] 2-(Difluoromethoxy)-1-fluoro-4-nitrobenzene (Intermediate 1) A solution of 2-fluoro-5-nitro-phenol (5.0 g, 32 mmol) and KOH (36 g, 637 mmol) in acetonitrile / water (1:1, 320 mL) was cooled to 0 °C. Bromodifluoromethyl diethylphosphonate (11 mL, 64 mmol) was added and the RM was stirred for 1 h. The RM was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The organic layer was washed with saturated aqueous NaCl, then the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (61 °C / 0.086 mbar) to give the title compound. LCMS (method 2): Rt=1.02 min 1 H-NMR (300MHz, DMSO-d6) δ(ppm):8.29-8.20(m,2H), 7.73(t,J=9.4Hz,1H), 7.44(t,J=72.7Hz,1H)

[0177] Intermediate 2 [ka]

[0178] 3-(Difluoromethoxy)-4-fluorobenzaldehyde (Intermediate 2) 4-Fluoro-3-hydroxy-benzaldehyde (500 mg, 3.57 mmol), sodium chlorodifluoroacetate (1251 mg, 8.21 mmol), and CsCO (1.63 g, 5.00 mmol) were suspended in DMF (8 mL) and stirred at 100 °C for 2 h. The RM was cooled to RT. Water (80 mL) was added, and the product was extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with saturated aqueous NaHCO (3 × 20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried over NaSO, and evaporated to dryness. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–30% EtOAc in cyclohexane to give the title compound (226 mg). LCMS (method 2): Rt=0.97 min 1 H-NMR (500MHz, CDCl3) δ(ppm):9.95(s,1H), 7.77-7.81(m,2H), 7.34-7.38(m,1H), 6.63(t,J=70.6Hz,1H)

[0179] Intermediate 3 [ka]

[0180] 2-Chloro-4-fluoro-5-methoxybenzaldehyde (Intermediate 3) 1-Bromo-2-chloro-4-fluoro-5-methoxy-benzene (1.0 g, 4.2 mmol) was dissolved in THF (10 mL) and cooled to −5 °C under a nitrogen blanket. i-PrMgCl·LiCl (1.3 M in THF, 6.42 mL, 8.4 mmol) was added dropwise at approximately 0 °C. The RM was stirred at 0 °C for 1 h, then DMF (1.62 mL, 21 mmol) was added, and the RM was stirred at RT for an additional 45 min. The RM was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaCl (20 mL) and evaporated under reduced pressure to give the title compound (800 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.07 min 1 H-NMR (300MHz, DMSO-d6) δ(ppm):10.24(s,1H), 7.68(d,J=10.9Hz,1H), 7.54(d,J=8.7Hz,1H)

[0181] Intermediate 4 [ka]

[0182] 4-Fluoro-3-methoxy-N-methylbenzenesulfonamide (Intermediate 4) 4-Fluoro-3-methoxy-benzenesulfonyl chloride (1.5, 6.7 mmol) was added to a solution of methylamine in THF (2.0 M, 17 mL, 33 mmol). The RM was stirred at RT for 16 h, then diluted with EtOAc (30 mL) and washed with water (2 x 20 mL). The organic layer was dried over NaSO and the solvent was removed under reduced pressure to give the title product (1.08 g), which was used in the next step without further purification. LCMS (method 2): Rt=0.80 min, ES - 218.1 [MH] -

[0183] Intermediate 5 [ka]

[0184] 4-Fluoro-3-methoxy-N-methylbenzamide (Intermediate 5) To a solution of 4-fluoro-3-methoxybenzoic acid (500 mg, 2.94 mmol) in DMF (3 mL) was added methylamine hydrochloride (595 mg, 8.82 mmol) and DIPEA (2.56 mL, 14.7 mmol), followed by HATU (1.23 g, 3.23 mmol). After 2 h, another equivalent of HATU was added, and the RM was stirred overnight. The RM was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were combined and washed with saturated aqueous NaHCO3 (3 x 10 mL), 5% (w / w) aqueous LiCl (10 mL), and saturated aqueous NaCl (10 mL). After drying over Na2SO4, the solvent was removed in vacuo, and the residue was dissolved in DCM (20 mL) and subsequently washed with 0.1 N HCl (7 x 10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title product (439 mg). LCMS (Method 1): Rt=0.67 min, ES + m / z 184.1 / 185.2 [M+H] +

[0185] Intermediate 6 [ka]

[0186] 5-Bromo-4-methoxy-N-methylpyridin-2-amine (Intermediate 6) A vial charged with 5-bromo-4-methoxy-pyridin-2-amine (300 mg, 1.48 mmol) and THF (7 mL) was cooled to 0 °C, followed by the addition of NaH (60% dispersion in mineral oil, 83 mg, 2.07 mmol). The RM was stirred at RT for 30 min and then cooled to 0 °C, after which methyl iodide (92 μL, 1.48 mmol) was added dropwise. The RM was stirred at RT for an additional 1 h, quenched with saturated aqueous NaCl (10 mL), and extracted with EtOAc (20 mL). The organic layer was dried over NaSO, the solvent was evaporated to dryness, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-30% EtOAc in cyclohexane to give the title product (104.7 mg). LCMS (method 2): Rt=0.79 min, ES + m / z 216.9 / 218.9 [M+H] +

[0187] Intermediate 7 Process 1 [ka]

[0188] tert-Butyl (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)carbamate (Intermediate 7-1) tert-Butyl N-(2-bromoethyl)carbamate (599 mg, 2.7 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (400 mg, 2.7 mmol) were suspended in DMF (10.0 mL). Potassium carbonate (739 mg, 5.3 mmol) was then added, and the RM was stirred at 65 °C for 4 days. The RM was cooled to RT, poured into ice-cold water, and extracted with DCM (4 x 10 mL). The organic layers were combined, dried over NaSO, and evaporated to dryness. The resulting crude material was chromatographed on a Si cartridge eluting with 0-30% DCM / MeOH / NHOH (90:9:0.5) in DCM to give the desired product (249 mg). 1H-NMR (500MHz, CDCl3) δ(ppm): 5.16(bs,1H), 3.64(d,J=10.4Hz,2H), 3.49(d,J=10.4Hz,2H), 3.16(m,2H), 2.98(m,2H), 2.34(m,2H), 1.85(s,4H), 1.44(s,9H)

[0189] Process 2 [ka]

[0190] 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-amine (Intermediate 7) Intermediate 7-1 (249 mg, 0.61 mmol) was dissolved in a mixture of DCM (2 mL) and TFA (0.91 mL, 12 mmol) and stirred at 20 °C for 16 h. The RM was loaded onto an SCX column, washed with methanol, and eluted with 2 M methanolic ammonia. Relevant fractions were pooled and evaporated to give the title product (126.6 mg). 1 H-NMR (500MHz, CDCl3) δ:3.68(d,J=9.9Hz,2H), 3.51(d,J=9.9Hz,2H), 3.00(bs,2H), 2.73(t,J=5.5Hz,2H), 2.33(t,J=5.5Hz,2H), 1.87(s,4H)

[0191] Intermediate 8 [ka]

[0192] 3-(Tributylstannyl)imidazo[1,2-b]pyridazine (Intermediate 8) A solution of 3-bromoimidazo[1,2-b]pyridazine (400 mg, 2.0 mmol) in THF (5 mL) was cooled to 0 °C, and then i-PrMgCl·LiCl complex (1.3 M solution in THF, 4.7 mL, 6.1 mmol) was added dropwise over 5 min. The RM was stirred at 0 °C for 15 min. Tri-n-butyltin chloride (685 μL, 2.5 mmol) was added dropwise, and the RM was further stirred at RT for 30 min. The RM was cooled in an ice bath, quenched with water (5 mL), saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (15 mL). The organic layer was washed with saturated aqueous NaCl (10 mL), dried over MgSO4, and evaporated under reduced pressure. The residue was purified by chromatography on neutral Al2O3 eluting with a mixture of cyclohexane and EtOAc to give the title product (285 mg). LCMS (method 2): Rt=1.82 min, ES + m / z (most abundant isotope) 410.0 [M+H] +

[0193] Intermediate 9a [ka]

[0194] 6-Chloro-1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 9a) A mixture of 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (1.00 g, 5.97 mmol), 1-fluoro-2-methoxy-4-nitro-benzene (1.02 g, 5.97 mmol), potassium carbonate (2.47 g, 17.9 mmol), and DMF (10.0 mL) was stirred at 80° C. for 45 min. The RM was cooled to RT and quenched with water (50 mL), and the formed precipitate was filtered, washed with water (2×35 mL), and dried to give the title product (2.28 g). LCMS (method 2): Rt=0.99 min 1H-NMR (300MHz, CDCl3) δ(ppm) 8.81(d,J=0.8Hz,1H), 8.03-7.96(m,2H), 7.67(d,J=8.5Hz,1H), 7.12(d,J=0.8Hz,1H), 3.97(s,3H), 2.69(s,3H)

[0195] Preparation of Intermediates 9b to 9e The following intermediates were prepared in a similar manner to Intermediate 9a by replacing 1-fluoro-2-methoxy-4-nitro-benzene with the indicated starting material. Where minor modifications to base, solvent, temperature and / or reaction time were made, they were detailed below in brackets.

[0196] [Table 26] [Table 27]

[0197] Intermediate 9j [ka]

[0198] Process 1 tert-Butyl 4-fluoro-3-methoxybenzoate (Intermediate 9j-1) A flask charged with DCM (100 mL), MgSO (5 g, 42.0 mmol), and concentrated 98% (w / w) HSO (0.6 mL, 11 mmol) was stirred at RT for 15 min, then 4-fluoro-3-methoxy-benzoic acid (1.78 g, 11 mmol) was added, followed by t-BuOH (5 mL, 52 mmol). The RM was stirred at RT for 20 h. An additional equivalent of HSO and MgSO was added, followed by an additional 5 mL of t-BuOH. The RM was stirred at RT overnight, then slowly poured onto ice and extracted with DCM (3 × 50 mL). The organic layers were combined, washed with saturated aqueous NaHCO (3 × 60 mL) and saturated aqueous NaCl (80 mL), dried over NaSO, filtered, and concentrated in vacuo to give the title product (1.77 g). LCMS (method 1): Rt=1.31 min 1 H-NMR (300mHz, CDCl3) δ(ppm):7.52-7.61(m,2H), 7.06(dd,J=10.8, 7.8Hz,1H), 3.91(s,3H), 1.56(s,9H)

[0199] Process 2 [ka]

[0200] tert-Butyl 4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzoate (Intermediate 9j-2) A vial charged with 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (250 mg, 1.37 mmol), intermediate 9j-1 (310 mg, 1.37 mmol), KCO (284 mg, 2.06 mmol), and DMF (2.00 mL) was stirred at 125 °C overnight. After cooling to RT, iodomethane (1.11 g, 7.82 mmol) was added, and the RM was stirred at RT for 2.5 h. The RM was quenched with water (100 mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with water (6 × 10 mL) and saturated aqueous NaCl (20 mL), dried over NaSO, and filtered to give the title product, which was used in the next step without further purification. LCMS (method 1): Rt=1.40 min, ES + m / z 374.3 / 376.2 [M+H] +

[0201] Process 3 [ka]

[0202] 4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzoic acid (intermediate 9j-3) TFA (20 mL, 246 mmol) was added dropwise to an ice-cold solution of intermediate 9j-2 (1.00 g, 2.67 mmol) in DCM (20 mL), and the RM was stirred at RT overnight. The RM was evaporated under reduced pressure, and the residue was treated with saturated aqueous NaHCO3 (20 mL) and washed with EtOAc (2 x 40 mL). The aqueous layer was brought to a pH of approximately 3-4.5 with concentrated aqueous HCl 36% w / w, and the formed precipitate was filtered and triturated with MeOH and toluene to give the title product (1.05 g). LCMS (method 1): Rt=0.91 min, ES + m / z 318.1 / 320.1 [M+H] +

[0203] Process 4 [ka]

[0204] 4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxy-N-phenylbenzamide (Intermediate 9j) A flask was charged with intermediate 9j-3 (120 mg, 0.30 mmol), HATU (126 mg, 0.33 mmol), DIPEA (110 μL, 0.6 mmol), and DMF (5 mL). Aniline (30 μL, 0.33 mmol) was then added, and the RM was stirred at RT for 1 h. The RM was quenched with water (5 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with saturated aqueous NaHCO (10×5 mL) and saturated aqueous NaCl (10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NHOH in DCM (90:9:1.5) to give the title product (82 mg). LCMS (Method 1): Rt=1.14 min, ES + m / z 393.1 / 395.1 [M+H] +

[0205] Intermediate 10a [ka]

[0206] 4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyaniline (Intermediate 10a) A three-necked round-bottom flask equipped with a magnetic stir bar, thermometer, and reflux condenser was charged with intermediate 9a (2.3 g, 7.2 mmol) and acetic acid (15 mL). The suspension was heated to 80 °C, and then iron powder (3.4 g, 62 mmol) was added portionwise. The mixture was stirred at 80 °C for 30 min. The RM was cooled to RT, and the precipitate was filtered and washed with acetic acid. The mother liquor was partitioned between water (2 × 100 mL) and EtOAc (20 mL). The organic layer was washed with saturated aqueous NaHCO and saturated aqueous NaCl, dried over NaSO, and concentrated in vacuo to give the title product (1.5 g). LCMS (method 2): RT=0.86 min, ES + m / z 289.2 / 291.0 [M+H] +

[0207] Intermediate 10b [ka]

[0208] 4-(6-chloro-3-methyl-pyrazolo[4,3-c]pyridin-1-yl)-3(difluoromethoxy)aniline (Intermediate 10b) The title product was prepared in a similar manner to intermediate 10a, starting from intermediate 9b. LCMS (method 2): Rt=0.95 min, ES + m / z 325.1 / 327.0 [M+H] +

[0209] Intermediate 10c [ka]

[0210] 6-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxypyridin-3-amine (Intermediate 10c) To a solution of intermediate 9c (144 mg, 0.45 mmol) in EtOH (4.1 mL) was added ammonium formate (170 mg, 2.7 mmol) and 3% Pt / C on sulfurized activated carbon (50% wet, 35 mg, 0.090 mmol). The RM was stirred at 85° C. for 3 h. The RM was cooled to RT, diluted with DCM, filtered through a pad of Celite®, and evaporated to give the product (151.9 mg), which was used directly in the next step. LCMS (method 2): Rt=0.70 min, ES + m / z 290.0 / 291.9 [M+H] +

[0211] Intermediate 10d [ka]

[0212] 5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-N-methylpyridin-2-amine (Intermediate 10d) A vial was charged with 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (80.8 mg, 0.482 mmol), Intermediate 6 (105 mg, 0.482 mmol), CsCO (471 mg, 1.45 mmol), and N,N-dimethylglycine (49.7 mg, 0.482 mmol) under argon. DMSO (2 mL) was added, followed by CuI (46 mg, 0.241 mmol), and the RM was stirred at 120 °C overnight. After cooling to RT, the RM was diluted with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over NaSO, and concentrated. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% MeOH / DCM (1:10) in DCM to give the title compound (43.7 mg). LCMS (method 2): Rt=0.80 min, ES + m / z 303.8 / 305.8 [M+H] +

[0213] Intermediate 11a [ka]

[0214] N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate 11a) A two-necked round-bottom flask equipped with a thermometer and a magnetic stir bar was charged with Intermediate 10a (1.0 g, 3.5 mmol) and DCM (15 mL). Methanesulfonyl chloride (375 μL, 4.8 mmol) and pyridine (822 mg, 10 mmol) were added, and the RM was stirred at RT for 20 min. The RM was diluted with water (20 mL) and extracted with DCM (2 × 15 mL). The organic layers were then combined, washed with 2 M aqueous citric acid (2 × 15 mL), saturated aqueous NaCl (15 mL each), and dried over NaSO. The solvent was removed under reduced pressure, and the residue was suspended in toluene and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–30% DCM / MeOH / NHOH (90:9:1.5) in DCM to give the title product (840.6 mg). LCMS (method 1): Rt=0.90 min, ES + m / z 367.1 / 369.1 [M+H] +

[0215] Preparation of Intermediates 11b to 11k The following intermediates were prepared in a similar manner to intermediate 11a by substituting intermediate 10a and / or methanesulfonyl chloride for the starting materials indicated.

[0216] [Table 28] [Table 29] [Table 30]

[0217] Intermediate 11l [ka]

[0218] N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-fluoro-5-methoxyphenyl)methanesulfonamide (Intermediate 11I) A round-bottom flask equipped with a magnetic stir bar, reflux condenser, and drying tube was charged with Intermediate 11a (180 mg, 0.49 mmol) and acetonitrile (10.0 mL). The mixture was heated to 80° C., and Selectfluor® (209 mg, 0.59 mmol) was added. The mixture was left stirring at 80° C. overnight, then another equivalent of Selectfluor® was added, and the mixture was stirred at 80° C. for 1 h. The RM was evaporated to dryness, and the residue was purified by flash chromatography on a Si cartridge, eluting with 0-35% EtOAc in cyclohexane, to give the desired product (28.6 mg). LCMS (Method 1): Rt=0.92 min, ES + m / z 385.1 / 387.1 [M+H] +

[0219] Intermediate 11m Process 1 [ka]

[0220] Methyl 3-(N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)sulfamoyl)propanoate (Intermediate 11m-1) Intermediate 11m-1 was prepared in a similar manner to intermediate 11a, starting from intermediate 10a and methyl 3-chlorosulfonylpropanoate. LCMS (method 2): Rt=0.93 min, ES + m / z 439.1 / 441.0 [M+H] +

[0221] Process 2 [ka]

[0222] 3-(N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)sulfamoyl)propanoic acid (Intermediate 11m-2) Intermediate 11m-1 (320 mg, 0.729 mmol) and THF (9 mL) were added to a solution of lithium hydroxide monohydrate (153 mg, 3.65 mmol) in water (4.5 mL) and stirred at RT overnight. The precipitate that formed was filtered to give the title product (140 mg). LCMS (Method 1): Rt=0.86 min, ES + m / z 425.1 / 427.1 [M+H] +

[0223] Process 3 [ka]

[0224] 3-(N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)sulfamoyl)propanamide (Intermediate 11m) To a solution of intermediate 11m-2 (50.0 mg, 0.12 mmol), ammonium chloride (31.5 mg, 0.59 mmol), and DIPEA (205 μL, 1.18 mmol) in dry DMF (1.8 mL) was added HATU (49.2 mg, 0.129 mmol). The RM was stirred at 50° C. for 2 h. An additional equivalent of ammonium chloride and HATU (22.4 mg, 0.0588 mmol) was added, and the RM was stirred for an additional 2 h. The RM was diluted with water (5 mL) and extracted with EtOAc and then with DCM / isopropanol (3×5 mL). The organic layers were combined and evaporated under reduced pressure, and the residue 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 product (26 mg). LCMS (Method 1): Rt=0.79 min, ES + m / z 424.1 / 426.1 [M+H] +

[0225] Intermediate 11n Process 1 [ka]

[0226] 2-(N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)sulfamoyl)methyl acetate (Intermediate 11n-1) The intermediate was prepared in a similar manner to intermediate 11a, starting from intermediate 10a and methyl 2-chlorosulfonylacetate. LCMS (method 2): Rt=0.96 min, ES + m / z 425.1 / 427.1 [M+H] +

[0227] Process 2 [ka]

[0228] 2-(N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)sulfamoyl)acetamide (Intermediate 11n-2) A solution of intermediate 11n-1 (40 mg, 0.094 mmol) and methanolic ammonia (7.0 M, 2.0 mL, 14 mmol) was heated in a MW reactor at 120 °C for 20 min. Another equivalent of methanolic ammonia was added, followed by irradiation at 120 °C for an additional 20 min. The RM was evaporated and the residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:9:0.5) in DCM to give the title product (17 mg). LCMS (method 2): Rt=0.44 min, ES + m / z 410.1 / 412.1 [M+H] +

[0229] Intermediate 11o [ka]

[0230] N-(6-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxypyridin-3-yl)benzamide (Intermediate 11o) Intermediate 10c (95 mg, 0.33 mmol) was dissolved in pyridine (3.7 mL), then benzoyl chloride (38 μL, 0.33 mmol) was added, and the reaction was stirred at RT overnight. The RM was diluted with DCM (20 mL), extracted with 2 M aqueous citric acid (10 mL), and the aqueous layer was back-extracted with DCM (3 × 20 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and the solvent was evaporated under reduced pressure. The residue was combined with toluene and evaporated under reduced pressure to give the crude material, which was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NHOH in DCM (90:9:1.5) to give the title product (82 mg). LCMS (method 2): Rt=1.01 min, ES +m / z 394.1 / 396.1 [M+H] +

[0231] Intermediate 11p [ka]

[0232] 1-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)-3-methylurea (Intermediate 11p) Intermediate 10a (150 mg, 0.52 mmol) and TEA (145 μL, 1 mmol) were dissolved in DCM (5 mL) and cooled in an ice bath, after which methylaminoformyl chloride (53 mg, 0.57 mmol) was added. The RM was stirred at RT overnight. An additional amount of TEA (50 μL) and methylaminoformyl chloride (25 mg) was added, and stirring was continued for another 48 h. The RM was diluted with DCM (4 mL) and washed with saturated aqueous NaHCO3 (8 mL), aqueous 0.1 M HCl (5 mL), and saturated aqueous NaCl (8 mL). The organic layer was evaporated under reduced pressure, and the resulting crude was triturated in DCM to give the title product (38 mg). LCMS (method 2): Rt=0.81 min, ES + m / z 346.1 / 348.1 [M+H] +

[0233] Intermediate 12a [ka]

[0234] 6-chloro-3-iodo-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine A suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (5.38 g, 19.3 mmol), 1-fluoro-2-methoxy-4-nitrobenzene (3.3 g, 19.3 mmol), and KCO (8.0 g, 57.8 mmol) in DMF (40 mL) was stirred at 65 °C for 3 h. The RM was cooled to RT and diluted with water (300 mL). The precipitate that formed was filtered, washed with water (4 × 100 mL), and dried overnight. Trituration in MeOH gave the title product (7.34 g). LCMS (method 2): Rt=1.24 min, ES + m / z 430.8 / 432.8 [M+H] +

[0235] Preparation of Intermediates 12b to 12f The following compounds were prepared in a similar manner to intermediate 12a by substituting 1-fluoro-2-methoxy-4-nitrobenzene for the starting material indicated. Where minor modifications to base, solvent, temperature and / or reaction time were made, they are detailed below in parentheses.

[0236] [Table 31]

[0237] Intermediate 13a [ka]

[0238] tert-Butyl (3-((6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)propyl)carbamate (Intermediate 13a) Intermediate 12a (200 mg, 0.464 mmol), proline (16 mg, 0.139 mmol), and KCO (385 mg, 2.79 mmol) were dissolved in DMSO (1.8 mL) and degassed by bubbling nitrogen through the solution. tert-Butyl N-(3-aminopropyl)carbamate (0.998 mL, 1.93 mmol) and copper(I) iodide (8.85 mg, 0.0464 mmol) were then added. The RM was heated under argon at 70 °C for 22 h, then cooled to RT, quenched with water (20 mL), and extracted with DCM (3 × 20 mL). The organic layers were combined, washed with aqueous NH3 (1 M, 20 mL) and saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give the product (505 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.24 min, ES + m / z=477.17 / 479.08 [M+H] +

[0239] Intermediate 13b Process 1 [ka]

[0240] 6-chloro-N-(2,4-dimethoxybenzyl)-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 13b-1) Intermediate 13b-1 was prepared in a similar manner to intermediate 13a, starting from intermediate 12a and (2,4-dimethoxyphenyl)methanamine. LCMS (method 2): Rt=1.31 min, ES + m / z=470.2 / 472.1 [M+H] +

[0241] Process 2 [ka]

[0242] tert-Butyl (6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)(2,4-dimethoxybenzyl)carbamate (Intermediate 13b) A solution of intermediate 13b-1 (320 mg, 0.681 mmol) in THF (8.8 mL) was cooled to 0 °C and purged with argon, then LiHMDS (1.3 M in THF, 1.05 mL, 1.36 mmol) was added under argon and the RM was stirred for 5 min, after which a solution of BocO (297 mg, 1.36 mmol) in THF (4 mL) was added dropwise. The RM was stirred at RT for 30 min, then quenched with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with saturated aqueous NaCl, dried, and concentrated to give the desired compound (400 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.47 min, ES + m / z 570.2 / 572.2 [M+H] +

[0243] Intermediate 13c [ka]

[0244] N1-(6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N3,N3-dimethylpropane-1,3-diamine (Intermediate 13c) The title compound was prepared in a similar manner to intermediate 13a, starting from intermediate 12a and N1,N1-dimethylpropane-1,3-diamine. LCMS (method 2): Rt=1.16, ES + m / z 405.2 / 407.2 [M+H] +

[0245] Intermediate 13d [ka]

[0246] N1-(6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate 13d) The title compound was prepared in a similar manner to intermediate 13a, starting from intermediate 12a and N1,N1-dimethylethane-1,2-diamine. LCMS (method 2): Rt=1.14, ES + m / z 391.2 / 393.2 [M+H] +

[0247] Intermediate 14a [ka]

[0248] tert-Butyl (3-((1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)propyl)carbamate (Intermediate 14a) Ammonium formate (61 mg, 0.96 mmol) and 3% Pt / C on sulfurized activated carbon (6.3 mg, 0.032 mmol) were added to a mixture of Intermediate 13a (153 mg, 0.32 mmol) in EtOH (2 mL), and the RM was then stirred at 65° C. for 16 h. Another equivalent of ammonium formate and 3% Pt / C on sulfurized activated carbon was added, and the RM was stirred at 80° C. for an additional 16 h. The RM was cooled to RT, filtered through a pad of Celite®, washed with EtOAc (50 mL), and evaporated to dryness to give the title product (70.1 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.00 min, ES + m / z=447.2 / 449.2 [M+H] +

[0249] Intermediate 14b [ka]

[0250] tert-Butyl (1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)(2,4-dimethoxybenzyl)carbamate (Intermediate 14b) To a solution of intermediate 13b (340 mg, 0.596 mmol) in a mixture of acetic acid (3 mL) and MeOH (7 mL), Zn (390 mg, 5.96 mmol) was added in one portion, and the RM was stirred at RT for 1 h. The RM was concentrated and redissolved in DCM (100 mL) and saturated aqueous NaHCO (50 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO (2 × 5 mL), saturated aqueous NaCl (1 × 10 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–50% EtOAc in cyclohexane to give the title product (160 mg). LCMS (Method 2): Rt=1.29 min, ES + m / z 540.3 / 542.2 [M+H] +

[0251] Intermediate 14c [ka]

[0252] N1-(1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N3,N3-dimethylpropane-1,3-diamine (Intermediate 14c) The title compound was prepared in a similar manner to intermediate 14a, starting from intermediate 13c. LCMS (method 2): Rt=0.89 min, ES + m / z 375.2 / 377.2 [M+H] +

[0253] Intermediate 15a [ka]

[0254] 4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyaniline (Intermediate 15a) Intermediate 12a (2.60 g, 6.04 mmol) in EtOH (30 mL) was heated at 80 °C, and a solution of ammonium chloride (1.29 g, 24.2 mmol) in water (8 mL) was added, followed by iron (4.05 g, 72.5 mmol). The RM was stirred for 2.5 h, cooled to RT, diluted with EtOAc, and filtered (the filtrate was washed thoroughly with EtOAc). The combined filtrates were evaporated, dissolved in EtOAc, washed with water, saturated aqueous NaCl, dried over NaSO, and the solvent was evaporated to dryness. The crude material was triturated with DCM / MeOH, and the solid was then filtered and dried to give the title product (688 mg). LCMS (method 2): Rt=1.07 min, ES + m / z 401.0 / 402.9 [M+H] +

[0255] Preparation of Intermediates 15b to 15c The following compounds were prepared using procedures similar to those used to prepare intermediate 15a, starting from the starting materials indicated.

[0256] [Table 32]

[0257] Intermediate 16a [ka]

[0258] N-(4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate 16a) A mixture of intermediate 15a (700 mg, 1.6 mmol) and DCM (14 mL) was cooled to 0 °C, and pyridine (145 μL, 1.8 mmol) was added, followed by methanesulfonyl chloride (138 μL, 1.8 mmol). The RM was stirred at RT for 16 h, then quenched with water (10 mL), the pH adjusted to 8, and then extracted with DCM (4 × 10 mL). The organic layers were combined, dried over NaSO, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–50% MeOH / DCM (1:20) in DCM to give the title product (420 mg). LCMS (method 2): Rt=0.64 min, ES + m / z 479.0 / 481.0 [M+H] +

[0259] Preparation of Intermediates 16b to 16f The following compounds were prepared using procedures similar to those used to prepare intermediate 16a, starting from the starting materials indicated.

[0260] [Table 33]

[0261] Preparation of Intermediates 17a to 17c The following compounds were prepared using procedures similar to those used to prepare intermediate 11a, starting from the starting materials indicated.

[0262] [Table 34]

[0263] Preparation of intermediates 17d to 17z The following intermediates were prepared from the indicated starting materials using procedures similar to those used to prepare intermediate 13a. Where minor modifications were made to the base, solvent, and / or temperature and / or copper source / ligand, they are detailed below in parentheses.

[0264] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40]

[0265] Intermediate 17ab Process 1 [ka]

[0266] tert-Butyl (2-((6-chloro-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)ethyl)(methyl)carbamate (Intermediate 17ab-1) Intermediate 17ab-1 was prepared starting from intermediate 16a and tert-butyl (2-aminoethyl)(methyl)carbamate using a procedure similar to that used to prepare intermediate 13a (reaction temperature: 100°C, reaction solvent of DCM was replaced with DMF). LCMS (method 2): Rt=0.68 min, ES + m / z 525.3 / 527.2 [M+H] +

[0267] Process 2 [ka]

[0268] N-(4-(6-chloro-3-((2-(methylamino)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate 17ab-2) To a solution of intermediate 17ab-1 (103 mg, 0.20 mmol) in DCM (1.5 mL) was added TFA (0.437 mL, 5.89 mmol) dropwise. The RM was stirred at RT for 1 h and then evaporated to dryness under reduced pressure. The residue was dissolved in DCM (10 mL), washed with saturated aqueous NaHCO3 (3 x 10 mL), and evaporated to dryness. The crude product was diluted with methanol, aqueous 6 M HCl was added, and stirred at RT for 2 h. The RM was partitioned between water (10 mL) / EtOAc (5 mL), and the pH was adjusted to 8. The aqueous layer was further extracted with EtOAc (4 x 5 mL), and the organic layers were combined, washed with saturated aqueous NaCl (2 x 15 mL), and then evaporated to dryness. The residue was chromatographed on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (35 mg). LCMS (method 2): Rt=0.48 min, ES + m / z 425.2 / 427.2 [M+H] +

[0269] Process 3 [ka]

[0270] N-(4-(6-chloro-3-((2-((2-fluoroethyl)(methyl)amino)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate 17ab-3) Intermediate 17ab-a (32 mg, 0.08 mmol), 1-bromo-2-fluoroethane (5.61 μL, 0.08 mmol), and DIPEA (78.7 μL, 0.45 mmol) in acetonitrile (1.2 mL) were stirred at RT for 1 h and then heated at 50° C. for 3 h. Half an equivalent of 1-bromo-2-fluoroethane was added and stirring continued at 50° C. overnight. The RM was evaporated and the residue was purified by flash chromatography on a Si cartridge eluting with 0-80% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (29 mg). LCMS (method 2): Rt=0.53 min, ES + m / z 471.2 / 473.2 [M+H] +

[0271] intermediate 17ac [ka]

[0272] N-(4-(3-amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate 17ac) To intermediate 17b (129 mg, 0.209 mmol) in DCM (5 mL) was added TFA (0.975 mL, 13.1 mmol) and stirred at RT for 1 h. The RM was evaporated under reduced pressure, and the residue was partitioned between DCM and saturated aqueous NaHCO. The organic layer was dried over NaSO and evaporated to dryness to give the desired product (77 mg), which was used in the next step without further purification. LCMS (method 2): Rt=0.42 min, ES + m / z 368.0 / 369.9 [M+H] +

[0273] intermediate 17ad [ka]

[0274] tert-Butyl (2-((6-chloro-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (Intermediate 17ad) A suspension of BOC-sarcosine (37.5 mg, 0.2 mmol) and EEDQ (49.0 mg, 0.2 mmol) in DCE (1 mL) was stirred at RT for 10 min, then a solution of intermediate 17ac (35.0 mg, 0.1 mmol) in DCE (2 mL) was added, and the RM was stirred at 80 °C overnight. After cooling to RT, the RM was diluted with DCM and washed with saturated aqueous NaHCO (2 × 5 mL). Evaporation of the organic layer gave the crude product, which was purified by flash chromatography on a Si cartridge eluting with 0–80% MeOH / DCM (1:10) in DCM to give the title product (25 mg). LCMS (Method 2): Rt 0.62 min, ES + m / z=539.1 / 541.0 [M+H] +

[0275] intermediate 17ae [ka]

[0276] N-(6-chloro-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylpiperidine-4-carboxamide (Intermediate 17ae) Intermediate 17ac (213 mg, 0.58 mmol) was suspended in dry DCM (50 mL), followed by the addition of TEA (0.48 mL, 3.47 mmol), and the RM was cooled to 0 °C. 1-Methylpiperidine-4-carbonyl chloride hydrochloride (172 mg, 0.87 mmol) was added, and the RM was stirred at RT overnight. An additional equivalent of 1-methylpiperidine-4-carbonyl chloride hydrochloride was added, and stirring was continued for another 3 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. The residue was dissolved in DCM / MeOH / concentrated aq. NH3 9 / 1 / 0.15 (50 mL), pyridine was added, and the mixture was stirred overnight. The RM was concentrated and purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title compound (175 mg). LCMS (Method 1): Rt=0.61 min, ES + m / z 493.2 / 495.0 [M+H] +

[0277] Intermediate 17af [ka]

[0278] N-(6-chloro-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylpyrrolidine-3-carboxamide (Intermediate 17af) 1-Methylpyrrolidine-3-carboxylic acid (80 mg, 0.62 mmol) was suspended in SOCl (1 mL) and stirred at RT for 2 h. The RM was then evaporated under reduced pressure. The residue was dissolved in dry THF (0.5 mL), cooled to 0 °C, and a suspension of intermediate 17ac (120 mg, 0.33 mmol) in THF (2 mL) / TEA (0.16 mL, 1.14 mmol) was added. The RM was stirred at RT overnight, quenched with saturated aqueous NaHCO (30 mL), and extracted with DCM (5 × 30 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and evaporated to dryness. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:9:1.5) in DCM to give the title compound (28 mg). LCMS (Method 1): Rt=0.61 min, ES + m / z 479.1 / 481.1 [M+H] +

[0279] Intermediate 18a [ka]

[0280] 6-Chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 18a) To a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (500 mg, 2.53 mmol) in dry DMF (7.5 mL) under an argon atmosphere, DBU (1.96 mL, 15.2 mmol) was added, followed by 1-fluoro-2-methoxy-4-nitrobenzene (520 mg, 3.94 mmol). The RM was stirred in a MW reactor at 65 °C for 45 min. Two identical batches of RM obtained above were combined and quenched with aqueous 1 N HCl (30 mL). The precipitate formed was filtered, washed with water, dried, and triturated with diethyl ether to give the title product (1.02 g). LCMS (method 1): Rt=0.95 min, ES +m / z 349.0 / 349.9 [M+H] +

[0281] Intermediate 18b [ka]

[0282] Ethyl 6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 18b) Intermediate 18a (1.04 g, 2.98 mmol), HBTU (2.82 g, 7.46 mmol), and DMAP (36.4 mg, 0.3 mmol) were dissolved in dry DCM (65 mL). DIPEA (2.6 mL, 14.9 mmol) and ethanol (556 mL, 8.95 mmol) were then added, and the RM was stirred at RT for 2 h. The solvent was removed under reduced pressure, and the residue was reconstituted with EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO (3 × 50 mL) and saturated aqueous NaCl (50 mL), and the organic layer was dried over NaSO. After removing the solvent under reduced pressure, the crude material was chromatographed on a Si cartridge eluting with 0–10% EtOAc in DCM to give the title product (748 mg). LCMS (method 1): Rt=1.20 min, ES + m / z 377.0 / 379.0 [M+H] +

[0283] Intermediate 18c [ka]

[0284] Methyl 6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 18c) To a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (250 mg, 1.27 mmol) in dry DMF (10 mL) under nitrogen, DBU (568 μL, 3.8 mmol) was added, followed by 1-fluoro-2-methoxy-4-nitrobenzene (260 mg, 1.52 mmol). The RM was stirred under MW irradiation at 60°C for 1 h, then another half equivalent of DBU was added, followed by another irradiation cycle at 60°C for 30 min. After cooling to RT, the RM was treated with methyl iodide (237 μL, 3.80 mmol) at RT overnight and 60°C for 30 min. The RM was quenched with water, and the formed precipitate was filtered, washed with water, and dried at 45°C overnight to give the title product (605 mg). LCMS (Method 1): Rt=1.13 min, ES + m / z 363.0 / 365.1 [M+H] +

[0285] Intermediate 19 [ka]

[0286] 6-Chloro-N-(3-(dimethylamino)propyl)-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 19) Intermediate 18a (100 mg, 0.29 mmol) was dissolved in dry DMF (2 mL), followed by the sequential addition of N',N'-dimethylpropane-1,3-diamine (43 μL, 0.36 mmol), DIPEA (100 μL, 0.57 mmol), and HATU (120 mg, 0.32 mmol). The RM was stirred at RT for 1 h, diluted with EtOAc (20 mL), and washed with saturated aqueous NaHCO (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was dried over NaSO, and the solvent was removed under reduced pressure to give the title product (136 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.08 min, ES +m / z 433.1 / 435.1 [M+H] +

[0287] Intermediate 20 [ka]

[0288] 1-(4-amino-2-methoxyphenyl)-6-chloro-N-(3-(dimethylamino)propyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 20) A suspension of intermediate 19 (134 mg, 0.31 mmol) and iron (52 mg, 0.92 mmol) in acetic acid (2 mL) was stirred at 70 °C for 30 min. The RM was cooled to RT, diluted with methanol, and loaded onto an SCX column. After washing with methanol, the product was eluted with methanolic ammonia. The fractions were pooled and evaporated under reduced pressure to give the desired product (96 mg), which was used in the next step without further purification. LCMS (method 2): Rt=0.90 min, ES + m / z 403.2 / 405.1 [M+H] +

[0289] Intermediate 21a [ka]

[0290] Ethyl 1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21a) A suspension of intermediate 18b (748 mg, 1.99 mmol) and iron (333 mg, 5.96 mmol) in acetic acid (12 mL) was stirred at 70 °C for 2 h. The RM was cooled to RT, neutralized with cold saturated aqueous NaHCO and extracted with DCM (5 × 25 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure to give the title compound (676 mg), which was used further purified in the next synthetic step. LCMS (Method 1): Rt=1.02 min, ES + m / z 347.0 / 349.0 [M+H] +

[0291] Intermediate 21b [ka]

[0292] Methyl 1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21b) Intermediate 18c (605 mg, 1.7 mmol) was heated at 80 °C in a mixture of ethanol (15 mL) and water (5 mL), followed by the addition of ammonium chloride (177 mg, 3.3 mmol) and iron (559 mg, 10 mmol). After 1 h at 80 °C, the RM was cooled to RT, diluted with EtOAc, and filtered (the filtered solid was washed thoroughly with EtOAc). The AcOEt fractions were collected and evaporated to dryness to give the desired product (375 mg), which was used in the next step without further purification. LCMS (method 1): Rt=0.94 min, ES + m / z 333.1 / 335.1 [M+H] +

[0293] Intermediate 22a [ka]

[0294] Ethyl 6-chloro-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 22a) Intermediate 22a was prepared in a similar manner to intermediate 11a, starting from intermediate 21a and methanesulfonyl chloride. LCMS (method 2): Rt=0.58 min, ES + m / z 425.2 / 427.0 [M+H] +

[0295] Intermediate 22b [ka]

[0296] Methyl 6-chloro-1-(2-methoxy-4-(propylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 22b) Intermediate 22b was prepared in a similar manner to intermediate 11a, starting from intermediate 21b and propanesulfonyl chloride. LCMS (method 1): Rt=1.07 min, ES + m / z 439.1 / 441.0 [M+H] +

[0297] Intermediate 23a [ka]

[0298] 6-Chloro-N-(3-(dimethylamino)propyl)-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 23a) Intermediate 23a was prepared in a similar manner to intermediate 16a, starting from intermediate 20 and methanesulfonyl chloride. LCMS (method 2): Rt=0.55 min, ES + m / z 481.2 / 483.1 [M+H] +

[0299] Intermediate 23b [ka]

[0300] 6-Chloro-N-(2-(dimethylamino)ethyl)-1-(2-methoxy-4-(methylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 23b) A mixture of intermediate 22a (100 mg, 0.24 mmol) and DABAL-Me3 (91 mg, 0.35 mmol) in THF (3 mL) was heated in a MW reactor at 130 °C for 10 min, followed by the addition of N',N'-dimethylethane-1,2-diamine (39 μL; 0.35 mmol). After cooling to RT, the RM was quenched with 4 M HCl and neutralized with methanolic ammonia (7 M). The mixture was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-80% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (83 mg). LCMS (method 2): Rt=0.50 min, ES + m / z 467.1 / 469.1 [M+H] +

[0301] Preparation of Intermediates 23c to 23e The following intermediates were prepared from the indicated starting materials using procedures similar to those used to prepare intermediate 23b.

[0302] [Table 41]

[0303] Preparation of Intermediates 24a-c The following intermediates were prepared from the indicated starting materials using procedures similar to those used to prepare intermediate 13a. Where minor modifications were made to the base, solvent, and / or temperature and / or copper source / ligand, they are detailed below in brackets.

[0304] [Table 42]

[0305] Intermediate 25a [ka]

[0306] N-(4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (Intermediate 25a) Intermediate 12e (1 g, 2.42 mmol) was mixed in DCM (20 mL), followed by the addition of (2,4-dimethoxyphenyl)methanamine (524 μL, 3.49 mmol) and acetic acid (692 μL, 12.1 mmol) and refluxed overnight. The RM was cooled to RT, and sodium triacetoxyborohydride (2.06 g, 9.74 mmol) was added portionwise, followed by stirring at RT for 3 h. The RM was partitioned between DCM (20 mL) and saturated aqueous NaHCO. The aqueous layer was further extracted with DCM (2 × 10 mL), and the organic layers were combined and concentrated under reduced pressure. The residue was chromatographed on a Si cartridge eluting with 0–100% EtOAc in DCM to give the title compound (1.26 g). LCMS (method 2): Rt=1.35 min, ES + m / z=565.0 / 566.9 [M+H] +

[0307] Intermediate 25b [ka] N-(2-chloro-4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (Intermediate 25b) Intermediate 25b was prepared in a similar manner to intermediate 25a, starting from intermediate 12f. LCMS (method 2): Rt=1.16 min, ES + m / z=599.2 [M+H] +

[0308] Intermediate 26a [ka]

[0309] N-(4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (Intermediate 26a) Intermediate 25a (250 mg, 0.44 mmol) was dissolved in dry DCM (4 mL), followed by the addition of methanesulfonyl chloride (41 μL, 0.53 mmol) and TEA (185 μL, 1.3 mmol). The RM was stirred at RT for 4 h, then 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, filtered, and evaporated to dryness to give the desired product (262 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.35 min, ES + m / z=643.0 / 645.0 [M+H] +

[0310] Intermediate 26b [ka]

[0311] N-(2-chloro-4-(6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxybenzyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (Intermediate 26b) Intermediate 26b was prepared in the same manner as intermediate 26a, starting from intermediate 25b. LCMS (Method 2): Rt=1.43 min, ES + m / z=677.2 / 679.2 / 681.2 [M+H] +

[0312] Preparation of Intermediates 27a to 27f The following intermediates were prepared from the indicated starting materials using procedures similar to those used to prepare intermediate 13a. Where minor modifications were made to the base, solvent, and / or temperature and / or copper source / ligand, they are detailed below in brackets.

[0313] [Table 43] [Table 44]

[0314] Intermediate 28 Process 1 [ka]

[0315] 6-chloro-1-(4-((N-(2,4-dimethoxybenzyl)methylsulfonamido)methyl)-2-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 28-1) An oven-dried reaction tube was charged with Pd(OAc) (1.4 mg, 6 μmol), Xantphos (3.5 mg, 6 μmol), and DMF (1 mL) under argon. Formic acid (53.4 μL, 1.42 mmol) and Intermediate 26a (130 mg, 0.202 mmol) were added, followed by DCC (83.4 mg, 0.404 mmol) and TEA (56.4 μL, 0.404 mmol). The reaction tube was sealed and the RM was stirred at 60 °C for 3 h, then cooled to RT and filtered. The filtrate was added with water, the pH adjusted to 10 with aqueous 1 M NaOH, and washed with DCM (3 × 10 mL). The aqueous layer was neutralized to pH 3.5 with aqueous 1 M HCl and extracted with EtOAc (2 × 10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), passed through a phase separator and the solvent was evaporated to give the crude product which was purified by flash chromatography on a Si cartridge eluting with 0-20% DCM / MeOH / formic acid in DCM (90:10:0.3) to give the title product (59 mg). LCMS (method 2): Rt=0.70 min, ES + m / z 561.1 / 563.1 [M+H] +

[0316] Process 2 [ka]

[0317] 6-Chloro-1-(4-((N-(2,4-dimethoxybenzyl)methylsulfonamido)methyl)-2-methoxyphenyl)-N-(3-(dimethylamino)propyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 28) Intermediate 28-1 (57.0 mg, 0.102 mmol), N',N'-dimethylpropane-1,3-diamine (16.7 μL, 0.132 mmol), and DIPEA (35.4 μL, 0.203 mmol) were dissolved in dry DMF (1 mL). HATU (42.5 mg, 0.112 mmol) was then added, and the RM was stirred at RT for 30 min. The RM was diluted with EtOAc (15 mL), washed with saturated aqueous NaHCO (3 × 10 mL) and saturated aqueous NaCl (10 mL), dried over NaSO, and concentrated in vacuo to give the title product (63 mg), which was used in the next step without further purification. LCMS (method 2): Rt=1.17 min, ES + m / z 644.9 / 646.8 [M+H] +

[0318] Intermediate 29 Process 1 [ka]

[0319] N-(4-(6-chloro-3-(isoxazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (Intermediate 29-1) A mixture of intermediate 26a (1.2 g, 2.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (622 mg, 3.19 mmol), Pd(dppf)Cl. CHCl (260 mg, 0.319 mmol), and NaCO (450 mg, 4.25 mmol) in 1,4-dioxane (14 mL) / water (7 mL) was purged with argon. The RM was stirred at 60 °C for 1 h, then diluted with EtOAc and washed with water (3 × 20 mL) and saturated aqueous NaCl (15 mL). The organic layer was passed through a phase separator and the solvent evaporated in vacuo to give the crude product, which was chromatographed on a Si cartridge eluting with 0–20% DCM / MeOH (9:1) in DCM to give the title compound (680 mg). LCMS (method 2): Rt=1.22 min, ES + m / z 506.2 [M+H] +

[0320] Process 2 [ka]

[0321] 2-(6-chloro-1-(4-(((2,4-dimethoxybenzyl)amino)methyl)-2-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetonitrile (Intermediate 29-2) Intermediate 29-1 (680 mg, 1.34 mmol) was dissolved in a mixture (12 mL) of DMF / water (2:1), KF (234 mg, 4.03 mmol) was added, and the RM was stirred at 120 °C overnight. The RM was diluted with EtOAc (25 mL) and then washed with saturated aqueous NaHCO (3 × 20 mL) and saturated aqueous NaCl (20 mL). The organic extract was dried over NaSO and concentrated in vacuo to give the crude product, which was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH in DCM (9:1) to give the title product (276 mg). LCMS (method 2): Rt=1.12 min, ES + m / z 478.2 / 480.2 [M+H] +

[0322] Process 3 [ka]

[0323] N-(4-(6-chloro-3-(cyanomethyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide Intermediate 29 was prepared in the same manner as Intermediate 11a, starting from Intermediate 29-2. LCMS (method 2): Rt=1.10 min, ES +m / z 556.1 / 558.1 [M+H] +

[0324] Intermediate 30a [ka]

[0325] 3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzaldehyde (Intermediate 30a) A round-bottom flask was charged (under nitrogen) with intermediate 9i (1.4 g, 4.4 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (1.62 g, 6.6 mmol), KPO (1.88 g, 8.8 mmol), and XPhos Pd G (187 mg, 0.22 mmol), and pre-degassed water (17 mL) and THF (35 mL) were added. The RM was stirred at 70 °C for 90 min, then water (10 mL) was added, and the mixture was stirred at 25 °C for 10 min. The RM was filtered, and the precipitate was collected, washed with water (3 × 2 mL), and dried to give the title product (1.73 g). LCMS (method 2): Rt=0.96 min, ES + m / z 385.3 [M+H] +

[0326] Intermediate 31 [ka]

[0327] N-(2,4-Dimethoxybenzyl)-1-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanamine (Intermediate 31) Intermediate 31 was prepared in the same manner as intermediate 25a, starting from intermediate 30a. LCMS (method 2): Rt=1.12 min, ES +m / z 536.4 [M+H] +

[0328] Intermediate 32a [ka]

[0329] N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-(difluoromethoxy)benzyl)-1-(2,4-dimethoxyphenyl)methanamine (Intermediate 32a) Intermediate 32a was prepared in a similar manner to intermediate 25a, starting from INT 9g. LCMS (Method 1): Rt=0.86 min, ES + m / z 489.1 / 491.1 [M+H] +

[0330] Intermediate 32b [ka]

[0331] 1-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)-N-(2,4-dimethoxybenzyl)ethan-1-amine (Intermediate 32b) A mixture of intermediate 9h (230 mg, 0.728 mmol) and 1,2-dichloroethane (5.0 mL) was cooled to 0 °C, and (2,4-dimethoxyphenyl)methanamine (164 μL, 1.09 mmol), TEA (122 μL, 0.874 mmol), and titanium(IV) isopropoxide (269 mg, 0.947 mmol) were added. The RM was heated at 45 °C for 2.5 h, then cooled to 0 °C, after which sodium triacetoxyborohydride (509 mg, 2.40 mmol) was added. The RM was heated at 45 °C for 12 h. After cooling to RT, the RM was quenched with saturated aqueous NaCl (10 mL) and DCM (20 mL). The mixture was filtered, and the filtrate was extracted with DCM (3 × 20 mL). The organic layers were combined, dried over Na2SO4, concentrated in vacuo and the crude product was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH in DCM (90:9:0.5) to give the title product (180 mg). LCMS (Method 1): Rt=0.87 min, ES + m / z 466.9 [M+H] +

[0332] Preparation of Intermediates 33a and 33b The following intermediates were prepared in a similar manner to intermediate 11a from the starting materials indicated.

[0333] [Table 45]

[0334] Preparation of Examples Example 1 [ka]

[0335] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide (Example 1) A mixture of Intermediate 11a (115 mg, 0.31 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (85 mg, 0.34 mmol), KPO (133 mg, 0.63 mmol), and XPhos Pd G3 (13 mg) was charged into a sealed reaction tube under an argon atmosphere, followed by the addition of degassed water (1 mL) and THF (2 mL). The RM was stirred at 65 °C for 1.5 h. After cooling to RT, the reaction mixture was partitioned between water (1 mL) and DCM (2 mL), and the aqueous layer was further extracted with DCM (4 × 2 mL). The organic layers were combined, dried over NaSO, and evaporated to dryness. The crude material was purified by flash chromatography on a Si cartridge eluting with 0-80% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (80 mg). LCMS (Method 5): Rt=2.50 min, ES + m / z 450.2 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm): 10.12(s,1H), 9.22(dd,J=7.0, 1.5Hz,1H), 9.13(d,J=1.2Hz,1H), 8.88(s,1H), 8.72(dd,J=4.1, 1.7Hz,1H), 8.21(d,J= 0.9Hz,1H), 7.46(d,J=8.5Hz,1H), 7.12-7.17(m,2H), 6.99(dd,J=8.5, 2.4Hz,1H), 3.78(s,3H), 3.15-3.17(m,3H), 2.64(s,3H)

[0336] Preparation of Examples 2 to 52 The following examples were prepared in a manner similar to Example 1 from the indicated intermediates.

[0337] [Table 46] [Table 47] [Table 48] Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71]

[0338] Example 53 Process 1 [ka]

[0339] N-(2,4-Dimethoxybenzyl)-N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Intermediate Step 1 - Example 53) The title product was prepared analogously to Example 1 starting from intermediate 27a. LCMS (method 2): Rt=1.04 min, ES + m / z 728.3 [M+H] +

[0340] Process 2 [ka]

[0341] N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide TFA (610 μL, 7.97 mmol) was added to a cooled solution of Intermediate Step 1 - Example 53 (58.0 mg, 0.08 mmol) in dry DCM (4 mL). The RM was stirred at RT for 2 h, then loaded onto an SCX column, washed with MeOH, and eluted with methanolic ammonia (15 mL). Relevant fractions were pooled and evaporated in vacuo to give the title compound (41 mg). LCMS (Method 7): Rt=3.13 min, ES + m / z 578.2 [M+H] + 1 H-NMR (300MHz, DMSO-d6) δ(ppm) 9.19(dd,J=7.1, 1.7Hz,1H), 9.06(d,J=0.9Hz,1H), 8.84(s,1H), 8.67(dd,J=4.1, 1.7Hz,1H ), 8.08(d,J=0.9Hz,1H), 7.66(t,J=6.3Hz,1H), 7.44(d,J=8.0Hz,1H), 7.29(d,J=1.2Hz,1H ), 7.05-7.17(m,2H), 6.69(t,J=5.6Hz,1H), 4.27(d,J=6.3Hz,2H), 3.86(s,3H), 3.59(brt, J=4.53Hz,4H), 3.43(q,J=6.2Hz,2H), 2.93(s,3H), 2.62(t,J=6.8Hz,2H), 2.40-2.47(m,4H)

[0342] Examples 54 to 62 The following examples were prepared in a two-step process in a manner similar to Example 53 from the starting materials indicated.

[0343] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77] [Table 78] [Table 79]

[0344] Example 63 Process 1 [ka]

[0345] N-(2,4-Dimethoxybenzyl)-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Intermediate Step 1 - Example 63) Intermediate Step 1 - Example 63 was prepared in the same manner as Intermediate 26a, starting from Intermediate 31 and methanesulfonyl chloride. LCMS (method 1): Rt=0.91 min, ES + m / z 614.3 [M+H] +

[0346] Process 2 [ka]

[0347] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Example 63) Example 63 was prepared in the same manner as Example 53, starting from intermediate step 1 - Example 63. LCMS (Method 7): Rt=3.87 min, ES + m / z 464.2 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm) 9.21(dd,J=6.87, 1.37Hz,1H), 9.14(s,1H), 8.89(s,1H), 8.69(dd,J=3.97, 1.22Hz,1H), 8.22(s,1H), 7.71(brt,J=6.10Hz, 1H), 7.49(d,J=7.93Hz,1H), 7.35(s,1H), 7.10-7.19(m,2H), 4.31(d,J=6.10Hz,2H), 3.84(s,3H), 2.95(s,3H), 2.65(s,3H)

[0348] Example 64 Process 1 [ka]

[0349] N-(2,4-Dimethoxybenzyl)-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)cyclopropanesulfonamide (Intermediate Step 1 - Example 64) Intermediate Step 1 - Example 64 was prepared in the same manner as Intermediate 26a, starting from Intermediate 31 and cyclopropanesulfonyl chloride. LCMS (Method 1): Rt=0.97 min, ES + m / z 640.3 [M+H] +

[0350] Process 2 [ka]

[0351] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)cyclopropanesulfonamide (Example 64) Example 64 was prepared in the same manner as Example 53, starting from intermediate step 1 - Example 64. LCMS (Method 7): Rt=4.22 min, ES + m / z 490.2 [M+H] + 1 H-NMR (500MHz, DMSO-d6, 352K) δ(ppm), 9.10-9.16(m,2H), 8.86(s,1H), 8.62-8.68(m,1H), 8.21(s,1H), 7.52-7.58(m,1H), 7.47(d,J=7.7Hz,1H), 7.38(s,1H), 7.18(d ,J=7.9Hz,1H), 7.08-7.13(m,1H), 4.36(d,J=6.1Hz,2H), 3.85(s,3H), 2.66(s,3H), 2.53-2.57(m,1H, overlapped with DMSO signal), 0.90-1.02(m,4H)

[0352] Example 65 [ka]

[0353] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-N-methylmethanesulfonamide (Example 65) Iodomethane (7.45 μL, 0.012 mmol) was added to an ice-cooled suspension of Example 63 (56.0 mg, 0.11 mmol) and KCO (30.1 mg, 0.22 mmol) in DMF (2 mL). The RM was stirred at RT for 1.5 h and then partitioned between EtOAc and water. The organic layer was washed with water, saturated aqueous NaCl, dried over NaSO, and evaporated to dryness. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH (20:1) in DCM. LCMS (Method 7): Rt=4.24 min, ES + m / z 478.2 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm) 9.22(d,J=7.02Hz,1H), 9.14(s,1H), 8.89(s,1H), 8.70(brd,J=3.66Hz,1H), 8.25(s,1H), 7.53(d,J=8.24 Hz,1H), 7.29(s,1H), 7.11-7.17(m,2H), 4.39(s,2H), 3.85(s,3H), 3.03(s,3H), 2.79(s,3H), 2.65(s,3H)

[0354] Example 66 [ka]

[0355] (3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanol (Example 66) Intermediate 30a (40 mg, 0.103 mmol) was suspended in THF (0.5 mL) and cooled in an ice bath, after which NaBH (3.90 mg, 0.103 mmol) was added portionwise. The RM was stirred at RT for 2 h, then quenched with water (1 mL), stirred at RT for 5 min, and the formed precipitate was filtered, washed with water (2 × 2 mL), and dried to give the title product (37.4 mg). LCMS (Method 7): Rt=3.69 min, ES + m / z 387.1 [M+H] + 1 H-NMR (500MHz, DMSO-d3) δ / ppm:9.21(dd,J=7.0, 1.5Hz,1H), 9.14(s,1H), 8.89(s,1H), 8.70(dd,J=4.1,1.7Hz,1H), 8.22(s,1H), 7.45(d,J=7.9Hz,1H), 7.3 1(s,1H), 7.14(dd,J=7.0, 4.0Hz,1H), 7.11(d,J=7.9Hz,1H), 5.41(t,J=5.8Hz,1H), 4.64(d,J=5.8Hz,2H), 3.82(s,3H), 2.64(s,3H)

[0356] Example 67 [ka]

[0357] (3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanamine (Example 67) Intermediate 31 (285 mg, 0.30 mmol) was dissolved in TFA (2.9 mL) and heated in a microwave reactor at 120 °C for 30 min. The RM was quenched with saturated aqueous NaHCO (5 mL) / DCM (10 mL) and the pH was adjusted to 11. The organic layer was washed with saturated aqueous NaHCO (2 x 5 mL) and concentrated in vacuo. The residue was purified by flash chromatography on a Si cartridge eluting with 0-80% DCM / MeOH / NHOH in DCM (90:9:0.5) to give the title compound. LCMS (Method 8): RT=4.59 min, ES + m / z 386.2 [M+H] + 1H-NMR (600MHz, DMSO-d6) δ(ppm) 9.21(dd,J=6.9, 1.4Hz,1H), 9.13(s,1H), 8.89(s,1H), 8.67-8.70(m,1H), 8.21(s,1H), 7.41(d,J=7.9Hz,1 H), 7.36(s,1H), 7.15(dd,J=6.9, 4.1Hz,1H), 7.12(d,J=7.6Hz,1H), 3.86(s,2H), 3.82(s,3H), 2.64(s,3H)

[0358] Example 68 [ka]

[0359] 1-cyano-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide (Example 68) Example 67 (30 mg, 0.08 mmol) was suspended in DCM (0.5 mL), followed by the addition of cyanomethanesulfonyl chloride (8.0 μL, 0.09 mmol) and pyridine (18 μL, 0.23 mmol). The RM was stirred at RT for 1 h. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by flash chromatography on a Si cartridge, eluting with 0-100% DCM / MeOH / NHOH (90:9:0.5) in DCM to give the title compound (2.4 mg). LCMS (Method 7): Rt=4.22 min, ES + m / z 489.2 [M+H] + 1H-NMR (600MHz, DMSO-d6) δ(ppm) 9.22(d,J=7.0Hz,1H), 9.14(s,1H), 8.89(s,1H), 8.78(t,J=6.1Hz,1H), 8.68(d,J=4.0Hz,1H), 8.23(s,1H), 7.5 0(d,J=7.9Hz,1H), 7.36(s,1H), 7.12-7.17(m,2H), 4.84(s,2H), 4.41(d,J=6.1Hz,2H), 3.85(s,3H), 2.65(s,3H)

[0360] Example 69 Process 1 [ka]

[0361] Methyl (2,4-dimethoxybenzyl)(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)carbamate (Intermediate Step 1 - Example 69) Intermediate 31 (100 mg, 0.12 mmol) and TEA (65 μL, 0.46 mL) were dissolved in DCM (0.5 mL), followed by the dropwise addition of a cooled solution of methyl chloroformate (63 μL, 0.81 mmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 15 min and partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over NaSO, and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:9:0.5) in DCM to give the desired product (47.2 mg). LCMS (method 2): Rt=1.19, ES m / z 594.5 [M+H] +

[0362] Process 2 [ka]

[0363] Methyl (3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)carbamate (Example 69) Example 69 was prepared in a similar manner to Example 53, Step 2, starting from intermediate Step 1 - Example 69. LCMS (Method 7): Rt=4.07 min, ES + m / z 444.1 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm) 9.22(dd,J=7.0Hz,J=1.8Hz,1H), 9.14(d,J=0.9Hz,1H), 8.89(s,1H), 8.70( dd,J=4.0Hz,J=1.5Hz,1H), 8.21(d,J=1.2Hz,1H),7.82(t,J=5.8Hz,1H),7. 46(d,J=8.2Hz,1H), 7.25(s,1H), 7.15(dd,J=7.0Hz,J=4.0Hz,1H), 7.04(d, J=7.9Hz,1H), 4.33(d,J=6.4Hz,2H), 3.82(s,3H), 3.60(s,3H), 2.64(s,3H)

[0364] Example 70 Process 1 [ka]

[0365] N-(2,4-Dimethoxybenzyl)-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)acetamide (Intermediate Step 1 - Example 70) Intermediate 31 (100 mg, 0.12 mmol) and TEA (65 μL, 0.46 mL) were dissolved in DCM (0.5 mL) and added dropwise to a cold solution of acetic anhydride (77 μL, 0.81 mmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 15 min. The mixture was diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over NaSO, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:9:1.5) in DCM to give the title compound (61.2 mg). LCMS (method 2): Rt=1.07, ES m / z 578.5 [M+H] +

[0366] Process 2 [ka]

[0367] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)acetamide (Example 70) Example 70 was prepared in a similar manner to Example 53, step 2, starting from intermediate step 1 - Example 70. LCMS (Method 7): Rt=3.62 min, ES + m / z 428.2 [M+H] + 1H-NMR (600MHz, DMSO-d6) δ(ppm) 9.25(dd,J=7.2, 1.4Hz,1H), 9.23(brs,1H), 8.93(s,1H), 8.73(d,J=2.7Hz,1H), 8.48(brt,J=6.0Hz,1H), 8.24(s,1H), 7.47(d,J=7.9Hz, 1H), 7.26(s,1H), 7.19(dd,J=6.9, 4.1Hz,1H), 7.05(d,J=8.2Hz,1H), 4.40(d,J=5.8Hz,2H), 3.82(s,3H), 2.64-2.69(m,3H), 1.94(s,3H)

[0368] Example 71 [ka]

[0369] 1-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-3-methylurea (Example 71) Example 53 (26 mg, 0.062 mmol) and TEA (35 μL, 0.25 mmol) were dissolved in DCM (0.5 mL) and added dropwise to a cooled solution of methylaminoformyl chloride (5.8 mg, 0.062 mmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 15 min. The RM was concentrated under reduced pressure, and the residue 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 desired product (3.8 mg). LCMS (Method 7): Rt=3.62 min, ES + m / z 443.2 [M+H] + 1H-NMR (600MHz, DMSO-d6) δ(ppm) 9.21(d,J=6.7Hz,1H), 9.13(s,1H), 8.88(s,1H), 8.70(d,J=4.0Hz,1H), 8 .21(s,1H), 7.44(d,J=7.9Hz,1H), 7.24(s,1H), 7.14(dd,J=6.9, 4.1Hz,1 H), 7.03(d,J=7.9Hz,1H), 6.54(brt,J=5.8Hz,1H), 5.90(brd,J=4.3Hz,1H), 4.34(d,J=6.1Hz,2H), 3.81(s,3H), 2.64(s,3H), 2.61(d,J=4.9Hz,3H)

[0370] Example 72 [ka]

[0371] 1-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-3-phenylurea (Example 72) Example 53 (70.0 mg, 0.11 mmol) was dissolved in DCM / DMF (1 mL), followed by the addition of phenyl isocyanate (16.6 μL, 0.15 mmol). The RM was stirred at 50° C. for 1.5 h. The RM was diluted with water (20 mL) and extracted with DCM (3×10 mL). The organic layers were combined, passed through a phase separator, and evaporated to dryness. The residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH / NH4OH in DCM (90:9:0.5) to give the title product (21 mg). LCMS (Method 7): Rt=4.71 min, ES + m / z 505.2 [M+H] + 1H-NMR (500MHz, DMSO-d6) δ(ppm) 9.21(d,J=7.0Hz,1H), 9.14(s,1H), 8.88(s,1H), 8.65-8.69(m,1H), 8.64 (s,1H), 8.22(s,1H), 7.42-7.48(m,3H), 7.30(s,1H), 7.24(t,J=7.5Hz,2H ), 7.14(dd,J=6.6, 4.4Hz,1H), 7.10(d,J=7.9Hz,1H), 6.91(t,J=7.3Hz,1 H), 6.76(t,J=6.0Hz,1H), 4.45(d,J=5.8Hz,2H), 3.83(s,3H), 2.64(s,3H)

[0372] Example 73 [ka]

[0373] 2,2-Difluoro-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)ethane-1-sulfonamide (Example 73) To a suspension of Example 17 (30 mg, 0.08 mmol) in dry DCM (1 mL) was added 2,2-difluoroethanesulfonyl chloride (10 μL, 0.10 mmol) and pyridine (20 μL, 0.24 mmol). The RM was stirred at RT for 1 h. The solvent was evaporated. The residue was dissolved in EtOAc (15 mL) and washed with water (1 × 10 mL) and 2 M aqueous citric acid (2 × 10 mL). The organic extract was dried over NaSO and concentrated in vacuo to give the crude product, which was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / CAN / MeOH in DCM (10:10:2) to give the title product (11 mg). LCMS (Method 5): Rt=2.91 min, ES + m / z 500.1 [M+H] + 1H-NMR (300MHz, DMSO-d6) δ(ppm): 10.58(s,1H), 9.18-9.33(m,2H), 8.93(s,1H), 8.69-8.77(m,1H), 8.24(s,1H), 7.49(d,J=8.5Hz,1H), 7.20(dd,J=7.0, 4.2Hz,1H) , 7.14(d,J=1.7Hz,1H), 6.99(dd,J=8.5, 1.7Hz,1H), 6.43(tt,J=54.3, 4.5Hz,1H), 4.11(td,J=14.8, 4.3Hz,2H), 3.79(s,3H), 2.66(s,3H)

[0374] Example 74 [ka]

[0375] N-(3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)benzamide (Example 74) Example 17 (33 mg, 0.09 mmol) was dissolved in pyridine (1.0 mL), followed by the addition of benzoyl chloride (10 μL, 0.09 mmol). The RM was stirred at RT for 48 h. An additional amount of benzoyl chloride (3 μL) was added, and stirring was continued at RT for 30 min. The precipitate that formed was filtered, washed with 2 M aqueous citric acid (4 × 5 mL), water (10 mL), and dried at 45 °C for 2 h to give the title compound (10.8 mg). LCMS (Method 5): Rt=3.27 min, ES + m / z 476.2 [M+H] + 1H-NMR (500MHz, DMSO) δ(ppm) 10.55(s,1H), 9.27(d,J=6.7Hz,2H), 8.98(s,1H), 8.77(d,J=2.8Hz,1H), 8.3(s,1H), 8.02(s,1H), 8.01(d,J=1.5Hz,1H) , 7.94(d,J=1.8Hz,1H), 7.56-7.66(m,4H), 7.52(d,J=8.3Hz,1H), 7.21(dd,J=7.2, 3.5Hz,1H), 3.83(s,3H), 2.69(s,3H)

[0376] Example 75 Process 1 [ka]

[0377] tert-Butyl (6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)(2-(dimethylamino)ethyl)carbamate (Intermediate Step 1 - Example 75) Intermediate 13d (1.3 g, 3.33 mmol) in THF (0 mL) was cooled to 0 °C under nitrogen, followed by the dropwise addition of LiHMDS (1.3 M in THF, 5.1 mL, 6.65 mmol). The RM was stirred for 15 min, followed by the dropwise addition of a solution of BocO (1.45 g, 6.65 mmol) in THF (5 mL). The RM was allowed to reach RT, quenched with water (60 mL), and extracted with EtOAc (100 mL). The organic layer was washed with saturated aqueous NaCl (50 mL), dried over NaSO, and the solvent was removed under reduced pressure. The residue was purified to give the title product (1.4 g). LCMS (method 2): Rt=1.37 min, ES + m / z 491.2 / 493 [M+H] +

[0378] Process 2 [ka]

[0379] tert-Butyl (1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)(2-(dimethylamino)ethyl)carbamate (Intermediate Step 2 - Example 75) Intermediate Step 2 - Example 75 was prepared in the same manner as Intermediate 10a, starting from Intermediate Step 1 - Example 75. LCMS (method 2): Rt=1.16, ES + m / z 461.3 / 463.3 [M+H] +

[0380] Process 3 [ka]

[0381] tert-Butyl (1-(4-amino-2-methoxyphenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)(2-(dimethylamino)ethyl)carbamate (Intermediate Step 3 - Example 75) Intermediate Step 3 - Example 75 was prepared analogously to Example 1, starting from Intermediate Step 2 - Example 75. LCMS (method 2): Rt=1.04, ES + m / z 544.4 [M+H] +

[0382] Process 4 [ka]

[0383] tert-Butyl (1-(4-benzamido-2-methoxyphenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)(2-(dimethylamino)ethyl)carbamate (Intermediate Step 4 - Example 75) Intermediate Step 3-Example 75 was prepared in the same manner as Intermediate 11o, starting from Intermediate Step 3-Example 75 and benzoyl chloride. LCMS (method 1): Rt=0.79, ES + m / z 648.4 [M+H] +

[0384] Process 5 [ka]

[0385] N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)benzamide (Example 75) Intermediate Step 4—Example 75 (40 mg, 0.06 mmol) was dissolved in DCM (2 mL), then TFA (159 μL, 2.08 mmol) was added and the RM was stirred at RT overnight. The RM was diluted with DCM (8 mL) and washed with saturated aqueous NaHCO (2×10 mL) and saturated aqueous NaCl (10 mL). The organic layer was concentrated and the residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH OH (90:9:0.5) in DCM to give the desired product (20 mg). LCMS (Method 7): Rt=3.85 min, ES + m / z 548.4 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm) 10.47(s,1H), 9.20(dd,J=6.6, 1.5Hz,1H), 9.08(s,1H), 8.86(s,1H), 8.70(dd,J=4.1 , 1.3Hz,1H), 8.09(s,1H), 7.99-8.04(m,2H), 7.88(d,J=1.2Hz,1H), 7.60-7.65(m,1H) , 7.54-7.60(m,3H), 7.45(d,J=8.2Hz,1H), 7.14(dd,J=6.6, 3.9Hz,1H), 6.60-6.67(m, 1H), 3.86(s,3H), 3.40-3.47(m,2H, overlaps with HDO), 2.58-2.69(m,2H, overlaps with DMSO), 2.28(s,6H)

[0386] Example 76 [ka]

[0387] N-(4-(6-(imidazo[1,2-b]pyridazin-3-yl)-3-((2-morpholinoethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Example 76) A vial charged with intermediate 17e (65 mg, 0.14 mmol), Pd(PPh3)2Cl2 (9.9 mg, 0.014 mmol), and DMF (1.5 mL) was degassed under nitrogen for 15 minutes, and then intermediate 8 (110 mg, 0.27 mmol) was added. The vial was sealed, evacuated / backfilled with nitrogen twice, and stirred at 110 °C overnight. After cooling to RT, the RM was partitioned between EtOAc (15 mL) / water (10 mL), and the organic layer was washed with water (2 × 10 mL). The aqueous layers were combined, neutralized to pH 8, and extracted with EtOAc (3 × 15 mL). The organic layers were combined and evaporated under reduced pressure. The crude product was purified by flash chromatography on a Si cartridge eluting with 0-75% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title compound (41 mg). LCMS (Method 7): Rt=3.35 min, ES + m / z 564.12 [M+H] + 1H-NMR (400MHz, DMSO-d6) δ(ppm) 9.99(s,1H), 9.12(d,J=1.1Hz,1H), 8.73(dd,J=1.7, 4.5Hz,1H), 8.50(s,1H), 8.31(d, J=1.1Hz,1H), 8.26(dd,J=1.7, 9.2Hz,1H), 7.44(d,J=8.4Hz,1H), 7.35-7.29(m,1H), 7. 11(d,J=2.3Hz,1H), 6.95(dd,J=2.3, 8.5Hz,1H), 6.74(t,J=5.6Hz,1H), 3.83(s,3H), 3 .64-3.55(m,4H), 3.49-3.38(m,2H), 3.11(s,3H), 2.62(t,J=6.8Hz,2H), 2.45(brs,4H)

[0388] Example 77 [ka]

[0389] N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Example 77) Example 77 was prepared in a manner similar to Example 76, starting from Intermediate 17n and Intermediate 8. LCMS (Method 7): Rt=3.66 min, ES + m / z 522.2 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ(ppm): 9.15(d,J=0.9Hz,1H), 8.74(dd,J=1.4, 4.4Hz,1H), 8.51(s,1H), 8.3 2(s,1H), 8.29-8.22(m,2H), 7.45(d,J=8.5Hz,1H), 7.33(dd,J=4.6, 9.2Hz,1 H), 7.12(d,J=2.1Hz,1H), 6.96(dd,J=2.3, 8.4Hz,1H), 6.72(t,J=5.8Hz,1H) , 3.84(s,3H), 3.44-3.39(m,2H), 3.12(s,3H), 2.60-2.54(m,2H), 2.23(s,6H)

[0390] Example 78 Process 1 [ka]

[0391] tert-Butyl ((1s,3s)-3-((1-(4-(cyclopropanesulfonamido)-2-methoxyphenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)cyclobutyl)carbamate (Intermediate Step 1 - Example 78) Intermediate Step 1 - Example 78 was prepared in a similar manner to Example 1 starting from Intermediate 17v. LCMS (method 2): Rt=0.74, ES + m / z 646.5 [M+H] +

[0392] Process 2 [ka]

[0393] N-(4-(3-(((1s,3s)-3-aminocyclobutyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide (Intermediate Step 2 - Example 78) Intermediate Step 1—Example 78 (100 mg, 0.15 mmol) in 1,4-dioxane (1 mL) was added with a solution of HCl in dioxane (4.0 M, 194 μL, 0.77 mmol) and stirred at RT overnight. The precipitate that formed was filtered, washed with 1,4-dioxane, and dried to give the desired product (55 mg), which was further purified and used in the next step. LCMS (method 2): Rt=0.54 min, ES + m / z 546.3 [M+H] +

[0394] Process 3 [ka]

[0395] N-(4-(3-(((1s,3s)-3-(dimethylamino)cyclobutyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide (Example 78) A vial charged with Intermediate Step 2—Example 78 (30 mg, 0.06 mmol), formic acid (83 μL, 2.2 mmol), and formaldehyde (37% solution in water, 164 μL, 2.2 mmol) was stirred overnight at RT. An additional amount of formaldehyde (10 equiv.) was added, and stirring was continued for another 4 h. EtOAc (15 mL) was added, and the resulting solution was washed with saturated aqueous NaHCO (3×15 mL) and saturated aqueous NaCl (1×15 mL). The organic phase was evaporated under reduced pressure, and the residue was chromatographed on a Si cartridge eluting with 0-80% DCM / MeOH / NH OH in DCM (90:9:0.5) to give the title product (8 mg). LCMS (Method 7): Rt=3.46 min, ES + m / z 574.2 [M+H] + 1H-NMR (600MHz, DMSO-d6) δ(ppm) 9.99(s,1H), 9.21(dd,J=6.8, 1.6Hz,1H), 9.05(d,J=0.9Hz,1H), 8.85(s,1H), 8.72(dd,J=4. 0, 1.9Hz,1H), 8.07(d,J=0.7Hz,1H), 7.40(d,J=8.6Hz,1H), 7.11-7.14(m,2H), 6.97(dd,J=8. 5, 2.4Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 3.83-3.92 (m, 1H), 3.81 (s, 3H), 2.75-2.81 (m, 1H), 2.51 -2.56(m,2H,overlapping with DMSO), 2.33-2.39(m,1H), 2.06(s,6H), 1.74-1.83(m,2H), 0.99-1.05(m,4H)

[0396] Example 79 Process 1 [ka]

[0397] tert-Butyl (2,4-dimethoxybenzyl)(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (Intermediate Step 1 - Example 79) Intermediate Step 1 - Example 79 was prepared in a similar manner to Example 1 starting from Intermediate 17b. LCMS (method 2): Rt=0.80, ES + m / z 701.3 [M+H] +

[0398] Process 2 [ka]

[0399] N-(4-(3-amino-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Example 79) TFA (200 μL, 2.69 mmol) was added to a solution of Intermediate Step 1 - Example 79 (30.0 mg, 0.04 mmol) in DCM (10 mL), and the RM was stirred at RT for 1 h. The RM was dried under reduced pressure, and the residue was partitioned between EtOAc / saturated NaHCO. The organic layer was washed with saturated aqueous NaHCO (2×5 mL) and saturated aqueous NaCl (5 mL), dried, concentrated in vacuo, and triturated with DCM / MeOH to give the crude title product (8.5 mg). LCMS (method 3): Rt=0.83 min, ES + m / z 451.27 [M+H] + 1 H-NMR (DMSO-d6, 300MHz): δ(ppm) 9.98(s,1H), 9.19(dd,J=7.0, 1.7Hz,1H), 9.02(d,J=1.0Hz,1H), 8.84(s,1H), 8.70(dd,J=4.0, 1.7Hz,1H), 8.06(d,J=1.0Hz,1H), 7.39( d,J=8.5Hz,1H), 7.13(dd,J=7.1, 4.1Hz,1H), 7.09(d,J=2.3Hz,1H), 6.93(dd,J=8.5, 2.3Hz,1H), 6.06(s,2H), 3.80(s,3H), 3.11(s,3H)

[0400] Example 80 Process 1 [ka]

[0401] tert-Butyl (2-((1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (Intermediate Step 1 - Example 80) Example 80 was prepared in a similar manner to Example 1, starting from intermediate 17ad. LCMS (method 1): Rt=0.80 min, ES + m / z 622.3 [M+H]+

[0402] Process 2 [ka]

[0403] N-(1-(2-Methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(methylamino)acetamide (Example 80) Intermediate Step 1—Example 80 (8.00 mg, 0.01 mmol) was dissolved in DCM (3 mL), TFA (60 μL, 0.81 mmol) was added, and the RM was stirred at RT for 1 h. The RM was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 (2×5 mL) and saturated aqueous NaCl (5 mL), passed through a phase separator, concentrated, and triturated with DCM to give the title product (6.0 mg). LCMS (method 3): Rt=0.70 min, ES + m / z 522.2 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ (ppm) 9.36 (s, 1H), 9.20 (dd, J = 7.0, 1.5 Hz, 1H), 8.87 (s, 1H), 8.74 (dd, J = 4.0, 1.5 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.13 (dd, J = 7.0, 4.0 Hz, 1H), 7.09-7.01 (m, 1H), 6.69 (brs, 1H), 6.63-6.57 (m, 1H), 3.64 (s, 3H), 2.70 (brs, 3H), 2.37 (s, 3H) (CH peak overlaps with HDO)

[0404] Example 81 Process 1 [ka]

[0405] N-(4-(3-((2,4-dimethoxybenzyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide (Intermediate Step 1 - Example 81) Intermediate Step 1 - Example 81 was prepared in a similar manner to Example 1 starting from Intermediate 17l. LCMS (method 2): Rt=0.68 min, ES + m / z 601.2 [M+H] +

[0406] Process 2 [ka]

[0407] 2-Chloro-N-(2,4-dimethoxybenzyl)-N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (Intermediate Step 2 - Example 81) Intermediate Step 2—Example 81 (50 mg, 0.083 mmol) was suspended in THF (1 mL), followed by the addition of TEA (17.4 μL, 0.125 mmol) and 2-chloroacetyl chloride (8 μL, 0.1 mmol). The RM was stirred at RT for 45 min and then partitioned between EtOAc and water (20 mL each). The aqueous layer was extracted with EtOAc (5×20 mL), and the organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and evaporated under reduced pressure to give the title product (146 mg), which was used in the next step without further purification. LCMS (method 2): Rt=0.65 min, ES + m / z 677.3 [M+H] +

[0408] Process 3 [ka]

[0409] N-(2,4-Dimethoxybenzyl)-N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide (Intermediate Step 3 - Example 81) Intermediate Step 2—Example 81 (57 mg, 0.08 mmol) was dissolved in DMF (0.6 mL), then 1-methylpiperazine (19 μL, 0.17 mmol) was added and the RM was stirred at 80° C. for 1 h. The RM was quenched with saturated aqueous NaHCO and extracted with EtOAc (5×25 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and evaporated under reduced pressure to give the desired product, which was used in the next synthetic step without further purification. LCMS (method 2): Rt=0.59, ES + m / z 741.5 [M+H] +

[0410] Process 4 [ka]

[0411] N-(1-(2-Methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide (Example 81) Intermediate Step 3 - Example 81 was dissolved in TFA (2 mL) and stirred overnight at 60° C. The RM was evaporated under reduced pressure and the residue 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 (12 mg). LCMS (method 3): Rt=0.76 min, ES + m / z 591.2 [M+H] + 1H-NMR (500MHz, DMSO-d6, 353K) δ(ppm) 10.26(bs,1H), 9.38(d,J=1.1Hz,1H), 9.12(dd,J=7.1, 1.7Hz,1H), 8.86(s,1H), 8 .68(dd,J=4.0, 1.7Hz,1H), 8.15(d,J=1.1Hz,1H), 7.45(d,J=8.5Hz), 7.17(d,J=2. 1Hz,1H), 7.11(dd,J=7.1, 4.0Hz,1H), 7.03(dd,J=8.5, 2.2Hz,1H), 3.81(s,3H), 3 .31(s,2H), 3.13(s,3H), 2.66(t,J=4.9Hz,4H), 2.43(t,J=4.9Hz,4H), 2.21(s,3H)

[0412] Example 82 Process 1 [ka]

[0413] N-(4-(3-((2,4-dimethoxybenzyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)propane-1-sulfonamide (Intermediate Step 1 - Example 82) Intermediate Step 1 - Example 82 was prepared in the same manner as Example 1 starting from Intermediate 17m. LCMS (method 2): Rt=0.82 min, ES + m / z 629.2 [M+H] +

[0414] Process 2 [ka]

[0415] N-(2,4-Dimethoxybenzyl)-N-(1-(2-methoxy-4-(propylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate Step 2 - Example 82) Intermediate Step 1—Example 82 (100 mg, 0.18 mmol) was dissolved in dry DMF (1 mL), TEA (77 μL, 0.55 mmol) was added, and the RM was cooled to 0° C., after which 3-chloropropanoyl chloride (35 μL, 0.54 mmol) was added. The RM was stirred at RT for 3 h, then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic phase was evaporated under reduced pressure. The residue was dissolved in DMF, and 1-methylpiperazine (60 μL, 0.54 mmol) was added. The RM was stirred at 80° C. for 3 h, then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (50 mg). LCMS (method 2): Rt=0.70 min, ES + m / z 783.3 [M+H] +

[0416] Process 3 [ka]

[0417] N-(1-(2-Methoxy-4-(propylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 82) Example 82 was synthesized in a similar manner to Example 81 - Step 3, starting from intermediate step 2 - Example 82. LCMS (Method 7): Rt=3.72 min, ES+ m / z 633.3 [M+H] + 1 H-NMR (DMSO-d6, 300MHz): δ(ppm) 11.04(s,1H), 10.14(brs,1H), 9.33(s,1H), 9.19-9.24(m,1H), 8.87(s,1H), 8 .69(dd,J=4.1, 1.7Hz,1H), 8.13(s,1H), 7.43(s,1H), 7.08-7.19(m,2H), 6.98( dd,J=8.4, 2.2Hz,1H), 3.77(s,3H), 3.18-3.27(m,2H), 2.56-2.77(m,6H), 2.5 4(m,2H, overlap with DMSO), 2.22-2.38(m,4H), 1.67-1.83(m,2H), 0.99(t,J=7.5Hz,3H)

[0418] Example 83 Process 1 [ka]

[0419] 3-(Bromomethyl)-6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine (Intermediate Step 1 - Example 83) A round-bottom flask was charged with Intermediate 9a (2.5 g, 7.84 mmol) and trifluorotoluene (35 mL) under argon. NBS (1.67 g, 9.4 mmol) and AIBN (258 mg, 1.57 mmol) were added, and the RM was stirred at 85 °C for 2.5 h. Another equivalent of NBS and AIBN was added, and the RM was stirred at 85 °C for an additional 8 h. After cooling to RT, the RM was diluted with EtOAc and washed with saturated aqueous NaHCO (3x) and saturated aqueous NaCl. The organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM in cyclohexane to give the desired compound (810 mg). LCMS (method 1): Rt=1.20 min, ES +m / z 396.9 / 398.9 / 400.8 [M+H] +

[0420] Process 2 [ka]

[0421] 1-(6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-methylmethanamine (Intermediate Step 2 - Example 83) Intermediate Step 1 - A solution of Example 83 (649 mg, 1.63 mmol) in THF (16.2 mL) was added dropwise to a solution of methylamine in THF (2.0 M, 13.1 mL, 26.1 mol). The RM was stirred at RT for 1 h and then evaporated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / MeOH (10:1) to give the title product. LCMS (method 2): Rt=0.97 min, ES + m / z 348.1 / 350.1 [M+H] +

[0422] Process 3 [ka]

[0423] tert-Butyl ((6-chloro-1-(2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate Step 3 - Example 83) BocO (418 mg, 1.92 mmol) was added to a solution of Intermediate Step 2 - Example 83 (606 mg, 1.74 mmol) and TEA (680 mg, 4.88 mmol) in DCM (8.2 mL). The RM was stirred at RT for 1.5 h and then partitioned between DCM and saturated aqueous NaHCO. The organic phase was washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with DCM / MeOH (30:1 to 20:1) to give the title product (774 mg). LCMS (method 2): Rt=1.32 min, ES + m / z 448.1 / 450.1 [M+H] +

[0424] Process 4 [ka]

[0425] tert-Butyl ((1-(4-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate Step 4 - Example 83) Intermediate Step 4-Example 83 was prepared in the same manner as Intermediate 10c, starting from Intermediate Step 3-Example 83. LCMS (method 2): Rt=1.12 min, ES + m / z 418.2 / 420.2 [M+H] +

[0426] Process 5 [ka]

[0427] tert-Butyl ((6-chloro-1-(2-methoxy-4-(propylsulfonamido)phenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate Step 5 - Example 83) Intermediate Step 5-Example 83 was prepared in the same manner as Intermediate 16a, starting from Intermediate Step 4-Example 83 and propanesulfonyl chloride. LCMS (method 2): Rt=0.86 min, ES + m / z 524.2 / 526.2 [M+H] +

[0428] Process 6 [ka]

[0429] tert-Butyl ((1-(2-methoxy-4-(propylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate Step 6 - Example 83) Intermediate Step 6-Example 83 was prepared analogously to Example 1, starting from Intermediate Step 5-Example 83. LCMS (method 2): Rt=0.79 min, ES + m / z 607.3 [M+H] +

[0430] Process 7 [ka]

[0431] N-(3-Methoxy-4-(3-((methylamino)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide (Example 83) Intermediate Step 6 - A solution of Example 83 (83 mg, 0.137 mmol) in DCM (1 mL) was treated with TFA (508 μL, 6.84 mmol). The RM was stirred at RT for 40 min. The RM was dried under reduced pressure, and the residue was purified by flash chromatography on silica to give the title product (59 mg). LCMS (Method 7): Rt=3.65 min, ES+ m / z 507.7 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ(ppm) 9.26-9.30(m,1H), 9.22(dd,J=6.87, 1.68Hz,1H), 8.88(s,1H), 8.68 -8.74(m,1H), 8.21(d,J=1.22Hz,1H), 7.44(d,J=8.54Hz,1H), 7.10-7.20(m,2H), 6.98(dd,J=8.54, 2.14Hz ,1H), 4.09(s,2H), 3.77(s,3H), 3.18-3.25(m,2H), 2.37(s,3H), 1.69-1.84(m,2H), 1.00(t,J=7.48Hz,3H)

[0432] Example 84 Process 1 [ka]

[0433] N-(4-(6-chloro-3-(cyanomethyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide (Intermediate Step 1 - Example 84) A mixture of intermediate 16e (100 mg, 0.198 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (38.6 mg, 0.198 mmol), Pd(dppf)Cl·CHCl (24.3 mg, 0.0297 mmol), and NaCO (42 mg, 0.396 mmol) in 1,4-dioxane (1.22 mL) / water (610 μL) was purged with argon, and the RM was stirred for 1.5 h at 50° C. Additional equivalents of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and Pd(dppf)Cl·CHCl were added, and the RM was stirred at 70° C. overnight. KF (34.5 mg, 0.594 mmol) was added to the RM and stirred at 100° C. overnight. The RM was passed through a pad of Celite® and the solvent was evaporated. The residue was dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (3×15 mL) and saturated aqueous NaCl (15 mL). The organic layer was passed through a phase separator and the solvent was evaporated in vacuo. The crude material was purified by flash chromatography on a Si cartridge eluting with 0-50% EtOAc in DCM to give the title product (38 mg). LCMS (method 2): Rt=0.57 min, ES- m / z 416.1 / 418.1 [MH] -

[0434] Process 2 [ka]

[0435] N-(4-(3-(cyanomethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide (Example 84) Example 84 was prepared in the same manner as Example 1, starting from intermediate step 1 - Example 84. LCMS (Method 7): Rt=4.47 min, ES + m / z 501.1[M+H] + 1 H-NMR (300MHz, DMSO-d6) δ(ppm) 10.16(s,1H), 9.16-9.29(m,2H), 8.90(s,1H), 8.64-8.77(m,1H), 8.23(s,1H), 7.49(d,J=8.5Hz,1H), 7. 11-7.23(m,2H), 7.04(m,1H), 4.61(s,2H), 3.77(s,3H), 2.83(quin,J=6.3Hz,1H), 1.04(d,J=6.3Hz,4H)

[0436] Example 85 Process 1 [ka]

[0437] N-(3-Methoxy-4-(6-((3-methoxypyrazin-2-yl)amino)-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide (Intermediate Step 1 - Example 85) A vial was charged with Intermediate 11a (150 mg, 0.41 mmol), 2-amino-3-methoxypyrazine (67 mg, 0.53 mmol), sodium t-butoxide (59 mg, 0.61 mmol), and XPhos-Pd-G3 (17 mg, 0.02 mmol), then sealed and backfilled with nitrogen / evacuated (x3). Pre-degassed 1,4-dioxane (2 mL) was added via syringe, and the RM was stirred at 100 °C for 4 h. After cooling to RT, the RM was partitioned between EtOAc (10 mL) and water (7 mL). The aqueous layer was extracted with a DCM / i-PrOH mixture (1:1, 3 x 10 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-50% MeOH / DCM in DCM to give the title product (180 mg). LCMS (method 2): Rt=0.61, ES + m / z 456.2 [M+H] +

[0438] Process 2 [ka]

[0439] N-(3-methoxy-4-(3-methyl-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide (Example 85) Intermediate Step 1 - Example 85 (180 mg, 0.39 mmol) was suspended in acetonitrile (6.5 mL) and TMS-Cl (150 μL, 1.19 mmol) and NaI (178 mg, 1.19 mmol) were added. The RM was stirred in a sealed vial at 85 °C for 30 min. The RM was allowed to cool to RT, and the precipitate that formed was collected. The solid was dissolved in DCM (25 mL) and washed with aqueous 10% NaSO (10 mL) and saturated aqueous NaCl (10 mL). The organic phase was dried over MgSO and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:9:0.5) in DCM to give the title compound (48 mg). LCMS (Method 5): Rt=2.55 min, ES + m / z 442.64 [M+H] + 1 H-NMR (500MHz, DMSO-d6) δ=12.22(brs,1H), 10.10(s,1H), 8.89(s,1H), 8.91(brs,1H), 8.10(s,1H), 7.42(d,J=8.5Hz,1H), 7.11(d,J=2.1Hz,1H), 6.98-6.94(m,2H), 6.91-6.88(m,1H), 3.77(s,3H), 3.14(s,3H), 2.59(s,3H)

[0440] Examples 86 to 92 The following examples were prepared in a two-step process in analogy to Example 85 from the starting materials indicated.

[0441] [Table 80] [Table 81] [Table 82] [Table 83] [Table 84] [Table 85]

[0442] Comparative Example C31 [ka]

[0443] Process 1 [ka]

[0444] 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate C31-I) Dihydropyran (3.4 mL, 37.4 mmol) and methanesulfonic acid (0.16 mL, 2.5 mmol) were added to 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.48 g, 11.1 mmol) in DCM (33 mL) and THF (16.6 mL). The RM was stirred at 40 °C for 2 h and then at RT overnight. The solvent was evaporated and the residue was purified by flash chromatography on a Si cartridge eluting with 0-100% EtOAc in cyclohexane to give the title product (1.48 g). LCMS (method 2): Rt=1.18 min, ES + m / z 364.0 / 366.0 [M+H] +

[0445] Process 2 [ka]

[0446] N1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C31-II) L-Proline (85.5 mg, 0.74 mmol) and copper(I) iodide (94.3 mg, 0.5 mmol) were added to a mixture of intermediate C31-I (900 mg, 2.48 mmol), N',N'-dimethylethane-1,2-diamine (1.23 mL, 11.3 mmol), and K2CO3 (2.05 g, 14.9 mmol) in DMF (8.0 mL), and the RM was stirred at 110 °C for 2 h under an argon atmosphere. After cooling to RT, the RM was diluted with water (80 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with saturated aqueous NaHCO3, passed through a phase separator, and concentrated in vacuo. The residue 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 compound (630 mg). LCMS (method 1): Rt=0.62 min, ES + m / z 323.9 / 325.9 [M+H] +

[0447] Process 3 [ka]

[0448] N1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C31-III) Triethylsilane (932 μL, 5.84 mmol) was added dropwise to intermediate C31-II (630 mg, 1.95 mmol) in DCM (9 mL) / TFA (2.29 mL, 29.9 mmol). The RM was stirred at RT for 1 h, then diluted with DCM and extracted with saturated aqueous NaHCO (10 mL). The aqueous layer (adjusted to pH 9.6) was further extracted with EtOAc (3×) followed by DCM / iPrOH (1:1). The organic layers were combined, passed through a phase separator, and evaporated under reduced pressure to give the title product (396 mg), which was used in the next step without further purification. LCMS (method 1): Rt=0.39 min, ES + m / z 240.0 / 242.0 [M+H] +

[0449] Process 4 [ka]

[0450] N1-(6-chloro-1-(2-methoxy-5-nitrophenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C31-IV) Intermediate C31-IV was prepared in the same manner as intermediate 10d, starting from intermediate C31-III and 2-bromo-1-methoxy-4-nitro-benzene. LCMS (Method 1): Rt=1.04 min, ES + m / z 391.1 / 393.1 [M+H] +

[0451] Process 5 [ka]

[0452] N1-(1-(5-amino-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C31-V) Intermediate C31-V was prepared in a similar manner to intermediate 10c, starting from intermediate C31-IV. LCMS (method 2): Rt=0.83, ES + m / z 361.1 / 363.1 [M+H] +

[0453] Process 6 [ka]

[0454] N1-(1-(5-N1-(1-(5-amino-2-methoxyphenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C31-VI) Intermediate C31-VI was prepared in the same manner as in Example 1. LCMS (method 1): Rt=0.76, ES + m / z 443.9 [M+H] +

[0455] Process 7 [ka]

[0456] N-(3-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxyphenyl)methanesulfonamide (Comparative Example C31) To a cooled (0 °C) mixture of intermediate C31-VI (14 mg, 0.03 mmol) was added pyridine (2.8 mg, 0.03 mmol), followed by methanesulfonyl chloride (2.2 μL, 0.03 mmol). The RM was stirred at 0 °C for 15 min and at RT overnight. The RM was diluted with saturated aqueous NaHCO and extracted with DCM (4 × 15 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH / NHOH (90:9:1.5) in DCM to give the title product (5 mg). LCMS (Method 7): Rt=3.14 min, ES + m / z 522.2 [M+H] + 1 H-NMR (600MHz, DMSO-d6) δ(ppm):9.61(bs,1H), 9.21(dd,J=7.1, 1.7Hz,1H), 9.09(d,J=1.0Hz,1H), 8.86(s,1H) , 8.70(dd,J=4.0, 1.7Hz,1H), 8.15(d,J=1.0Hz,1H), 7.37(d,J=2.6Hz,1H), 7.31(d,J= 8.9Hz,1H), 7.28(dd,J=8.9, 2.6Hz,1H), 7.15(dd,J=7.1, 4.1Hz,1H), 6.74(t,J=5.6Hz) ,1H), 3.87(s,3H), 3.42(q,J=6.1Hz,2H), 2.98(s,3H), 2.60-2.56(m,2H), 2.24(s,6H)

[0457] Pharmacological activity of compound (1-92) of the present invention Biochemical potency against JAK1, JAK2, JAK3 and Tyk2 Assay principle The purpose of this study was to evaluate the ability of compounds of the present invention 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, which involves the interaction of two labeled binding partners, detected by energy transfer from an excited donor to an acceptor dye and measurement of the emission emitted by the acceptor dye. The LANCE Ultra kinase assay was used. In the presence of JAK1, JAK2, JAK3, and TYK2 kinases and ATP (corresponding to the Km), the ULight peptide substrate (LANCE Ulight-JAK-1(Tyr1023) Peptide, Perkin Elmer, TRF0121) is phosphorylated. It is then captured by a Eu-antiphosphosubstrate antibody (LANCE Eu-W1024 anti-phosphotyrosine (PT66), Perkin-Elmer, AD0069), thereby bringing the Eu-chelate donor and ULight acceptor dye into close proximity. Upon excitation at 320 nm, the Eu-chelate transfers its energy to the ULight dye, resulting in fluorescence emission at 665 nm.

[0458] Compound testing Serial dilutions of compounds in pure DMSO were prepared from a 10 mM DMSO stock solution. Compounds were tested in 384-well plates using 11 serial 5-fold dilutions (20 μM–2 pM), starting with a top concentration of 20 μM. 200 nL of compound was transferred from the mother plate to the test plate using a Mosquito (TTP Labtech). Assays were performed in 384-well Perkin-Elmer test plates with a 20 μL assay volume (kinase reaction) and a 40 μL total volume (stop reagent and antibody detection reagent). 10 μL of substrate solution (peptide + ATP) was added to JAK1, JAK2, JAK3, and TYK2 at 30 / 50 / 20 / 10 nM peptide and 20 / 0.7 / 0.2 / 12 μM ATP, respectively. Ten microliters of enzyme solution was added to the kinase reactions at these concentrations of 0.15, 0.083, 0.025, and 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 of eutopium-anti-phospho antibody, final: 0.5 nM) were added. After incubation for 1 hour, readings were taken on an EnVision 2104 reader (Perkin Elmer).

[0459] Calculation of IC50 data, curves, and QC analysis was performed using Excel tools and GraphPadPrism software, v9. Briefly, individual concentration-effect curves were generated by plotting the logarithm of the test concentration of the test compound (X) against the corresponding percent inhibition value (Y) using ordinary least squares (OLS) fit. The optimal IC50 value was calculated using the equation Log(inhibitor) vs. normalized response-variable slope, where Y = 100 / (1 + 10^((LogIC50-X) * HillSlope)). QC criteria parameters (Z', S:Z, R2, HillSlope)) were checked for all IC curves. Calculation of IC50 data, curves, and QC analysis was performed using Excel tools and GraphPadPrism software. QC criteria parameters: Z' > 0.5, hill gradient range 0.5~5, S:B>2

[0460] The compounds of the present invention (including the compounds of Examples 1a-10a and 1-92) are evaluated for their inhibitory activity against all JAK isoforms in terms of inhibitory concentration. < Most compounds preferably exhibit a pIC50 value of greater than 6, which corresponds to 1 μM. Most compounds exhibit a value of greater than 7.3, more preferably greater than 8.3, for their inhibitory activity against JAK1, which corresponds to a value of greater than 6, which corresponds to a value of greater than ... < 50 nM, more preferably < Corresponding to 5nM.

[0461] Data for compounds 1-92 are reported in the table below. [Table 86] [Table 87] [Table 88]

[0462] The compounds are classified in the above table in terms of potency with respect to their inhibitory activity against JAK1, JAK2, JAK3 and Tyk2 isoforms according to the following classification criteria: +++:pIC50 > 8.3 ++ :8.3>pIC50 > 7.3 + :pIC50<7.3

[0463] Where a numerical limit or range is given in the specification, the endpoints are included, and all values ​​and subranges within that numerical limit or range are also included, unless specifically and expressly stated otherwise. As used herein, terms such as "a" and "an" mean "one or more." Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. Formula Io: 【Chemistry 1】 [In the formula, W is heteroaryl selected from pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-b]pyridazin-3-yl, and (3-oxo-3,4-dihydropyrazin-2-yl)amino; R １ is selected from the group pyridinyl, piperidinyl, phenyl or benzyl, which is halogen, -OH, -CN, -NO ２ 、 -(CH ２ ) ｍ NR ４ R ５ 、 (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio- (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, and optionally substituted with 1, 2, or 3 groups independently selected from R １ is phenyl, the group represented by formula K: 【Chemistry 2】 (In the formula: L is absent or O, S, S(O) ２ , (CO), C(O)O, O(O)C, C(O)N(R ６ ), N(R ６ )C(O),NHCONH,N(R ６ ) S (O) ２ , S(O) ２ N (R ６ is a divalent group selected from Z is H, —OH, —CN, or —NO ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkoxy(C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxycarbonyl, —(CH ２ ) ｍ NR ４ R ５ , -C(O)NH(R ６ ), (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) heterocycloalkyl; wherein said (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) Heterocycloalkyl is (C １ -C １０ ) alkyl, alkanoyl, (C １ -C ６ ) alkoxycarbonyl, oxo, —C(O)NH(R ６ ), (C １ -C ６ ) alkoxy(C １ -C ６ ) alkyl, is further substituted in the para position relative to the point of attachment of R 1 to the remainder of the molecule with at least one group of the formula: R ２ and R ３ is H, (C １ -C ６ ) alkyl, and a group of formula J: 【Transformation 3】 (In the formula: V is absent or O, S, S(O) ２ , C(O), C(O)O, O(O)C, C(O)N(R ６ ), N(R ６ )C(O);N(R ６ )-(CH ２ ) ｍ -N(R ６ ), -N(R ６ )- is a divalent group selected from; Q is H, —CN, —OH, (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkoxycarbonyl, hydroxycarbonyl, -(CH ２ ) ｍ NR ４ R ５ , —C(O)NR ４ R ５ , -N(R ６ ) C(O)R ６ , -CH(CN)NR ４ R ５ , (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) heterocycloalkyl; wherein said (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) Heterocycloalkyl is —OH, oxo, (C １ -C １０ ) alkyl, (C １ -C １０ ) alkyl-S(O) ２ —O—, alkanoyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) alkoxy(C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkoxycarbonyl-NH-, -N(R ６ ) (CH ２ ) ｍ C(O)NR ４ R ５ , -NR ４ R ５ , (C ３ -C ６ ) heterocycloalkyl; and are independently selected from the group consisting of: 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 １ -C ６ ) hydroxyalkyl, Alkanoyl, (C １ -C ６ ) alkoxycarbonyl, and (C ３ -C ６ ) heterocycloalkyl selected from the group consisting of: R ６ is independently expressed in each occurrence as H,(C １ -C ６ ) alkyl, (C １ -C ６ ) selected from the group consisting of hydroxyalkyl, and alkanoyl; R ７ is independently expressed in each occurrence as H,(C １ -C ６ ) alkyl, —NR ４ R ５ selected from the group consisting of 1. A compound of the formula: embedded image wherein: single enantiomers, diastereomers and mixtures thereof, or pharmaceutically acceptable salts or solvates thereof.

2. Formula Ia: 【Chemistry 4】 [In the formula, R ８ teeth (C １ -C ６ ) alkoxy, (C １ -C ６ ) Haloalkoxy selected from the group consisting of: L is N(R ６ ) S (O) ２ , S(O) ２ N (R ６ ) and Z is H, (C １ -C ６ ) alkyl, , (C １ -C ６ ) haloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkoxycarbonyl, —(CH ２ ) ｍ NR ４ R ５ , -C(O)NH(R ６ ), (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) heterocycloalkyl; ３ -C ８ ) cycloalkyl, aryl, heteroaryl and (C ３ -C ６ ) Heterocycloalkyl is (C １ -C １０ ) alkyl, alkanoyl, (C １ -C ６ ) alkoxycarbonyl, oxo, —C(O)NH(R ６ ), (C １ -C ６ ) alkoxy(C １ -C ６ ) optionally substituted with one or more substituents selected from the group consisting of alkyl; V is absent or -N(R ６ )- is a divalent group consisting of; Q is H, (C １ -C ６ ) alkyl, —(CH ２ ) ｍ NR ４ R ５ and (C ３ -C ６ ) heterocycloalkyl; ３ -C ６ ) heterocycloalkyl is one or more (C １ -C １０ ) optionally substituted with alkyl; n and m, in each occurrence, are independently 0 or an integer from 1 to 4; R ４ and R ５ are the same or different, -H, (C １ -C ６ ) alkyl selected from the group consisting of: R ６ is independently, in each occurrence, H,(C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl; R ７ is independently, in each occurrence, H,(C １ -C ６ ) alkyl] 2. The compound of claim 1, wherein: [0022] the single enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof.

3. R ８ But (C １ -C ６ ) alkoxy; L is -N(R ６ ) S (O) ２ - and; Z is H; (C １ -C ６ ) alkyl; and (C ３ -C ８ ) cycloalkyl selected from the group consisting of: V is absent or -N(R ６ )- and; Q is -CN, (C １ -C ６ ) alkyl, - (CH ２ ) ｍ NR ４ R ５ , and (C ３ -C ６ ) heterocycloalkyl selected from the group consisting of: In the group K, n is 0 and m is 0 or 1; in the group J, n is 0, 1 or 2 and m is 0 or 1; R ４ and R ５ may be the same or different, -H, (C １ -C ６ ) alkyl, preferably methyl selected from the group consisting of: R ６ is H; R ７ is H, 3. The compound of claim 2, its single enantiomers, diastereomers, and mixtures, or pharmaceutically acceptable salts or solvates thereof.

4. N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-1-(tetrahydrofuran-2-yl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)tetrahydro-2H-pyran-4-sulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide; 1-cyclopropyl-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(3-(difluoromethoxy)-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)oxetane-3-sulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)tetrahydrofuran-3-sulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide; N-(5-methoxy-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-3-yl)methanesulfonamide; N-(2-fluoro-5-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; 3-(N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)sulfamoyl)propanamide; 2-(N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)sulfamoyl)acetamide; 3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile; 4-Methoxy-N-methyl-5-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-amine; 3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)aniline; 1-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-3-methylurea; 3-Methoxy-N-methyl-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzamide; 3-Methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-N-phenylbenzamide; tert-butyl (3-((1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)propyl)carbamate; N-(4-(3-((3-(dimethylamino)propyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(3-methoxy-4-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-(difluoromethoxy)-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(4-(3-((2-hydroxyethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(3-methoxy-4-(3-(((1-(2-methoxyethyl)piperidin-4-yl)methyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-(((4-methylmorpholin-2-yl)methyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(6-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxypyridin-3-yl)cyclopropanesulfonamide; N-(4-(3-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-((3-morpholinopropyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-((2-(piperidin-1-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-((2-(piperidin-1-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-((2-(4-methylpiperazin-1-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(4-(3-((2-((2-fluoroethyl)(methyl)amino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(3-methoxy-4-(3-(methyl(2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylpiperidine-4-carboxamide; N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylpyrrolidine-3-carboxamide; N-(3-(dimethylamino)propyl)-1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; N-(2-(dimethylamino)ethyl)-1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 1-(2-methoxy-4-(methylsulfonamido)phenyl)-N-(2-morpholinoethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; N-(3-(dimethylamino)propyl)-1-(2-methoxy-4-(propylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 1-(2-methoxy-4-(propylsulfonamido)phenyl)-N-(3-morpholinopropyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; N-(5-methoxy-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-3-yl)benzamide; 3-Methoxy-N-methyl-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzenesulfonamide; 3-Methoxy-N-methyl-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzenesulfonamide; 3-Methoxy-N-methyl-4-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzenesulfonamide; 4-(3-((3-(dimethylamino)propyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxy-N-methylbenzenesulfonamide; N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(3-methoxy-4-(3-((2-(piperidin-1-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(3-methoxy-4-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide; N-(2-chloro-5-methoxy-4-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(2-chloro-5-methoxy-4-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(3-(dimethylamino)propyl)-1-(2-methoxy-4-(methylsulfonamidomethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; N-(4-(3-(cyanomethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxybenzyl)methanesulfonamide; N-(3-(difluoromethoxy)-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(1-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)ethyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-N-methylmethanesulfonamide; (3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanol; (3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanamine; 1-cyano-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide; Methyl (3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)carbamate; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)acetamide; 1-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-3-methylurea; 1-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)-3-phenylurea; 2,2-difluoro-N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)ethane-1-sulfonamide; N-(3-methoxy-4-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)benzamide; N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)benzamide; N-(4-(6-(imidazo[1,2-b]pyridazin-3-yl)-3-((2-morpholinoethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(4-(3-((2-(dimethylamino)ethyl)amino)-6-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(4-(3-(((1s,3s)-3-(dimethylamino)cyclobutyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide; N-(4-(3-amino-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(methylamino)acetamide; N-(1-(2-methoxy-4-(methylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide; N-(1-(2-methoxy-4-(propylsulfonamido)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(3-methoxy-4-(3-((methylamino)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide; N-(4-(3-(cyanomethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)cyclopropanesulfonamide; N-(3-methoxy-4-(3-methyl-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(3-methyl-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide; N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)methanesulfonamide; N-(3-methoxy-4-(6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-((2-(piperidin-1-yl)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide; N-(3-(difluoromethoxy)-4-(3-((2-morpholinoethyl)amino)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide; N-(4-(3-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-methoxyphenyl)methanesulfonamide; N-(3-methoxy-4-(3-(methylamino)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)propane-1-sulfonamide; N-(3-methoxy-4-(3-((2-morpholinoethyl)amino)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzyl)methanesulfonamide 10. The compound of claim 1, single enantiomers, diastereomers, and mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, selected from:

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carriers or excipients.

6. 6. A pharmaceutical composition according to claim 5, suitable for administration by inhalation, selected from an inhalable powder, a propellant-containing metered aerosol, or a propellant-free inhalable formulation.

7. 10. A device for delivering the pharmaceutical composition of claim 6, wherein the device is a single or multi-dose dry powder inhaler, a metered dose inhaler, or a soft mist nebulizer.

8. The pharmaceutical composition according to any one of claims 1 to 6 for use as a medicine.

9. 9. The pharmaceutical composition according to claim 8, 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).

10. 5. A combination of a compound according to any one of claims 1 to 4 with one or more active ingredients selected from beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P39MAP kinase) inhibitors, inhibitors of nuclear factor kappa-B kinase subunit beta (IKK2), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modifiers, nonsteroidal anti-inflammatory drugs (NSAIDs) and mucus modifiers.

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