Heterocyclic derivatives as Janus kinase inhibitors

Abstract

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

Description

[Technical Field]

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

[0002] Background of the Invention The JAK family consists of non-receptor tyrosine protein kinases and has four major members: JAK1, JAK2, JAK3, and TYK2. Over 50 cytokines and growth factors bind to type I and type II receptors, which non-covalently associate with various combinations of JAK kinases. Ligand-induced signal transduction involves tyrosine phosphorylation of the receptor by JAK and recruitment of one or more STAT proteins. Tyrosine-phosphorylated STATs dimerize and are then transported across the nuclear membrane to the nucleus, where they regulate specific genes. JAKs contain seven homology domains (JAK homology domains, or JHs). Starting from the carboxyl terminus, JH1 is the first JH known as the kinase domain and consists of approximately 250 amino acid residues. JH1 encodes a kinase protein that constitutes the kinase structural domain, which phosphorylates substrates; JH2 is a pseudokinase domain that regulates the activity of the kinase domain. JAK3 is expressed in the bone marrow and lymphoid system, as well as in endothelial and vascular smooth muscle cells; other members are expressed in nearly all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26;6(1):402). Many cellular processes are downstream of JAK / STAT signaling: hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis. Various biological responses are regulated by specific pairings of JAK isoforms. The JAK1 / JAK3 combination mediates IL-2, -4, -7, -9, -15, and -21 signaling, which is associated with lymphoid cell proliferation / maturation, T cell / NK cell differentiation / homeostasis, B cell class switching, and other inflammatory processes. The JAK1 / TYK2-JAK1 / JAK2 combination regulates signals associated with innate immune responses, such as IL-6 and type I interferons, which are involved in naive T cell differentiation, T cell homeostasis, granulopoiesis, and other inflammatory processes (Howell MD et al., Front. Immunol. 2019, 10, 2342).JAK2, often associated with itself (JAK2 / JAK2), regulates the signaling of various cytokines and growth factors, including IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Hodge et al., Clin Exp Rheumatol 2016; 34(2):318-28).

[0003] Genetically engineered mouse models and human diseases demonstrate the importance of the JAK / STAT pathway in immune fitness. In particular, overexpression or mutation of certain JAK isoforms and aberrant JAK / STAT signaling lead to hematopoietic and lymphoid malignancies and inflammatory disorders. Currently, several US Food and Drug Administration (FDA)- and / or EU-approved JAK inhibitors are in clinical use. Two small molecules (ruxolitinib and fedratinib) are used to treat hematological disorders such as myelofibrosis and polycythemia vera; six JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, filgotinib, upadacitinib, and delgocitinib in Japan) are used to treat immune-mediated disorders such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis, and acute graft-versus-host disease. Furthermore, some of these drugs and others are currently in Phase II and III clinical trials for indications ranging from autoimmune diseases (lupus, vitiligo, etc.), inflammatory bowel disease to non-Hodgkin's lymphoma and COVID-19 (Hu X. et al., Sig Transduct Target Ther 2021, 6: 402).

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

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

[0006] Asthma is one of many immune-mediated diseases whose pathogenesis is characterized by the essential role of JAK / STAT signaling. It is a chronic inflammatory disease of the airways resulting from a complex interplay between immune responses, genetic susceptibility, and nonspecific external stimuli such as cold, allergens, and exercise, leading to hyperresponsiveness, airway remodeling, and ultimately contributing to airflow limitation. Severe asthma, including adult asthma, affects 5-15% of the population (300 million worldwide) and represents a public health problem associated with increased mortality, hospitalizations, significant symptom burden, medical costs, and work and school absences (Steve NG et al., J Allergy Clin Immunol 2021;148:953-63). Severe asthma represents a subset of asthma that is difficult to treat and occurs in patients whose disease remains uncontrolled with high-dose inhaled corticosteroids (ICS) in combination with long-acting beta-agonists or other control agents. To date, four types of biologics have been approved for severe asthma: omalizumab (anti-immunoglobulin E antibody), mepolizumab and reslizumab (anti-interleukin [IL]-5 antibodies), benralizumab (anti-IL-5 receptor α antibody), and dupilumab (anti-IL-4 receptor alpha antibody). Despite their efficacy, many patients continue to experience exacerbations or loss of disease control, indicating the need for novel therapeutic agents (Israel E, Reddel HK. N Engl J Med 2017; 377:965-76).

[0007] In recent years, a better understanding of the pathogenesis of asthma has led to a shift from phenotypic classification to the introduction of the concept of "endotypes." According to the latter, classification is based on pathophysiological mechanisms and clinical biomarkers associated with a given patient (Wenzel SE et al., Am J Respir Crit Care Med 2021;203:809-21). There are two major endotypes of asthma: type 2 and non-type 2. The type 2 pathway is defined by the activation of cytokines derived from Th2 cells and type 2 innate lymphoid cells (ILC2s); these include IL-4, IL-5, and IL-13, which cause airway inflammation by activating eosinophils, B cells, airway epithelial cells, and other cell types. Biomarkers of type 2 asthma include increased blood / sputum eosinophilia and elevated levels of exhaled nitric oxide (FENO) and IgE. The type 2-low pathway is characterized by the absence of type 2-high cytokines and biomarkers, manifested by increased neutrophil levels or a granulocyte-poor profile in the airways, with normal airway neutrophil and eosinophil levels. Type 2-low asthma is currently poorly understood and may encompass multiple distinct endotypes. Potential mediators and / or biomarkers for the T2-low endotype under investigation include IL-6, IL-17A / F, IL-23, type I interferons, CXCL10, TNF, and alarmins (Hinks TSC et al., ERJ 2021, 57 (1) 2000528).

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

[0009] Despite the strong rationale for JAK inhibitors in asthma, safety concerns may arise with systemic administration or limit administration to certain patients, such as children. Given that asthma is a pulmonary disorder, the inhaled route of administration of JAK inhibitors may offer the advantage of therapeutic efficacy while limiting systemic exposure and associated side effects. To date, several companies are developing inhaled JAK inhibitors for the treatment of asthma. Astrazeneca's pipeline includes AZD-0449 (Phase I clinical trials completed) and AZD-4604 (Phase I clinical trials ongoing); Theravance Biopharma has initiated a novel preclinical program with the inhaled JAK inhibitor TD-8236, and Kinaset / Vectura is developing VR588 (Phase I clinical trials ongoing) as an inhaled compound. Numerous preclinical studies supported by these companies have demonstrated the efficacy of JAK inhibitors in controlling asthma. In the preclinical phase of drug development, the orally administered JAK1 / 3 inhibitor R256 (now called AZD0449) was shown to be effective in reducing airway resistance, BAL eosinophilia, and mucus production, and, when administered during sensitization, also in reducing TH2 cytokine responses (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). Genentech's iJak-381, given as a dry powder, reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in OVA-challenged mice. Furthermore, it reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in a mouse model of chronic exposure to AAH allergen (Dengler HS et al., Sci Transl Med 2018;10:eaao2151). Furthermore, oral JAK inhibitors such as tofacitinib, formulated for administration as an aerosol, reduced eosinophil counts in a house dust mite mouse model of asthma (Younis US et al., AAPS PharmSci-Tech 2019;20:167).

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

[0011] In view of the many pathological responses mediated by JAK enzymes, there continues to be a need for JAK enzyme inhibitors that may be useful in the treatment of many disorders and particularly respiratory diseases.

[0012] Therefore, the discovery of novel and potent JAK inhibitors suitable for local administration to the lung for the treatment of asthma and respiratory diseases remains an important need.

[0013] There continues to be a strong demand for JAK inhibitors, and in particular inhaled JAK inhibitors, that may provide compounds with improved safety. Regardless of inhaled administration, safety concerns may still arise due to the drug levels that reach the systemic circulation after inhalation of JAKi. In addition to a profile that is well suited for inhalation, JAKi preferably have additional properties that can further limit systemic exposure after inhalation. [Means for solving the problem]

[0014] Overview of this project Thus, compounds of formula (I) are useful as JAK kinase inhibitors [ka] wherein R, R, R, X, Y, Z, K, G, n, V, and Q are as defined in the detailed description of the invention. It is an object of the present invention to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] It is another object of the present invention to provide pharmaceutical compositions containing such compounds, methods of using such compounds in the treatment of respiratory disorders, and processes and intermediates useful in the preparation of such compounds.

[0016] In certain embodiments, the present invention provides a compound of formula (I) for use as a medicament. In certain embodiments, the present invention provides the use of a compound of the present invention for the manufacture of a medicament.

[0017] In a further aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of any disease associated with the JAK enzyme mechanism.

[0018] In another aspect, the present invention provides a method for the prevention and / or treatment of any disease associated with the JAK enzyme mechanism as defined above, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0019] In certain embodiments, the compounds of the present invention, alone or in combination with other active ingredients, may be administered for the prevention and / or treatment of pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung disease and idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention definition The term "pharmaceutically acceptable salts" refers to derivatives of compounds of formula (I) wherein the parent compound, if any free acid or basic group is present, is suitably modified to form the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0021] Thus, suitable examples of such salts may include inorganic or organic acid addition salts of basic residues such as amino groups and inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0022] Cations of inorganic bases which may be suitably used in preparing the salts of the present invention include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by reacting an inorganic or organic acid with a base-functioning compound to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0023] Many organic compounds can form complexes with the solvent in which they are reacted or precipitated or crystallized. These complexes are known as "solvates" and are also the subject of the present invention. Polymorphs and crystalline forms of the compound of formula (I) or its pharmaceutically acceptable salts or solvates are also the subject of the present invention.

[0024] The term "halogen" or "halogen atom" includes fluorine, chlorine, bromine, and iodine atoms, meaning fluoro, chloro, bromo, iodo as substituents.

[0025] 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.

[0026] The expression "(C-C)haloalkyl" refers to a "(C-C)alkyl" group as defined above in which one or more hydrogen atoms have been replaced with one or more halogen atoms, which may be the same or different. Examples include halogenated, polyhalogenated, and fully halogenated alkyl groups (in which all of the hydrogen atoms have been replaced with halogen atoms, e.g., trifluoromethyl or difluoromethyl groups).

[0027] In a similar way, the term "(C1-C x ) hydroxyalkyl" or "(C1-C x "(C-C)aminoalkyl" refers to a "(C-C)aminoalkyl" as defined above, in which one or more hydrogen atoms have been replaced by one or more hydroxy (OH) or amino groups, respectively. x Thus, "(C1-C6)hydroxyalkyl" or "(C1-C6)aminoalkyl" refers to such hydroxy- or amino-alkyl groups having in the range of 1 to 6 carbon atoms.

[0028] The definition of aminoalkyl includes alkyl groups substituted with one or more amino groups (-NR4R5) (i.e., "(C1-C6) alkyl" groups). Examples of aminoalkyl are R4R5N-(C1-C6) alkyl or -(CH2) m and mono-aminoalkyl groups such as NR4R5, where R4 and R5 and m are as defined in the detailed description of the invention.

[0029] With reference to the substituents R4 and R5 defined above, when either R4 or R5, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocyclic radical, at least one additional ring carbon atom in the heterocyclic radical can be replaced with at least one heteroatom or hetero-group (e.g., N, NH, S, or O) or can carry an -oxo (=O) substituent. The heterocyclic radical is optionally further substituted at an available point in the ring, i.e., a carbon atom or heteroatom or hetero-group available for substitution. Thus, examples of heterocyclic radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4-yl-2-one, and 4-methylpiperazin-1-yl.

[0030] The term “(C3-C 10 "(C-C)cycloalkyl," as well as "(C-C)cycloalkyl," refer to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and polycyclic ring systems such as adamantane-yl.

[0031] 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).

[0032] Examples of aryl or heteroaryl monocyclic ring systems include, for example, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl groups and the like.

[0033] Examples of aryl or heteroaryl bicyclic ring systems include naphthalenyl, biphenylenyl, purinyl, pteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzimidazol-yl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothiophenyl, benzodioxinyl, dihydrobenzodioxinyl, indenyl, dihydro-indenyl, dihydrobenzo[1,4]dioxinyl, benzothiazol-2-yl, dihydrobenzodioxepinyl, benzoxazinyl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl, 5,6,7,8-tetrahydro-1,7-naphthyridine radicals, and the like.

[0034] Examples of aryl or heteroaryl tricyclic ring systems include fluorenyl groups as well as benzo-fused derivatives of the above heteroaryl bicyclic ring systems.

[0035] The derived expression "(C3-C 10 "(C-C)heterocycloalkyl" and similarly "(C-C)heterocycloalkyl" refer to saturated or partially unsaturated mono-, bi-, or tricycloalkyl groups of the indicated number of carbon atoms in which at least one ring carbon atom is replaced with at least one heteroatom (e.g., N, NH, S, or O) and / or may have an -oxo (=O) substituent (e.g., C(=O), S(=O)). The heterocycloalkyl (i.e., heterocyclic radical or group) is optionally further substituted at any available point on the ring, i.e., at any carbon atom or heteroatom available for substitution.

[0036] Substitution of carbon atoms includes spirodisubstitution and substitution of two adjacent carbon atoms, in either case thus forming a further fused 5-6 membered heterocyclic ring.

[0037] The derived expression "hydroxyl-(C3-C6)heterocycloalkyl" refers to said heterocycloalkyl group being substituted at any available point of the ring, i.e., a carbon atom or heteroatom available for substitution, with a hydroxyl group.

[0038] Examples of (C3-C6)heterocycloalkyl are oxetanyl, tetrahydro-furanyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one. -yl, dihydropyrrolyl, 5-oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl, 1,1-dioxidethiomorpholino, octahydrocyclopenta[c]pyrrol-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl; 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, and the like.

[0039] Other examples of such heterocyclic radicals are 1-methyl-2-pyrrolidinyl, piperazin-4-yl-2-one, 4-methylpiperazin-1-yl, 1-methylpiperidin-4-yl, 4-methylpiperazin-1-yl-2-one, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 2-methyl-2,9-diazaspiro[5.5]undecan-9-yl, 9-methyl-3,9-diazaspiro[ 5.5]undecan-3-yl and (3aR,6aS)-5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl, 3-hydroxyoxetan-3-yl.

[0040] The term "aryl(C1-C6)alkyl" refers to an aryl ring linked to a straight or branched alkyl group having from 1 to 6 member carbon atoms, such as phenylmethyl (ie, benzyl), phenylethyl, or phenylpropyl.

[0041] Similarly, the term "heteroaryl(C1-C6)alkyl" refers to a heteroaryl ring linked to a straight or branched alkyl group having from 1 to 6 member carbon atoms, such as furanylmethyl.

[0042] The term "alkanoyl" refers to an HC(O)- or alkylcarbonyl group (e.g., (C1-C6)alkylC(O)-), where the group "alkyl" has the meaning defined above. Examples include formyl, acetyl, propanoyl, butanoyl.

[0043] The term “(C1-C 10 )alkoxy" or "(C1-C 10 "(C-C)alkoxyl," similarly "(C-C)alkoxy" or "(C-C)alkoxyl," etc., refer to a linear or branched hydrocarbon of the indicated number of carbon atoms attached to the remainder of the molecule through an oxygen bridge. "(C-C)alkylthio" refers to the above hydrocarbon attached through a sulfur bridge.

[0044] 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.

[0045] Similarly derived expressions "(C3-C6)heterocycloalkyl-(C1-C6)alkyl" and "(C3-C6)cycloalkyl-(C1-C6)alkyl" refer to heterocycloalkyl and cycloalkyl groups as defined above attached to the remainder of the molecule via an alkyl group having the indicated number of carbon atoms, e.g., piperidin-4-yl-methyl, cyclohexylethyl.

[0046] The derived expression "(C1-C6)alkoxy(C1-C6)alkyl" refers to an alkoxy group as defined above, such as methoxymethyl, attached to the remainder of the molecule via an alkyl group having the indicated number of carbon atoms.

[0047] Similarly, "(C1-C6)haloalkoxy(C1-C6)alkyl" refers to a (C1-C6)haloalkoxy" group as defined above attached to the remainder of the molecule via an alkyl group of the indicated number of carbon atoms, e.g., difluoromethoxypropyl.

[0048] Similarly, "(C1-C6)alkoxycarbonyl" refers to an alkoxy group as defined above attached to the remainder of the molecule via a carbonyl group.

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

[0050] And "(C1-C6)alkoxycarbonyl-(C1-C6)alkylthio" refers to a linked group such as ultimately methoxycarbonylmethylthio.

[0051] An oxo moiety is represented by (O) instead of other common notations, such as (=O). Thus, in terms of general formulas, a carbonyl group is preferably represented herein by -C(O)- instead of other common notations such as -CO, -(CO)-, or -C(=O)-. Generally, groups in parentheses are side chain groups that are not included in a chain, and parentheses are used when considered useful to aid in the clarity of linear chemical formulas; for example, the sulfonyl group -SO- is also represented as -S(O)-, for example, to provide clarity relative to the sulfinic group -S(O)O-.

[0052] When an index is present, the statement (value) "p is zero..." or "p is 0" means that there is no substituent or group having p, e.g., Ip, present, i.e., there are no optional substituents other than H. Similarly, when an index is attached to a bridging divalent group (e.g., (CH2)n), the statement "n in each instance is zero..." or "n is 0" means that there is no bridging group, i.e., it is a bond.

[0053] When basic amino or quaternary ammonium is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate.Similarly, when an acidic group such as a COOH group is present, the corresponding physiological cation salts may also be present, for example, containing alkali or alkaline earth metal ions.

[0054] When the compounds of formula (I) contain one or more asymmetric centers, they can exist as optical stereoisomers.

[0055] When the compounds of the present invention have at least one asymmetric center, they can therefore exist as enantiomers. When the compounds of the present invention have two or more asymmetric centers, they can also exist as diastereoisomers. It should be understood that all such single enantiomers, diastereoisomers, and mixtures thereof in any ratio are within the scope of the present invention. The absolute configuration (R) or (S) about the carbon bearing the asymmetric center is assigned based on the Cahn-Ingold-Prelog nomenclature system, which is based on group priority.

[0056] When "single stereoisomer," "single diastereoisomer," or "single enantiomer" is listed near the chemical name of a compound, it means that the isomer has been isolated as a single diastereoisomer or enantiomer (e.g., by chiral chromatography), but the absolute configuration of the relevant asymmetric center has not been determined / assigned.

[0057] Atropisomers result from restricted rotation about a single bond, where the steric strain barrier for rotation is high enough to allow the isolation of conformers (Bringmann G et al, Angew. Chemie Int. Ed. 44 (34), 5384-5427, 2005. doi:10.1002 / anie.200462661).

[0058] Oki defined atropisomers as conformational isomers that interconvert with half-lives of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).

[0059] Atropisomers differ from other chiral compounds in that they can often be thermally equilibrated, whereas other forms of chiral isomerization are usually only possible chemically.

[0060] Separation of atropisomers is possible through chiral resolution methods such as selective crystallization. In atropo-enantioselective or atroposelective synthesis, one atropisomer is formed at the expense of the other. Atroposelective synthesis can be achieved through the use of chiral auxiliaries such as the proline-derived asymmetric catalyst Corey-Bakshi-Shibata (CBS) catalyst, or by approaches based on thermodynamic equilibration when the isomerization reaction favors one atropisomer over the other.

[0061] The racemates of the compounds of formula (I) as well as the individual atropisomers (substantially free of the corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are within the scope of the present invention.

[0062] The present invention further relates to the corresponding deuterated derivatives of the compounds of formula (I). In the context of this invention, a deuterated derivative means that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount greater than the natural abundance. Preferably, the percentage of deuterium at that position is at least 90%, more preferably at least 95%, and even more preferably 99%.

[0063] All preferred groups or embodiments described above and below for compounds of formula (I) can be applied mutatis mutandis in combination with one another.

[0064] As noted above, the present invention provides compounds of general formula (I) that act as JAK inhibitors, methods for their preparation, and pharmaceutical compositions comprising them alone or in combination with one or more active ingredients, in admixture with one or more pharmaceutically acceptable carriers.

[0065] In a first aspect, the present invention provides compounds of formula (I) which are single enantiomers, diastereoisomers and mixtures thereof in any ratio. [ka] [During the ceremony, R1 is a heteroaryl group selected from imidazo[1,2-b]pyridazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, 3-oxo-(3,4-dihydropyrazin-2-yl)amino; R2 is a substituent that connects to the molecular scaffold, [ka] is the basis of where: V is absent (meaning a bond) or a divalent radical selected from O, S, N(R), C(O)N(R), N(R)C(O), N(R)C(O)O, N(R)S(O), N(R)C(O)N(R); Q is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, -(CH2) m NR4R5, (C3-C8)cycloalkyl, (C3-C 10 )heterocycloalkyl, —S—(C3-C6)heterocycloalkyl, and —N(R6)—(C3-C6)heterocycloalkyl; wherein said (C3-C8)cycloalkyl and (C3-C 10 ) Heterocycloalkyl is optionally —OH, oxo (i.e., (═O)), (C-C 10 ) alkyl, (C1-C6) alkoxy; halogen, (C1-C6) haloalkyl, alkanoyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy (C1-C6) alkyl, -N(R6)(CH2) m C(O)NR4R5, -(CO)NR4R5, -(CH2) m further substituted with one or more substituents selected from the group consisting of NR4R5, (C3-C8)cycloalkyl(C1-C6)alkyl; (C3-C6)heterocycloalkyl(C1-C6)alkyl, (C3-C6)heterocycloalkyl, and hydroxyl-(C3-C6)heterocycloalkyl; R3 is [ka] where the dashed line --- indicates a single or double bond; X is selected from N, S, and C; Y is selected from C, N; Z is selected from C, N, and O; K is absent (meaning a bond) or selected from O, C, S; G is absent (meaning a bond) or selected from C, O; (wherein each of X, Y, Z, K and G is attached to a ring and has the correct number of H or substituents depending on the valence) [ka] is the point of attachment of the substituent to the rest of the molecule (referring to the bond connecting the substituent R1, R2 or R3 to the molecular scaffold); n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; (R7) n In the formula (I), n=0 means that there is no substituent R7, i.e., R7 is H, and similarly, n=0 or m=0 means that there is no linking group -(CH2) n -or-(CH2) m There is no -(CH2) n -or-(CH2) m - means each is a bond); R4 and R5 are the same or different; -H, (C1-C6) alkyl, (C1-C6)haloalkyl and (C3-C6)heterocycloalkyl selected from the group consisting of: R6, independently at each occurrence, is selected from the group consisting of H, (C1-C6) alkyl, and (C1-C6) hydroxyalkyl; R7, independently at each occurrence, is -OH, oxo (i.e., =O), (C1-C6) alkyl, halogen, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, -(CH2) m one or more groups (preferably one or two) selected from the group consisting of NR4R5, (C1-C6)alkyl-S(O)2- and (C1-C6)alkyl-S(O)2N(R6)-; The R8 is (C1-C6)alkoxy, (C1-C6) haloalkoxy selected from the group consisting of: Preferably, R8 is methoxy, fluoromethoxy, or difluoromethoxy. or a pharmaceutically acceptable salt or solvate thereof.

[0066] In a preferred embodiment, the bicyclic moiety R [ka] teeth [ka] is selected from.

[0067] In a further preferred embodiment, the bicyclic moiety R3 is 13 [ka] is selected from the group consisting of:

[0068] One particularly preferred group of compounds is R3 is J1 and R8 is methoxy It is of formula I.

[0069] One such group of preferred compounds is the formula Ia [ka] [During the ceremony, R1 is pyrazolo[1,5-a]pyrimidin-3-yl or (3-oxo-3,4-dihydropyrazin-2-yl)amino; V is a divalent group selected from C(O)N(R6), N(R6)C(O)O; Q is (C1-C6) alkyl, (C1-C6) alkoxy, -(CH2) m NR4R5, (C3-C8)cycloalkyl and (C3-C 12 )heterocycloalkyl; wherein said (C3-C8)cycloalkyl and (C3-C 12 ) Heterocycloalkyl is optionally oxo (i.e., the group (=O)), (C1-C 10 ) alkyl, halogen, (C1-C6) hydroxyalkyl, —(CO)NR4R5; (C3-C8) cycloalkyl (C1-C6) alkyl; (C3-C6) heterocycloalkyl; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R4 and R5 are the same or different; -H, (C1-C6) alkyl, (C1-C6)haloalkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0070] Even more preferred within this group are: V is N(R6)C(O)O; Q is (C1-C6) alkyl, (C1-C6) alkoxy, -(CH2) m and (C3-C6)heterocycloalkyl; wherein said (C3-C6)heterocycloalkyl is selected from the group [ka] wherein X1 is selected from CH2, O, S, NH, NCH3, (C=O) and S(=O)2; The compound is of formula Ia above.

[0071] Even more preferred is V is C(O)N(R6), Q is -(CH2) m and (C3-C6)heterocycloalkyl; wherein said (C3-C6)heterocycloalkyl is selected from the group [ka] wherein X1 is selected from the group consisting of CHR9, O, S, NH, NCH3, CF2, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl, wherein R9 is H or —(CO)NR4R5; The compound is of formula Ia above.

[0072] Even more preferred is Q is [ka] wherein the tetrahydro-1H,3H-512-furo[3,4-c]pyrrol-1-one is (C3-C6)heterocycloalkyl, -S-(C3-C6)heterocycloalkyl or -N(R6)-(C3-C6)heterocycloalkyl selected from the group consisting of: [ka] is.

[0073] In certain embodiments, the present invention provides the compounds of Examples 1-86 listed in the table below, or pharmaceutically acceptable salts and solvates thereof. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0074] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the methods and procedures described in the experimental section below, or by slightly modified procedures readily available to one of ordinary skill in the art. While specific embodiments of the present invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Although optimal reaction conditions may vary depending on the particular reactants or solvents used, such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures. The preparations described below and in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0075] In some cases, known protecting groups (PGs) can be used to mask or protect sensitive or reactive moieties, requiring only one step according to general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0076] Here, and for clarity, the compounds of formula (I) described herein, including all compounds listed above, can generally be prepared according to the procedures set out in the schemes below. Where specific details or steps differ from the general schemes, they are detailed in the specific examples and / or additional schemes. [ka]

[0077] Compounds of formula (I) can be prepared according to Scheme 1. Compound IV is an intermediate, in which the general groups r1, r2, and r3 can be converted to R1, R2, and R3, respectively, by means of procedures well known to those skilled in the art, such as protecting group deprotection and / or functional group transformation, which may involve more than one step. The procedures can be applied to one or more of these groups (r1, r2, and r3) to convert intermediate IV to compounds of general formula I, which are detailed for specific examples in the experimental section. When such a transformation is not required (when r1, r2, and r3 correspond to R1, R2, and R3, respectively), it is clear that any of the general approaches described below for the preparation of intermediate IV will provide compounds of general formula I. [ka]

[0078] For synthetic convenience, cyclic and / or exocyclic NH moieties that may be present in r2 and / or r3 may need to be protected during the synthesis sequence. Suitable protecting groups for such NH moieties may be carbamate-type protecting groups such as Boc (tert-butoxycarbonyl) and / or hemiaminals such as SEM (2-(trimethylsilyl)ethoxymethyl). The Boc group may be inserted by reacting the NH derivative with BocO in 4, for example, in the presence of a base such as DMAP or pyridine at room temperature. The SEM group may be inserted by reacting the NH derivative with SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride) in a suitable organic solvent such as DMF in the presence of a strong base such as NaH or LiHMDS (lithium hexamethyldisilazide) at a low temperature such as 0°C.

[0079] The Boc group can be readily removed by treating the Boc-protected intermediate IV (or from other convenient upstream intermediates) with a strong organic or inorganic acid under acidic conditions. For example, the Boc group can be cleaved by treating the intermediate with neat trifluoroacetic acid or a mixture with DCM, DCE, THF, or a similar organic solvent, typically at room temperature for a short period of time (typically 1-3 hours). The SEM group can be removed by treating intermediate IV (or from other convenient upstream intermediates) under acidic conditions similar to Boc group removal. In some cases, SEM removal with acidic treatment is incomplete, thereby requiring further treatment with concentrated ammonia for complete removal of the formaldehyde adduct resistant to acidic treatment. It is understood that insertion and removal of the NH protecting group on r2 / r3 can be performed at more convenient times in the synthetic sequence.

[0080] Compounds of formula I (or intermediate IV) can be obtained by direct introduction of R1 (or r1) via a metal / palladium catalyzed cross-coupling reaction such as Suzuki coupling, Stille coupling, Buchwald-Hartwig or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005) by reaction of intermediate II with intermediate III.

[0081] For example, when R is pyrazolo[1,5-a]pyrimidin-3-yl, a suitable palladium-catalyzed cross-coupling for the introduction of R is the Suzuki coupling. The Suzuki coupling can be carried out by reacting intermediate II with an appropriate boronic acid or boron pinacolate derivative (intermediate III, where r is pyrazolo[1,5-a]pyrimidin-3-yl and A is dihydroxyboryl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) using a Pd catalyst such as tetrakistriphenylphosphinepalladium(0), PdCl(dppf) or a ligand-palladacycle catalyst precursor, such as XPhos-Pd-G3 [(2-dicyclohexylphosphino-2',4',6'-trimethyl-1,3,2-dioxaborolanyl)]. This reaction can be carried out in the presence of palladium(II) methanesulfonate (isopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate in an organic solvent such as 1,4-dioxane, THF, 1,2-dimethoxyethane, 2-propanol, or DMF, in the presence or absence of 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), under heating (typically in the range of 50-100°C) for a short period of time (typically 1-3 hours). Boronic acids and pinacoloborate boronic acid esters are generally commercially available or can be easily prepared by those skilled in the art starting from commercially available reagents.

[0082] A suitable palladium-catalyzed cross-coupling for introducing R1 when R1 is imidazo[1,2-b]pyridazin-3-yl is a Stille coupling, which can be carried out by reacting intermediate II with an appropriate stannane reagent (intermediate III, where r1 is imidazo[1,2-b]pyridazin-3-yl and A is tributylstannyl or trimethylstannyl) in the presence of a suitable palladium catalyst (e.g., Pd(PPh3)2Cl2) in a polar organic solvent (e.g., DMF or dioxane) with or without an additive (e.g., 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.

[0083] A suitable palladium-catalyzed cross-coupling for the introduction of r1 when r1 is (3-oxo-3,4-dihydropyrazin-2-yl)amino is the Buchwald-Hartwig coupling. For synthetic convenience, it may be necessary to protect the lactam group of (3-oxo-3,4-dihydropyrazin-2-yl)amino as an alkoxyimino group (e.g., methoxyimino, -C(OMe)=N-), which can be deprotected at the end of the synthesis from intermediate IV. Intermediate II and intermediate III (where r1 is 3-methoxypyrazine-2-aminyl and A is H) can be reacted with an appropriate 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). Reaction of the dopaladacycle system, or in general a suitable Pd source (e.g., Pd2(dba)3 or Pd(OAc)2) with a suitable phosphine ligand, such as a biphenylphosphine ligand type (RuPhos, X-Phos or similar), in the presence of a strong organic base such as sodium tert-butoxide or an inorganic base such as Cs2CO3 in an organic solvent such as 1,4-dioxane, THF or toluene, under heating at elevated temperature (typically 80-120 °C) for a short period of time (typically overnight) can provide intermediate IV, where r1 is 3-methoxypyrazine-2-aminyl. The preparation of compounds of formula I in which R1 is 3-oxo-3,4-dihydropyrazin-2-yl)amino can be achieved by means of demethylation of the corresponding methoxy-imino derivative by treatment of the protected precursor with TMS-Cl (trimethylsilyl chloride) and sodium iodide in acetonitrile for 1-5 hours at 60-100°C; these conditions can also ultimately lead to deprotection of the Boc / SEM groups present in r2 / r3.

[0084] The above method can provide at least one non-limiting synthetic route to the example compounds of the present invention starting from the appropriate intermediate II.

[0085] A potential approach for the preparation of intermediate II is shown in Scheme 2. Intermediate II can be prepared by N-arylation of intermediate V with halide intermediate VI using a copper-catalyzed Ullmann-type reaction. The Ullmann reaction between NH heteroaryl and aryl / heteroaryl halides (bromides or iodides) can be carried out in the presence of a suitable copper(I) catalyst / promoter such as CuI, CuO, or CuTC (copper thiophenecarboxylate), either ligand-free or in the presence of a suitable ligand such as N,N-dimethylglycine, proline, phenanthroline, or dimethylcyclohexane-1,2-diamine (DMCHA), in the presence of an inorganic base such as KCO or CsCO, in a polar organic solvent such as DMSO, DMF, or DMA, with heating overnight or longer (typically at 90-150 °C). [ka]

[0086] In other approaches, II i (for n: 0) and II ii Intermediate II, where r3 / R3 is J2 (shown as (n: 1, R7: 3-oxo), can be synthesized by means of a multi-step synthesis as shown in Scheme 3. Intermediate V and intermediate VIIa can undergo nucleophilic aromatic substitution (SNAr) to give intermediate VIIIa by reacting them in an organic solvent such as DMF, DMSO, or 1,4-dioxane in the presence of an organic base such as DBU or DIPEA or an inorganic base such as KCO3 or CsCO3 at room temperature or higher (up to 120 °C) for a short period of time (typically 1-4 hours). Similarly, intermediates VIIIb and VIIIc can be prepared from V by reaction with VIIb and VIIc, respectively.

[0087] Intermediate VIIIa can be reacted with mercaptoethanol (r5-SH, where r5 is ethanol-2-yl) under Pd-catalyzed C-S coupling conditions to give intermediate IXa. The C-S coupling can be carried out by reacting aryl bromide VIIIa with mercaptoethanol in the presence of a suitable catalyst system such as Pd2(dba)3 / Xantphos or other suitable palladium / phosphine source in an organic solvent such as 1,4-dioxane, toluene, or DMA in the presence of an organic base such as DIPEA or DBU at temperatures up to 100 °C for a short time (typically 3-5 h).

[0088] Intermediate IXb can be synthesized by nucleophilic aromatic substitution (SNAr) of intermediate VIIIa with methyl 2-sulfanylacetate (r5-SH, where r5 is methylethanoate-2-yl) by reacting intermediate IXb in an organic solvent such as acetonitrile or dioxane at elevated temperature (typically 120 °C) for a short period of time (typically 3-6 h). [ka]

[0089] Intermediate IXa can be converted to intermediate II in a three-step process including 1) nitro reduction, 2) chlorination and cyclization. i Nitro reduction can be achieved by heating intermediate IXa with a reducing agent such as iron or zinc powder in an organic solvent such as methanol or ethanol in the presence of an aqueous solution of a weak inorganic acid salt such as ammonium chloride at temperatures up to 80°C for a short period of time (typically 4-5 hours). Subsequent conversion of the alcohol to the corresponding chloride can be achieved by reaction with neat thionyl chloride or oxalyl chloride at low temperature (approximately 0°C). The chloride intermediate can be cyclized by heating (typically 80-100°C) in a suitable organic solvent such as DMF or 1,4-dioxane in the presence of an inorganic base such as potassium carbonate or sodium carbonate and an additive such as sodium iodide to give intermediate II. i can be obtained.

[0090] Intermediate IXb can be converted to intermediate II by a method involving nitro reduction and cyclization to a lactam. ii The nitro reduction of intermediate IXb can be accomplished similarly to that described for intermediate IXa. Cyclization can occur spontaneously during the nitro reduction step or can be promoted in a separate step by treatment with a strong organic acid such as TFA.

[0091] In another approach, intermediate II ii to the corresponding lactam with a borane such as the BH3*THF complex to give intermediate II i can be converted to

[0092] In another approach, intermediate II i to intermediate II by oxidation of the sulfide to a sulfone using an oxidizing agent such as m-CPBA in an organic solvent such as DCM at a temperature of about 0° C. iii can be converted to

[0093] Alternatively, in Scheme 3, II iv Intermediate II, shown as where r3 / R3 is J8, can be prepared by a multi-step process starting from intermediate VIIIa. In the first step, intermediate VIIIa can undergo aromatic nucleophilic substitution with a malonate ester such as diethyl malonate by heating the reagents (typically 60-70°C) in an organic solvent such as DMSO or DMF. In the second step, treatment with iron powder at elevated temperature (e.g., 90°C) in acetic acid as solvent promotes a one-pot nitro reduction, cyclization, and decarboxylation to give intermediate II. iv can be obtained.

[0094] In another approach, intermediate II iv II in a two-step procedure involving 1) NH protection with an SEM group and 2) cyclopropanation with a sulfur vinyl ylide such as vinyldiphenylsulfonium triflate. v can be converted to

[0095] In a different way, intermediate II viIntermediate II and Intermediate II when r3 / R3 is J6 (n:0) vii Intermediate II, shown as: when r3 / R3 is J1 (n:3, R7:3-oxo, 1,1-difluoro), can be prepared according to Scheme 4.

[0096] Intermediate VIIIb can be converted to intermediate X by a two-step process involving 1) deallylation and 2) nitro reduction. The deallylation reaction can be carried out by treating intermediate VIIIb with an inorganic base such as potassium carbonate or cesium carbonate in an organic solvent such as methanol or ethanol and in the presence of a Pd catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) chloride (typically at 50-70 °C). The subsequent nitro reduction can be carried out similarly as described in Scheme 3 for the reduction of intermediate IXa. Intermediate X can be selectively acylated at the aniline nitrogen to form the corresponding amide by transamination of methyl 2-2,2-dibromo-difluoroacetate promoted by DABAL-Me3 in an organic solvent such as THF at elevated temperatures (typically 130 °C). Subsequent cyclization of the amide intermediate promoted by an organic base such as DBU or DIPEA with heating (100-120 °C) in an organic solvent such as THF or dioxane affords intermediate II. vii can be obtained. [ka]

[0097] In another approach, intermediate II vi can be obtained from intermediate VIIIc by a two-step process involving mesylation of the free hydroxyl group of r4 (when r4 is propan-3-ol-1-oxyl), followed by one-pot nitro reduction and cyclization. Mesylation can be carried out by treating the alcohol with methanesulfonyl chloride in an organic solvent such as DMF at room temperature, followed by one-pot nitro reduction and cyclization by heating (about 80°C) the intermediate with iron in the presence of a weak inorganic acid such as aqueous ammonium chloride in an organic solvent such as ethanol.

[0098] In a different way, shown as IIa, r2 is -NR6(CH2) n Intermediate II, when Q', can be prepared according to Scheme 5. Q' is a group that, although different from Q, can be easily converted to Q by procedures well known to those skilled in the art, such as protective group deprotection procedures and / or functional group transformations, which may involve more than one step. [ka]

[0099] Intermediate XI can be prepared by 1) NH protection, 2) HNR(CH) n Intermediate Va can be converted to intermediate XI in a multi-step process involving CN coupling at Q' and 3) N-PG deprotection. A suitable protecting group for this NH of intermediate XI is, for example, the THP group (tetrahydropyranyl). THP introduction can be achieved by heating intermediate XI with a dihydropyran in an organic solvent such as THF, DCM, or a mixture thereof, in the presence of a sulfonic acid such as methanesulfonic acid, for several hours (12 hours or more) at about 40°C. The THP-protected intermediate XI can be converted to intermediate XI with HNR6(CH2). n C-N coupling between -Q' can be achieved by heating (typically 60-100 °C) the heteroaromatic iodide and amine in an organic solvent such as DMF or DMSO in the presence of a copper(I) catalyst / promoter such as CuI, CuO, or CuTC (copper thiophenecarboxylate), either ligand-free or in the presence of a suitable ligand such as proline, N,N-dimethylglycine, or dimethylcyclohexane-1,2-diamine (DMCHA), in the presence of an inorganic base such as KCO or CsCO. Finally, THP removal can be achieved by acidic treatment with an organic acid such as TFA or methanesulfonic acid in the presence of a silane scavenger such as triethylsilane in an organic solvent such as DMF or THF for a short period (approximately 2 hours) at room temperature. Conversion of intermediate Va to intermediate IIa can be achieved using conditions similar to those described in Scheme 2 for the conversion of intermediate V to intermediate II.

[0100] Alternatively, intermediates XI and VIIa can be converted to intermediate XIIa with SNAr in the same manner as described for the conversion of V and VIIa to VIIIa. Conversion of intermediate XIIa to VIIIa' can be carried out using conditions similar to those described above for CN coupling. Finally, conversion of VIIIa' to intermediate IIa (when r3 / R3 is J2) can be carried out by reaction of II of IXb. ii This can be achieved by applying conditions similar to those already described in Scheme 3 for the conversion to

[0101] In another approach, intermediate II can be obtained by further elaboration of the r group by generally accepted methods and in accordance with chemical principles. In the following schemes, the most common transformations that can be used to obtain specific intermediates II are detailed. For clarity, they are labeled with additional letter indices. [ka]

[0102] In one of these alternative approaches, intermediate IIc (where r2 is -C(O)N(R6)-(CH2) n Intermediate IIb (intermediate II where r2 is -C(O)OH) can be reacted with HNR6(CH2) according to Scheme 6, starting from intermediate IIb (intermediate II where r2 is -C(O)OH). n The amide coupling can be carried out by reacting an amine with an acid in an organic solvent such as DMF, DCM, or THF in the presence of a coupling agent such as HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), or COMU ((1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium) and an organic base such as DIPEA, TEA, or pyridine.

[0103] Alternatively, when synthetically convenient, intermediate IIb can be synthesized as a methyl ester and converted directly to the amide by transamination with the corresponding amine promoted by DABAL-Me3 in an organic solvent such as THF at elevated temperature (typically 130 °C).

[0104] In another approach, intermediate IIc can be prepared from intermediate IIe by displacement of Lg" by alkylation at the primary / secondary nitrogen present in the Q' moiety by treating amine Q' and halide IIe with an inorganic iodide such as sodium iodide in the presence of an organic base such as DIPEA, TEA, or an inorganic base such as sodium carbonate in an organic solvent such as DMF, acetone, or 1,4-dioxane at room temperature or above (e.g., 40°C) for a short period of time to overnight. Intermediate IIe can be converted to intermediate IIb and HNR6(CH2) by an amide coupling reaction using conditions similar to those described above in this scheme for the conversion of intermediate IIb to intermediate IIc. n It can be obtained from Lg''.

[0105] Intermediate IIb can be prepared starting from the appropriate intermediate V where r2 is -COOH or -COOMe using the conditions described above for the general synthesis of intermediate II in Scheme 2, Scheme 3 and Scheme 4.

[0106] In another approach, depicted in Scheme 7, intermediate IIg (or IIh) can be prepared by reacting intermediate IIf and HO(CH) n Q' (or HNR6(CH2) nQ') can be prepared from IIf via a two-step / one-pot process involving 1) isocyanate formation and 2) reaction with an alcohol (or amine) to form the corresponding carbamate (or urea). Intermediate IIf can be reacted with bis(trichloromethyl)carbonate in an organic solvent such as DCM, THF, or Me-THF at low temperatures, such as dry ice temperature (~78°C), in the presence of an organic base such as TEA or DIPEA for up to 1 or 2 hours to form the corresponding isocyanate; addition of the intermediate alcohol (or amine) and reaction at room temperature forms the carbamate of formula IIg (or urea of ​​formula IIh). Another method for forming the isocyanate intermediate from IIf is to use carbonyldiimidazole (CDI) in an organic solvent such as 2-Me-THF, heated overnight at a temperature of about 90°C.

[0107] In a different approach, carbamate IIg was prepared by the reaction of amine IIf with the corresponding alcohol chloroformate (Cl-C(O)O(CH) n Q') in an organic solvent such as DCM or THF and in the presence of a base such as pyridine or DIPEA.

[0108] [ka] In another method, intermediates of formula IIg (and IIh) can be prepared by reacting intermediate IIb and the alcohol intermediate HO(CH) n Q' (or the amine intermediate HNR6(CH2) nFrom Q'), intermediate IIb can be obtained by a two-step / one-pot method involving 1) acyl azide formation and Curtius rearrangement to give the corresponding isocyanate intermediate and 2) one-pot reaction of an isocyanate with an alcohol (or amine) to form the corresponding carbamate (or urea). The corresponding acyl azide of intermediate IIb can be obtained by reaction of IIb with an azide source such as azido(trimethyl)silane in the presence of a suitable coupling agent such as an alkylphosphonic anhydride such as T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution) and an organic base such as TEA or DIPEA in an organic solvent such as 2-methyl-THF, DMF, or toluene. The subsequent Curtius rearrangement can be carried out by thermolysis at about the solvent reflux temperature (typically 50°C-100°C) for several hours (typically 1-3 hours) to give the corresponding isocyanate; after isocyanate formation, the alcohol intermediate HO(CH2) n Q' (or amine HNR6(CH2) n Q') can be added and reflux continued overnight to form the corresponding carbamate of formula IIg (or urea IIh).

[0109] Intermediate IIf can be prepared starting from the appropriate intermediate V where r2 is -NH2 using the conditions described above for the general synthesis of intermediate II in Scheme 2, Scheme 3 and subsequent Scheme 4.

[0110] [ka] In another approach, depicted in Scheme 8, intermediate IIa, in which the exocyclic NH is protected by a Boc group, designated as Boc-IIa, can be prepared by 1) Boc insertion into the exocyclic amine and 2) Lg-(CH2) nIIf can be prepared by a two-step process involving alkylation with -Q'. Boc protection can be achieved by reacting IIf with BocO in an organic solvent such as THF or 1,4-dioxane and in the presence of a strong base such as LiHMDS (lithium hexamethyldisilazide) or NaH at a low temperature such as 0°C. Alkylation can be achieved by reacting the Boc intermediate with Lg-(CH) in an organic solvent such as DMF or THF in the presence of a strong base such as NaH at a low temperature such as 0°C. n -Q'.

[0111] In a different approach, intermediate II can be obtained by further conversion of the Q' group to Q" by means of functional group transformations summarized in Table 1, details of which are provided in the experimental section. Q" when different from Q is a group that can be easily converted to Q by means of procedures well known to those skilled in the art, such as protecting group deprotection and / or functional group transformations, which may involve more than one step. [Table 9]

[0112] In a different approach, intermediate IV can be obtained by further conversion of the Q' group to Q" by means of functional group transformations summarized in Table 2, details of which are provided in the experimental section. Q" when different from Q is a group that can be easily converted to Q by means of procedures well known to those skilled in the art, such as protecting group deprotection and / or functional group transformations, which may involve more than one step. [Table 10]

[0113] As detailed herein, the compounds of the present invention are kinase activity inhibitors that inhibit JAK kinase activity, particularly for the treatment of JAK-dependent diseases.

[0114] In one aspect, the present invention provides a compound of the present invention, i.e. a compound of formula (I) or a pharmaceutical composition thereof, for use as a medicament, preferably for respiratory and particularly pulmonary diseases.

[0115] In a further aspect, the present invention provides the use of Compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of disorders associated with the JAK mechanism, in particular for the treatment of disorders such as respiratory and pulmonary diseases.

[0116] In particular, the present invention provides a compound of formula (I) for use in the prevention and / or treatment of a pulmonary disease selected from the group consisting of asthma, chronic obstructive pulmonary disease COPD, idiopathic pulmonary fibrosis (IPF) acute lung injury and acute respiratory distress syndrome (ARDS).

[0117] Furthermore, the present invention provides a method for preventing and / or treating disorders associated with the JAK mechanism, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0118] In particular, the present invention provides methods for the prevention and / or treatment wherein the disorder is a respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

[0119] The use of the compounds of the invention for the prevention of the above-mentioned disorders is preferred.

[0120] The use of the compounds of the invention for the treatment of the above disorders is equally preferred.

[0121] Generally speaking, compounds that are JAK inhibitors may be useful in the treatment of many disorders associated with the JAK enzymatic mechanism.

[0122] In certain embodiments, the disorder that can be treated by the compounds of the present invention is selected from the group consisting of interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS).

[0123] In a further embodiment, the disorder is selected from asthma and chronic obstructive pulmonary disease (COPD).

[0124] The treatment method of the present invention comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, "effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means both a compound sufficient to treat the patient's condition but low enough to avoid significant side effects, which can nevertheless be routinely determined by one skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered once or according to a dosing regimen of multiple administrations at various intervals over a period of time. Typical daily dosages can vary depending on the particular route of administration selected.

[0125] The present invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0126] The present invention also relates to the use of the compounds of the present invention and pharmaceutical compositions thereof for various routes of administration.

[0127] Administration of the compounds of the present invention and pharmaceutical compositions thereof may be achieved, for example, by oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and infusion), inhalation, rectal, vaginal, topical, local, transdermal and ocular administration, depending on the needs of the patient.

[0128] A variety of solid oral dosage forms can be used to administer the compounds of the present invention, including solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known additives, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. Time-release capsules, tablets, and gels are also advantageous.

[0129] Various liquid oral dosage forms, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs, can also be used to administer the compounds of the present invention. Such dosage forms may also contain suitable known inert diluents such as water, and suitable known additives such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention can be formulated as an injectable composition in the form of an isotonic sterile solution, for example, for intravenous injection. Other formulations are also possible.

[0130] 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.

[0131] Formulations for vaginal administration are also known which may be in the form of creams, gels, pastes, foams or spray formulations which contain, in addition to the active ingredient, suitable carriers, etc.

[0132] For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, salve, lotion, emulsion, suspension, gel, solution, paste, powder, spray, or drops suitable for application to the skin, eye, ear, or nose. Topical administration may also include transdermal administration by means of a transdermal patch or the like.

[0133] The compound of the present invention can show a profile suitable for oral administration.The optimization of a drug for oral delivery requires certain characteristics that enable the orally administered compound to be absorbed and hardly removed by the GI (gastrointestinal) tract, in order to obtain good bioavailability (F%), and therefore maintain sufficient concentration in plasma and target tissue for a suitable time to sustain pharmacological effect.In order to enhance oral bioavailability, it is necessary to optimize one or more properties of the compound, such as but not limited to maximizing membrane permeability and reducing metabolic hotspots (in vitro clearance optimization).

[0134] For the treatment of diseases of the respiratory tract, as noted above, it may also be preferable to administer the compounds of the invention by inhalation.

[0135] Certain preferred compounds of the invention exhibit a profile suitable for administration by the inhaled route.

[0136] Drugs optimized for inhalation delivery require specific characteristics that allow the compound, when administered to the lung, to maintain a sufficient local concentration (pulmonary retention) to exert a pharmacological effect for a desired period of time, minimize drug absorption in the GI tract for the swallowed fraction, and generally insignificant levels in undesired compartments (i.e., plasma).To this end, one or more properties of the compound are optimized, including, but not limited to, membrane permeability, dissolution rate, and basicity of the compound to enhance binding to phospholipid-rich lung tissue or via lysosomal trapping.In some embodiments, the compounds of the present invention exhibit one or more of the above properties within the range desired for an inhalation compound.Inhaled JAKi preferably have additional properties that can further limit systemic exposure after inhalation.

[0137] A method to limit systemic exposure after local administration is soft drug design, which in the present invention means the introduction of specific moieties, e.g., cyclic esters or lactones, that favor controlled and rapid systemic metabolism (in the liver and / or in the blood) to metabolites that are predicted to be functionally less active compared to the parent compound. To this end, one approach has led to the optimization of "appropriately designed lactone derivatives" that can be substrates for liver and / or blood esterases, which can be beneficial in achieving enhanced clearance in vivo.

[0138] Thus, preferred compounds of the present invention exhibit one or more of the following properties: high biochemical activity on the target, strong functional activity (e.g., cell-based activity), and rapid clearance in representative assays (stability in liver microsomes and / or hepatocytes, plasma stability), potentially resulting in compounds with improved safety.

[0139] For the treatment of diseases of the respiratory tract, the compounds of the invention may be administered by inhalation, as described above.

[0140] Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations, which may be administered via a suitable inhalation device which may be selected from a dry powder inhaler, a pressurized metered dose inhaler or a nebulizer, respectively.

[0141] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0142] A diluent or carrier, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the invention.

[0143] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and other additives as desired.

[0144] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic or hydroalcoholic medium and may be nebulized using jet or ultrasonic nebulizers known from the prior art or by Respimat, a registered trademark of Boehringer Ingelheim Pharmaceuticals. (登録商標) It can be delivered by a soft mist nebulizer such as (Wachtel, H., Kattenbeck, s., Dunne, s. et al. Pulm Ther (2017) 3: 19).

[0145] Regardless of the route of administration, the compounds of the invention may be administered as single agents or in combination with other pharmaceutically active ingredients (i.e., as co-therapeutic agents administered as a fixed dose combination or in a combination therapy of separately formulated active ingredients).

[0146] The compounds of the present invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used to treat respiratory disorders and known to those skilled in the art, such as beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinase), nuclear factor kappa-B kinase subunit beta inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory drugs (NSAIDs) and mucus control agents.

[0147] The present invention also relates to kits comprising a pharmaceutical composition comprising a compound of the invention, alone or in combination or admixture with one or more pharmaceutically acceptable carriers and / or excipients, and a device, which may be a single or multiple dose dry powder inhaler, a metered dose inhaler, or a nebulizer.

[0148] The dosage of the compounds of the invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, the frequency of administration intervals, the particular compound utilized, the efficacy, toxicological and pharmacokinetic profile of the compound.

[0149] Pharmaceutical compositions comprising the compounds of the present invention suitable for administration by inhalation are in various inhalable forms such as inhalable powders (DPIs), propellant-containing metered dose aerosols (PMDIs) or propellant-free inhalable formulations (e.g., UDVs).

[0150] The present invention also relates to devices containing pharmaceutical compositions comprising the compounds of the invention, which may be single or multiple dose dry powder inhalers, metered dose inhalers and nebulizers, especially soft mist nebulizers.

[0151] The following examples will further illustrate the invention.

[0152] The features of the present invention will become apparent as the following description of exemplary embodiments is read, which are given by way of illustration of the invention and are not intended to be limiting thereof.

[0153] Preparation of Intermediates and Example Compounds General Experiment Details Chemical names of compounds were generated using Structure To Name Enterprise 10.0 Cambridge Software or the latest version.

[0154] When the reaction is carried out at a temperature above the boiling point of the solvent, it is contemplated that the reaction is carried out in a sealed vessel with conventional or microwave heating.

[0155] Purification by "chromatography" or "flash chromatography" refers to purification using a Biotage SP1 or Interchim puriFlash purification system or a Biotage Isolera Four purification system equipped with a Biotage Dalton 2000 mass detector, or equivalent MPLC using a pre-packed polypropylene column containing the stationary phase (cartridge). When the product was purified using a Si cartridge, this refers to an Interchim (or equivalent) pre-packed polypropylene column containing unbonded activated silica with spherical particles of 15 μm average particle size, or an Isolute® (or equivalent) pre-packed polypropylene column containing unbonded activated silica with irregularly shaped particles of 50 μm average particle size. Fractions containing the desired product (identified by TLC and / or LCMS analysis) were pooled and concentrated under reduced pressure. Purification by "reverse phase chromatography" or "reverse phase flash chromatography" refers to purification using a Biotage Sfar C 18This refers to purification on an MPLC instrument equipped with a C18-functionalized silica cartridge, such as a HPLC-MS / ...

[0156] NMR method NMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probehead), a Bruker DRX 500, a Bruker Avance AV 400 (5 mm RT direct probehead), or a Bruker DPX 300 spectrometer using standard Bruker pulse sequences. Alternatively, NMR spectra were recorded on a Varian MR-400 MHz spectrometer operating at 400 MHz or a Varian Unity Inova 400 spectrometer equipped with a 5 mm inverse-detected triple resonance probe operating at 400 MHz. DMSO-d6 or CDCl3 was used as the solvent. Chemical shifts are reported relative to the internal standard tetramethylsilane or to the solvent residual peak. All experiments were recorded at 298 K unless otherwise noted. Coupling constants (J values) are given in Hertz (Hz) and multiplicities are noted using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, nd = undetermined.

[0157] LCMS method Method 1 Acquity UPLC coupled to SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; [Table 11] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0158] Method 2 Acquity UPLC coupled to SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; [Table 12] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0159] Method 3 Acquity UPLC coupled to SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% v / v formic acid in water, mobile phase B: 0.1% v / v formic acid in acetonitrile; [Table 13] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1500AMU.

[0160] Method 4 Agilent LC 1260 Infinity with SFC and Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS; column: Acquity UPLC BEH C 18 (100 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.05% aqueous ammonia, mobile phase B: acetonitrile; [Table 14] Column temperature: 40°C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0161] Method 5 Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer;Column:Acquity UPLC BEH C 18 (100 mm × 2.1 mm id, 1.7 μm packing diameter), mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; [Table 15] Column temperature: 25°C; UV detection: 215 nm and 254 nm; MS conditions: ionization mode: alternate scan positive and negative electrospray (ES) + / ES - ), Scanning range: 100~1000AMU.

[0162] HPLC-MDAP Method 1 Agilent 1290 Infinity II Purification System; Column: Waters XBridge® (C18, 100 mm × 19 mm id, 5 μm), Mobile Phase A: 0.1% (v / v) formic acid in water, Mobile Phase B: acetonitrile; [Table 16]

[0163] Abbreviations used: AIBN = azobisisobutyronitrile; aq. = aqueous; Boc2O = di-tert-butyl dicarbonate; CDI = carbonyldiimidazole; 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; DMAP = 4-dimethylaminopyridine; DM CHDA = trans-N,N'-dimethylcyclohexane-1,2-diamine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); LCMS = liquid chromatography-mass spectrometry; LiHMDS = lithium bis(trimethylsilyl)amide; NBS = N-bromosuccinimide; μW = microwave; 1 H-NMR = proton nuclear magnetic resonance; RM = reaction mixture; Rt = retention time; RT = room temperature; Saturated = saturated; T3P (登録商標) = propylphosphonic anhydride; TEA = triethylamine; TFA - trifluoroacetic acid; THF = tetrahydrofuran; XPhos-Pd-G3-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0164] In the following procedures, some of the starting materials are identified through "Intermediate" or "Example" numbers followed by step numbers, which are provided solely as an aid to those skilled in the art of chemistry.

[0165] "Similar" or "equivalent" procedures means that such procedures may include minor variations, such as reaction temperatures, amounts of reagents / solvents, reaction conditions, work-up conditions and / or chromatographic purification conditions.

[0166] The stereochemistry of example compounds, when indicated, has been assigned with the assumption that any resolved stereocenters in the starting materials will be maintained throughout all subsequent reaction conditions.

[0167] Unless otherwise stated, when the absolute configuration (R) or (S) is stated in the compound name, the ee% should be considered to be 90% or greater.

[0168] Intermediate Production Intermediate 1 Process 1 [ka] 4-(Difluoromethoxy)-2-nitrophenol (Intermediate 1-1) A solution of 4-(difluoromethoxy)phenol (385 μL, 3.12 mmol) in DCE (3 mL) was cooled to 0° C. Concentrated nitric acid 63% w / w (456 μL) was added dropwise and the RM was stirred at 0° C. for 3 h. The RM was poured into an ice / water mixture and extracted with DCE (10 mL). The organic layer was separated, dried and evaporated under reduced pressure to give the desired product (630 mg), which was used in the next step without further purification. LCMS (Method 1): Rt = 0.40 min 1H-NMR (500 MHz, DMSO-d6) δ: 11.09 (bs, 1H), 7.73 (d, J = 2.9 Hz, 1H), 7.42 (dd, J = 9.0, 2.9 Hz, 1H), 7.18 (t, J = 73.1 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H).

[0169] Process 2 [ka] 1-(2-Bromoethoxy)-4-(difluoromethoxy)-2-nitrobenzene (Intermediate 1-2) A mixture of intermediate 1-1 (630 mg, 3.07 mmol) and K2CO3 (1.27 g, 9.21 mmol) in DMF (10 mL) and 1,2-dibromoethane (265 μL, 3.07 mmol) was stirred at 60 °C overnight. After cooling to RT, the RM was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried, and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–20% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (466 mg). LCMS (Method 1): Rt = 1.15 min, No MS data 1 H-NMR (500 MHz, DMSO-d6) δ: 7.80 (d, J = 2.4 Hz, 1H), 7.44-7.52 (m, 2H), 7.23 (t, J = 73.1 Hz, 1H), 4.50 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.4Hz, 2H).

[0170] Process 3 [ka] 6-(Difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 1-3) Intermediate 1-2 (466 mg, 0.78 mmol) was dissolved in ethanol (42 mL) and heated at 80°C. Then, a solution of NH4Cl (166 mg, 3.10 mmol) in water (5 mL) was added, followed by the addition of iron (434 mg, 7.80 mmol). The RM was stirred at 80°C for 3 h. After cooling to RT, the RM was diluted with water and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-20% EtOAc in cyclohexane to give the title product (88 mg). LCMS (Method 1): Rt = 0.99 min, ES + m / z 202.1 [M+H] + .

[0171] Process 4 [ka] 7-Bromo-6-(difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 1) To a solution of intermediate 1-3 (44.0 mg, 0.22 mmol) in EtOAc (1 mL) cooled to 0 °C, NBS (38.9 mg, 0.22 mmol) was added and the RM was stirred at RT for 5 h. The RM was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, passed through a phase separator, and concentrated under reduced pressure to give the desired product (63 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.14 min, ES + m / z 280.0 / 282.1 [M+H] + .

[0172] Intermediate 2 Process 1 [ka] 7-Bromo-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 2-1) A solution of 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (3.0 g, 18.20 mmol) in EtOAc (30.0 mL) was cooled to 0 °C. 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (2.6 g, 9.08 mmol) was added portionwise over 15 min. The RM was stirred for an additional 30 min at 0 °C and quenched with aqueous KCO (10% w / w; 60 mL). The organic layer was separated, washed with saturated aqueous NaCl, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–30% EtOAc in cyclohexane to give the title product (3.5 g). LCMS (Method 1): Rt = 0.97 min, ES + m / z 243.9 / 245.9 [M+H] + .

[0173] Process 2 [ka] tert-Butyl 7-bromo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 2) THF (15 mL) was added to a mixture of intermediate 2-1 (1.4 g, 5.74 mmol), DMAP (840.9 mg, 6.88 mmol), and BocO (2.80 g, 13.19 mmol), and the RM was then stirred at RT overnight. The RM was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was washed with 2 M aqueous citric acid (2 × 20 mL), saturated aqueous NaCl (20 mL), and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in cyclohexane to give the title compound (1.26 g). LCMS (Method 1): Rt = 1.27 min 1 H-NMR (300 MHz, CDCl3) δ: 7.56 (brs, 1H), 7.05 (s, 1H), 4.14-4.18 (m, 2H), 3.82 (s, 3H), 3.78-3.82 (m, 2H), 1.53 (s, 9H).

[0174] Intermediate 3 Process 1 [ka] tert-Butyl 7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 3-1) A solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (500 mg, 3.06 mmol), DMAP (449 mg, 3.68 mmol), and BocO (1.54 g, 7.05 mmol) in THF (10 mL) was stirred at RT overnight. Additional BocO was added, and stirring continued at RT. The RM was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was washed with 2 M aqueous citric acid (2 × 15 mL), saturated aqueous NaCl (20 mL), and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in cyclohexane to give the title product (228 mg). LCMS (Method 1): Rt = 1.35 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.18 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.57 (dd, J = 8.5, 2.6 Hz, 1H), 3.69 (s, 3H), 3.56-3.60 (m, 2H), 2.63 (t, J = 6.46 Hz, 2H), 1.74-1.82 (m, 2H), 1.45 (s, 9H).

[0175] Process 2 [ka] tert-Butyl 6-bromo-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 3) A solution of intermediate 3-1 (228 mg, 0.86 mmol) in EtOAc (10 mL) was cooled to 0 °C. 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (124 mg, 43.3 mmol) was added portionwise over 15 min. The RM was stirred at 0 °C for 20 min and then quenched with 10% (w / w) aqueous K2CO3 (20 mL). The organic layer was separated, washed with saturated aqueous NaCl (20 mL), and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–15% EtOAc in cyclohexane to give the title product (240 mg). LCMS (Method 1): Rt = 1.46 min, ES + m / z 285.9 / 287.9 ​​[M+H] + .

[0176] Intermediate 4 [ka] 7-Bromo-8-methoxy-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (Intermediate 4) 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (123 mg, 0.43 mmol) was added portionwise over 10 min to a solution of 8-methoxy-1,3,4,5-tetrahydro-1-benzazepin-2-one (165 mg, 0.86 mmol) in EtOAc (4 mL) at 0 °C, and the RM was stirred at RT overnight. The RM was quenched with saturated aqueous NaHCO and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, passed through a phase separator, and concentrated under reduced pressure to give the title product (230 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 0.93, ES + m / z 270.0 / 272.0 [M+H] + .

[0177] Intermediate 5 Process 1 [ka] tert-Butyl 7-methoxy-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 5-1) A solution of 7-methoxy-2,3-dihydro-1H-quinolin-4-one (100.0 mg, 0.56 mmol), DMAP (20.7 mg, 0.17 mmol), and BoCO (147.8 mg, 0.68 mmol) in THF (1.0 mL) was stirred at RT for 2 h. The RM was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, passed through a phase separator, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in cyclohexane to give the title product (138 mg). LCMS (Method 1): Rt = 1.11 min 1 H-NMR (500 MHz, DMSO-d6) δ: 7.79 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 8.4, 2.0 Hz, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.66 (t, J = 6.1 Hz, 2H), 1.51 (s, 9H).

[0178] Process 2 [ka] tert-Butyl 6-bromo-7-methoxy-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 5) A solution of intermediate 5-1 (100.0 mg, 0.36 mmol) in EtOAc (2.0 mL) was cooled to 0 °C, followed by the addition of NBS (64.2 mg, 0.36 mmol). The RM was warmed to RT and heated at 65 °C for 30 h. After cooling to RT, the RM was diluted with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl and passed through a phase separator. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–40% EtOAc in cyclohexane to give the title product (153 mg). LCMS (Method 1): Rt = 1.30 min. 1H-NMR (500 MHz, DMSO-d6) δ: 7.93 (s, 1H), 7.46 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 2.69 (t, J = 6.0 Hz, 2H), 1.52 (s, 9H).

[0179] Intermediate 6 Process 1 [ka] tert-Butyl 6-methoxyindoline-1-carboxylate (Intermediate 6-1) A solution of 6-methoxyindoline (1.0 g, 6.70 mmol), BoCO (1.76 mg, 8.04 mmol), and DMAP (819 mg, 6.70 mmol) in THF (20 mL) was stirred at RT for 6 h. The RM was partitioned between EtOAc (50 mL) and water (30 mL), and the organic layer was washed with 10% w / w aqueous citric acid (2 × 50 mL), saturated aqueous NaHCO (50 mL), and saturated aqueous NaCl (50 mL). The organic phase was evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–15% EtOAc in cyclohexane to give the title product (1.16 g). LCMS (Method 1): Rt = 1.25 min, ES + m / z 250.0 [M+H] + .

[0180] Process 2 [ka] tert-Butyl 5-bromo-6-methoxyindoline-1-carboxylate (Intermediate 6) 1,3-Dibromo-5,5-dimethyl-imidazolidine-2,4-dione (0.66 g, 2.3 mmol) was added portionwise over 15 min to a solution of intermediate 6-1 (1.16 g, 4.65 mmol) in EtOAc (70 mL) at 0 °C. The RM was stirred at RT for 2 h and then quenched with 10% w / w aqueous KCO (75 mL). The organic layer was separated, washed with saturated aqueous NaCl (35 mL), and concentrated under reduced pressure to give the desired product (1.52 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.40 min, ES + m / z 228.0 / 230.0 [M+H] + .

[0181] Intermediate 7 Process 1 [ka] tert-Butyl 6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 7-1) The title compound was prepared in a manner analogous to Intermediate 3-Step 1, starting from 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine. LCMS (Method 5): Rt = 2.5 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.47 - 7.38 (m, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 8.9, 3.0 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.80 - 3.72 (m, 2H), 3.68 (s, 3H), 1.50 (s, 9H).

[0182] Process 2 [ka] tert-Butyl 7-iodo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 7) Intermediate 7-1 (5.9 g, 22.1 mmol) was dissolved in DMF (60 mL), then N-iodohydroxysuccinimide (12.7 g, 111 mmol) was added, and the RM was stirred at 40 °C overnight. The RM was quenched with cold water and extracted with EtOAc. The combined organic layers were evaporated to dryness, and the residue was purified by silica gel chromatography with a gradient elution of 1:1 to 3:2 DCM-hexane to give the title compound (7.38 g). LCMS (Method 1): Rt = 2.8 min 1 H-NMR (300 MHz, DMSO-d6) δ: 7.50 (s, 1H), 7.24 (s, 1H), 4.14 (dd, J = 5.3, 3.8 Hz, 2H), 3.80 - 3.75 (m, 2H), 3.74 (s, 3H), 1.51 (s, 9H).

[0183] Intermediate 8 Process 1 [ka] 5-Methoxybenzo[d]oxazol-2(3H)-one (Intermediate 8-1) CDI (2.40 g, 14.8 mmol) was added portionwise over 1 h to a refluxing solution of 2-amino-4-methoxy-phenol (1.00 g, 14.4 mmol) in THF (20 mL), and the RM was refluxed for an additional 1 h. The RM was cooled to RT, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with water (3 × 30 mL) and saturated aqueous NaCl (2 × 30 mL). The organic layer was dried over MgSO and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–80% DCM / MeOH / NHOH (90:5:0.5) in DCM to give the title product (700 mg). LCMS (Method 1): Rt = 0.70 min, ES + m / z 166.1 [M+H] + .

[0184] Process 2 [ka] 6-Iodo-5-methoxybenzo[d]oxazol-2(3H)-one (Intermediate 8-2) A solution of intermediate 8-1 (400 mg, 2.42 mmol) and NIS (817 mg, 3.63 mmol) in DMF (5 mL) was stirred at RT for 1 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with water (3 × 20 mL) and saturated aqueous NaCl (2 × 10 mL). The organic phase was evaporated under reduced pressure to give the title product (626 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 0.93 min, ES + m / z 291.9 [M+H] + .

[0185] Process 3 [ka] 6-Iodo-5-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 8) A solution of intermediate 8-2 (300 mg, 1.03 mmol) in DMF (9 mL) was added to a suspension of NaH (60.0% in mineral oil, 41.2 mg, 1.03 mmol) in DMF (5 mL) cooled to 0 °C. The RM was stirred for 30 min while allowing to reach RT. After cooling the RM to 0 °C, 2-(chloromethoxy)ethyl-trimethyl-silane (192 μL, 1.03 mmol) was added dropwise. The RM was stirred for 2 h while allowing to reach RT. The RM was quenched with saturated aqueous NaHCO (15 mM) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (20 mL), saturated aqueous NaCl (20 mL), dried over MgSO, and concentrated under reduced pressure to give the desired product (300 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.49 min. 1H-NMR (300 MHz, DMSO-d6) δ: 7.78 (s, 1H), 7.13 (s, 1H), 5.25 (s, 2H), 3.83 (s, 3H), 3.61 (t, J = 8.2 Hz, 2H), 0.86 (t, J = 8.0 Hz, 2H), -0.06 (s, 9H).

[0186] Intermediate 9 Process 1 [ka] 1-Bromo-4,5-bis(bromomethyl)-2-methoxybenzene (Intermediate 9-1) 1-Bromo-2-methoxy-4,5-dimethyl-benzene (200 mg, 0.93 mmol) was dissolved in α,α,α-trifluorotoluene (10.0 mL). NBS (331 mg, 1.86 mmol) and AIBN (30.5 mg, 0.19 mmol) were added, and the RM was stirred at 90 °C for 3 h. After cooling to RT, the RM was diluted with EtOAc, washed with water and saturated aqueous NaCl, dried on a phase separator, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–30% EtOAc in cyclohexane to give the title product (246 mg). LCMS (Method 1): Rt = 1.34 min. 1 H-NMR (300 MHz, DMSO-d6) δ: 7.74 (s, 1H), 7.26 (s, 1H), 4.80 (s, 2H), 4.79 (s, 2H), 3.87 (s, 3H).

[0187] Process 2 [ka] 5-Bromo-6-methoxy-2-(methylsulfonyl)isoindoline (Intermediate 9) NaH (60.0%, 56.6 mg, 1.42 mmol) was added to a solution of methanesulfonamide (135 mg, 1.42 mmol) in DMF (10.0 mL), and the RM was stirred for 1 h. A solution of intermediate 9-1 (240 mg, 0.64 mmol) in DMF (10.0 mL) was added dropwise, and the resulting solution was stirred at 50 °C for 3 h and at RT overnight. The RM was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous NaCl, passed through a phase separator, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–30% EtOAc in cyclohexane to give the title product (160 mg). LCMS (Method 1): Rt = 1.34 min. 1 H-NMR (300 MHz, DMSO-d6) δ: 7.56 (s, 1H), 7.12 (s, 1H), 4.57 (s, 2H), 4.55 (s, 2H), 3.83 (s, 3H), 2.96 (s, 3H).

[0188] Intermediate 10 Process 1 [ka] 5-Bromo-2-(tert-butylthio)-4-methoxybenzaldehyde (Intermediate 10-1) A mixture of 5-bromo-2-fluoro-4-methoxy-benzaldehyde (1.0 g, 4.29 mmol), 2-methyl-2-propanethiol (726 μL, 6.44 mmol) and KCO (949 mg, 6.87 mmol) in DMF (15 mL) was stirred at 80° C. for 3 h. The RM was cooled to RT and poured into water (30 mL). The formed precipitate was collected by filtration, washed with water (2×10 mL), and dried at 45° C. for 3 h to give the title product (1 g). LCMS (Method 1): Rt = 1.40 min. 1H-NMR (300 MHz, CDCl3) δ: 10.6 (s, 1H), 8.20 (s, 1H), 7.08 (s, 1H), 3.98 (s, 3H), 1.32 (s, 9H).

[0189] Process 2 [ka] 5-Bromo-2-(tert-butylthio)-4-methoxybenzaldehyde oxime (Intermediate 10-2) A solution of intermediate 10-1 (0.9 g, 0.3 mmol), hydroxylamine chloride (413 mg, 0.59 mmol), and sodium acetate (584 mg, 7.12 mmol) in EtOH (9 mL) was stirred at RT for 1 h. The RM was filtered to remove residual solids, and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc (25 mL), washed with water (15 mL), saturated aqueous NaCl (15 mL), dried over MgSO, and the solvent was removed under reduced pressure to give the desired product (997 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.26 min. 1 H-NMR (300 MHz, DMSO-d6) δ: 11.34 (s, 1H), 8.90 (s, 1H), 7.99 (s, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 1.24 (s, 9H).

[0190] Process 3 [ka] 5-Bromo-6-methoxybenzo[d]isothiazole (Intermediate 10) A solution of intermediate 10-2 (0.87 g, 2.73 mmol) and TsOH (52 mg, 0.27 mmol) in i-PrOH (8 mL) was stirred at 100 °C overnight and then at 110 °C for 30 min in a μW reactor. A second portion of TsOH was added, and the RM was further stirred in a μW reactor at 120 °C for 1 h for two cycles. After cooling to RT, the formed precipitate was collected by filtration and dried at 45 °C to give the desired product (280 mg). LCMS (Method 1): Rt = 1.10 min. 1 H-NMR (500 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 3.96 (s, 3H).

[0191] Intermediate 11 Process 1 [ka] Methyl (4-bromo-2-formyl-5-methoxyphenyl)carbamate (Intermediate 11-1) Methyl chloroformate (170 μL, 2.2 mmol) was added dropwise to a solution of 2-amino-5-bromo-4-methoxy-benzaldehyde (200 mg, 0.87 mmol) and DIPEA (0.61 mL, 3.5 mmol) in DCM (5 mL) cooled to 0 °C. The RM was stirred at 40 °C for 2 days. The RM was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-25% DCM / MeOH (9:1) in DCM to give the title product (190 mg). LCMS (Method 1): Rt = 1.16 min, ES + m / z 288.0 / 290.0 [M+H] +

[0192] Process 2 [ka] 6-Bromo-7-methoxy-3-methyl-3,4-dihydroquinazolin-2(1H)-one (Intermediate 11) A solution of intermediate 11-1 (185 mg, 0.64 mmol) and methanolic methylamine (9.8 M, 97 μL, 0.95 mmol) in AcOH (2 mL) was stirred at 130 °C for 15 min in a μW reactor. The RM was cooled to RT, and formic acid (1.2 mL, 32 mmol) was added. The RM was stirred at 150 °C for 30 min. The RM was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (154 mg). LCMS (Method 1): Rt = 0.88 min, ES + m / z 271.1 / 273. [M+H] +

[0193] Intermediate 12 [ka] 3-(Tributylstannyl)imidazo[1,2-b]pyridazine (Intermediate 12) 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, then tri-n-butyltin chloride (685 μL, 2.5 mmol) was added dropwise, and the RM was stirred at RT for an additional 30 min. The RM was cooled in an ice bath, quenched with water (5 mL) along with 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 alumina (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] +

[0194] Intermediate 13 [ka] 3-((2-hydroxyethyl)thio)dihydrofuran-2(3H)-one (Intermediate 13) A solution of 3-bromotetrahydrofuran-2-one (822 μL, 9.09 mmol), 2-sulfanylethanol (2.55 mL, 36.4 mmol), and DIPEA (1.74 mL, 10.0 mmol) in THF (4 mL) was stirred at RT overnight. The RM was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-50% EtOAc in DCM to give the title product (1.43 g). 1 H-NMR (300 MHz, CDCl3) δ: 4.42 (dt, J = 8.9, 7.4 Hz, 1H), 4.31 (ddd, J = 9.1, 8.0, 4.8 Hz, 1H), 3.82-3.87 (m, 2H), 3.63 (dd, J = 8.7, 5.5 Hz, 1H), 3.07 (ddd, J = 14.3, 5.9, 4.8, 1H), 2.75-2.78 (m, 1H), 2.67 (ddd, J = 15.9, 13.8, 8.0, 1H), 2.08-2.16 (m, 1H).

[0195] Intermediate 14 [ka] 3-((2-hydroxyethyl)(methyl)amino)dihydrofuran-2(3H)-one (Intermediate 14) A solution of 3-bromotetrahydrofuran-2-one (782 μL, 8.65 mmol), 2-(methylamino)ethanol (1.39 mL, 17.3 mmol) in THF (4 mL) was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH (9:1) in DCM to give the title product (295 mg). 1H-NMR (300 MHz, CDCl3) δ: 4.37 (dt, J = 9.1, 2.1 Hz, 1H), 4.18 (ddd, J = 10.2, 9.6, 6.6 Hz, 1H), 3.73 (dd, J = 10.9, 8.9 Hz, 1H), 3.63 (t, J = 5.3, 2H), 2.76-2.81 (m, 2H), 2.42 (s, 3H), 2.11-2.39 (m, 1H).

[0196] Intermediate 15 Process 1 [ka] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)piperidine-4-carboxylate (Intermediate 15-1) A suspension of tert-butyl N-(2-bromoethyl)carbamate (3 g, 13.0 mmol), ethyl piperidine-4-carboxylate (2.1 mL, 13.0 mmol), and K2CO3 (3.7 g, 27 mmol) in DMF (30.0 mL) was stirred at 65 °C for 24 h. After cooling to RT, the RM was diluted with water (80 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (80 mL) and saturated aqueous NaCl (50 mL). The organic solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM:MeOH (93:7) in DCM to give the title product (3.24 g). LCMS (Method 2): Rt = 1.05 min, ES + m / z 301.3 [M+H] + .

[0197] Process 2 [ka] Ethyl 1-(2-aminoethyl)piperidine-4-carboxylate (Intermediate 15) A solution of intermediate 15-1 (1.77 g, 5.9 mmol) and TFA (8.8 mL, 118 mmol) in DCM (14 mL) was stirred at RT overnight. The volatiles were removed under reduced pressure, and the crude product was passed through an SCX cartridge, washed with EtOH (500 mL), and eluted with 15% aqueous NH in EtOH (100 mL) to give the title product (1.16 g). 1 H-NMR (300 MHz, CDCl3) δ: 4.13 (q, J = 6.9 Hz, 2H), 2.84-2.88 (m, 2H), 2.78 (t, J = 6.2 Hz, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.24-230 (m, 1H), 2.02 (t, J = 11.5 Hz, 2H), 1.87-1.91 (m, 2H), 1.71-1.79 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H).

[0198] Intermediate 16 [ka] 4-(3-Hydroxypropyl)morpholin-2-one (Intermediate 16) A solution of 3-(2-hydroxyethylamino)propan-1-ol (393 mg, 3.30 mmol), methyl 2-bromoacetate (344 μL, 3.63 mmol), and KCO (502 mg, 3.63 mmol) in dry acetonitrile (14 mL) was stirred at RT overnight. The RM was filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (10 mL). The combined organic layers were passed through a phase separator, and the solvent was removed under reduced pressure to give the desired product (120 mg), which was used in the next synthetic step without further purification. 1H-NMR (300 MHz, CDCl3) δ: 4.37-4.40 (m, 2H), 3.67-3.82 (m, 2H), 3.34 (s, 2H), 3.05 (m, 1H), 2.73 (t, J = 5.1 Hz, 2H), 2.62 (t, J = 6.2 Hz, 2H), 1.74 (quint, J = 5.5 Hz, 2H).

[0199] Intermediate 17 [ka] 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 17) Dihydropyran (9.79 mL, 107 mmol) and methanesulfonic acid (464 μL, 7.16 mmol) were added to a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (10 g, 35.8 mmol) in DCM (100 mL) and THF (50 mL). The RM was stirred at 40 °C for 4 h and then at RT overnight. The RM was evaporated to dryness, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–40% EtOAc in cyclohexane to give the title product (7.5 g). LCMS (Method 2): Rt = 1.22 min, ES + m / z 364.0 / 366.0 [M+H] + .

[0200] Intermediate 18a Process 1 [ka] 6-Chloro-N-(2-morpholinoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18a-1) A solution of degassed intermediate 17 (900 mg, 2.48 mmol), 2-morpholinoethanamine (1.30 mL, 12.7 mmol), KCO (2.05 g, 14.9 mmol), proline (85.5 mg, 0.74 mmol), and CuI (94.3 mg, 0.50 mmol) in DMF (10 mL) was stirred under nitrogen at 100 °C for 2 h. After cooling to RT, the RM was diluted with water (30 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with 10% w / w aqueous ammonia solution (2 × 15 mL), water (2 × 20 mL), and saturated aqueous NaCl solution (40 mL). The organic phase was evaporated under reduced pressure and the residue purified by flash chromatography on a Si cartridge eluting with 0-80% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (750 mg). LCMS (Method 2): Rt = 0.94 min, ES + m / z 366.3 / 368.3 [M+H] + .

[0201] Process 2 [ka] 6-Chloro-N-(2-morpholinoethyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18a) A solution of intermediate 18a-1 (635 mg, 1.88 mmol), TFA (2.66 mL, 34.7 mmol), and triethylsilane (0.9 mL, 5.64 mmol) in DCM (20 mL) was stirred at RT for 2 h. The RM was quenched with water (15 mL) and the pH was adjusted to 9.5. The aqueous phase was further extracted with DCM (3 × 20 mL), and the combined organic layers were evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (250 mg). LCMS (Method 1): Rt = 0.42 min, ES + m / z 282.0 / 283.9 [M+H] +

[0202] Intermediate 18b Process 1 [ka] 6-Chloro-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18b-1) The title product was prepared in a manner similar to intermediate 18a-1 (step 1) starting from intermediate 17 (230 mg, 0.63 mmol) and methylamine hydrochloride (171 mg, 2.5 mmol). DMSO was used as the reaction solvent instead of DMF. LCMS (Method 2): Rt = 0.94 min, ES + m / z 267.1 / 269.1 [M+H] + .

[0203] Process 2 [ka] 6-Chloro-N-methyl-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18b) The title compound was prepared analogously to intermediate 18a (step 2) starting from intermediate 18b-1. LCMS (Method 2): Rt = 0.51 min, ES + m / z 183.1 / 185.1 [M+H] +

[0204] Intermediate 19 [ka] 6-(6-chloro-3-((2-morpholinoethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 19) A degassed mixture of intermediate 18a (102 mg, 0.36 mmol), intermediate 8 (85.0 mg, 0.18 mmol), K2CO3 (151 mg, 1.09 mmol), proline (6.27 mg, 0.05 mmol), and CuI (6.9 mg, 36 μmol) in DMF (2 mL) was stirred under nitrogen at 100 °C for 8 h. After cooling to RT, the RM was diluted with water (10 mL) and extracted with EtOAc (5 × 5 mL). The combined organic layers were washed with 10% w / w aqueous ammonia solution (2 × 10 mL), water (2 × 20 mL), and saturated aqueous NaCl (30 mL). The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–80% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (15 mg). LCMS (Method 1): Rt = 1.07 min, ES + m / z 575.4 / 577.4 [M+H] + .

[0205] Intermediate 20 [ka] 6-Chloro-1-(6-methoxybenzo[d]isothiazol-5-yl)-N-(2-morpholinoethyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 20) A degassed mixture of Intermediate 18a (120 mg, 0.43 mmol), Intermediate 10 (156 mg, 0.64 mmol), CuI (40.6 mg, 0.21 mmol), N,N-dimethylglycine (43.9 mg, 0.43 mmol), and KCO (118 mg, 0.85 mmol) in DMSO (2.5 mL) was heated overnight at 100 °C under nitrogen. After cooling to RT, the RM was diluted with EtOAc (15 mL) and washed with water (2 × 10 mL) and saturated aqueous NaCl (10 mL). The RM was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–80% DCM / MeOH / NHOH (90:5:0.5) in DCM to give the title product (105 mg). LCMS (Method 1): Rt = 0.99 min, ES + m / z 445.2 / 447.2 [M+H] +

[0206] Intermediate 21 Process 1 [ka] Methyl 1-(5-bromo-2-methoxy-4-nitrophenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-1) 6-Chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (3.00 g, 15.2 mmol) was added to a solution of 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (3.80 g, 20.2 mmol) and DBU (5.88 mL, 45.6 mmol) in DMF (48 mL). The RM was stirred at RT for 4 h. Iodomethane (3.78 mL, 60.7 mmol) was added, and the RM was stirred at RT overnight. The RM was quenched with water (200 mL), and the formed precipitate was collected by filtration and dried. The crude material was triturated with EtOAc and washed with EtOAc to give the title product (5.83 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.08 min, ES + m / z 426.9 / 428.9 / 430.9 [M+H] + .

[0207] Process 2 [ka] Methyl 6-chloro-1-(5-((2-hydroxyethyl)thio)-2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-2) A degassed mixture of intermediate 21-1 (5.0 g, 11 mmol), 2-sulfanylethanol (1.13 mL, 12 mmol), DIPEA (5.91 mL, 20 mmol), Xantphos (820 mg, 1.4 mmol), and Pd(dba) (330 mg, 0.57 mmol) in 1,4-dioxane (100 mL) was stirred at 100 °C under argon for 3 h. After cooling to RT, the reaction was quenched with water. The formed precipitate was collected by filtration, washed with a small amount of EtOAc, and dried to give the title compound (5.3 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.08 min, ES + m / z 439.0 / 441.0 [M+H] + .

[0208] Process 3 [ka] Methyl 1-(4-amino-5-((2-hydroxyethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-3) A solution of intermediate 21-2 (5.3 g, 12 mmol) in MeOH (200 mL) was stirred at 80 °C, followed by the addition of a solution of NH4Cl (6.5 g, 121 mmol) in water (20 mL) and iron powder (6.7 g, 121 mmol). The RM was stirred at 80 °C for 4.5 h, then filtered while hot, and the filtrate was concentrated under reduced pressure. The crude material was diluted with saturated aqueous NaHCO3, the resulting suspension was sonicated, and the solid was collected by filtration. The solid was washed several times with water and dried to give the title product (3.13 g). LCMS (Method 1): Rt = 0.92 min, ES + m / z 409.1 / 411.1 [M+H] + .

[0209] Process 4 [ka] Methyl 1-(4-amino-5-((2-chloroethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-4) Intermediate 21-3 (4.4 g, 11 mmol) was mixed with thionyl chloride (12 mL, 165 mmol) at 0 °C. The RM was warmed to RT and stirred for 2 h, then the volatiles were removed under reduced pressure and the residue was dissolved in saturated aqueous NaHCO3. The formed slurry was sonicated, and the solid was collected by filtration, washed with water, and dried. The resulting crude was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in DCM to give the title product (2.7 g). LCMS (Method 1): Rt = 1.24 min, ES + m / z 427.0 / 429.0 / 431.0 [M+H] + .

[0210] Process 5 [ka] Methyl 6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-5) A solution of intermediate 21-4 (2.70 g, 6.32 mmol), K2CO3 (2.62 g, 19 mmol), and NaI (189 mg, 1.26 mmol) in DMF (80 mL) was stirred at 90 °C overnight. After cooling to RT, the RM was diluted with water (200 mL). The formed precipitate was filtered, washed several times with water, and dried. The resulting material was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / acetonitrile (9:1) in DCM to give the title product (730 mg). LCMS (Method 1): Rt = 1.13 min, ES + m / z 391.1 / 393.1 [M+H] + .

[0211] Process 6 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 21) Intermediate 21-5 (730 mg, 1.87 mmol) was suspended in THF (15 mL) and LiOH solution (1.0 M aqueous solution, 9 mL, 9 mmol) was added. The RM was stirred at 40 °C for 2.5 h. The organic solvent was removed under reduced pressure and the residue was diluted with water. The pH was adjusted to 2.5 using 1 M aqueous HCl. The formed precipitate was filtered, washed several times with water and dried to give the title compound (698 mg). LCMS (Method 1): Rt = 0.95 min, ES + m / z 377.1 / 379.0 [M+H] + .

[0212] Intermediate 22 Process 1 [ka] Methyl 6-chloro-1-(2-methoxy-5-((2-methoxy-2-oxoethyl)thio)-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 22-1) The intermediate was prepared similarly to intermediate 21-2 starting from intermediate 21-1 and methyl 2-sulfanylacetate. LCMS (Method 1): Rt = 1.18 min, ES + m / z 467.1 / 469.1 [M+H] + .

[0213] Process 2 [ka] Methyl 1-(4-amino-2-methoxy-5-((2-methoxy-2-oxoethyl)thio)phenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 22-2) A solution of intermediate 22-1 (265 mg, 0.51 mmol) in ethanol (6.0 mL) was stirred at 80 °C, followed by the addition of a solution of NH4Cl (109 mg, 2.0 mmol) in water (3.0 mL) and iron (340 mg, 6.1 mmol). The RM was stirred at 80 °C for 16 h. After cooling to RT, the RM was filtered, and the filter was washed with additional EtOAc. The combined organic layers were evaporated under reduced pressure to give the desired product (1.03 g), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.09 min, ES + m / z 437.2 / 439.1 [M+H] + .

[0214] Process 3 [ka] Methyl 6-chloro-1-(6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 22-3) TFA (1.3 mL, 17.0 mmol) was added to a suspension of intermediate 22-2 (1.0 g, 1.7 mmol) in DCM (12.0 mL). The RM was stirred at RT for 24 h. The RM was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0-60% DCM / MeOH (20:1) in DCM to give the title product (341.5 mg). LCMS (Method 1): Rt = 0.99 min, ES +m / z 405.2 / 407.1 [M+H] + .

[0215] Process 4 [ka] 6-Chloro-1-(6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 22) Aqueous LiOH (1.0 M, 7.5 mL, 7.5 mmol) was added to a suspension of intermediate 22-3 (340 mg, 0.84 mmol) in THF (10 mL). The RM was stirred at RT for 2 h. THF was removed under reduced pressure. The residue was diluted with water and acidified to pH 2.5 using 1 M aqueous HCl. The formed precipitate was collected by filtration, washed with water, and dried to give the title product (320 mg). LCMS (Method 2): Rt = 0.48 min, ES + m / z 391.0 / 393.0 [M+H] + .

[0216] Intermediate 23a Process 1 [ka] 1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (Intermediate 23a-1) A mixture of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.50 g, 5.37 mmol), 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (1.34 g, 5.37 mmol), and K2CO3 (2.23 g, 16.1 mmol) in DMF (30 mL) was stirred at 65 °C for 2 h. The reaction was repeated on a 17.4 mmol scale and combined with the previous one after cooling to RT. The combined RM was poured into water (400 mL), and the precipitate was collected by filtration. The collected solid was thoroughly washed with water and azeotroped with toluene to give the title product (11.1 g). LCMS (Method 2): Rt = 1.36 min, ES + m / z 508.9 / 510.9 / 512.8 [M+H] + .

[0217] Process 2 [ka] 1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-N-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 23a-2) A degassed mixture of intermediate 23a-1 (800 mg, 1.57 mmol), 2-(4-methylpiperazin-1-yl)ethanamine (366 μL, 2.83 mmol), proline (90.4 mg, 0.79 mmol), K2CO3 (1.3 g, 9.42 mmol), and CuI (89.7 mg, 0.47 mmol) in dry DMSO (6 mL) was stirred at 75 °C for 5 h. A second portion of CuI and proline was added. After cooling to RT, the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The aqueous layer was further extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaCl (20 mL) and concentrated under reduced pressure. The residue was purified twice by flash chromatography on a Si cartridge eluting with DCM / MeOH / NH4OH (90:15:1.5) to give the title product (243 mg). LCMS (Method 2): Rt = 1.08 min, ES + m / z 524.1 / 526.1 / 528.1 [M+H] + .

[0218] Process 3 [ka] Methyl 2-((5-(6-chloro-3-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)thio)acetate (Intermediate 23a-3) A solution of intermediate 23a-2 (240 mg, 0.46 mmol), DIPEA (199 μL, 1.1 mmol), and methyl 2-sulfanylacetate (102 μL, 1.1 mmol) in dry acetonitrile (14 mL) was stirred at 120 °C overnight. 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 (90:15:1.5) in DCM to give the title product (87 mg). LCMS (Method 2): Rt = 0.97 min, ES + m / z 550.2 / 552.2 [M+H]+ .

[0219] Process 4 [ka] 7-(6-chloro-3-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Intermediate 23a) A solution of intermediate 23a-3 (85 mg, 0.15 mmol) in EtOH (20 mL) was stirred at 80 °C, followed by the addition of a solution of iron (0.16 g, 2.9 mmol) in NH4Cl (70 mg, 1.3 mmol) and water (5 mL). The RM was stirred at 80 °C for 4.5 h. A second portion of iron and NH4Cl was added, and the RM was further stirred at 80 °C for 1 h. The RM was quenched with 2 N aqueous HCl (1 mL) and stirred at 80 °C for 2 h. After cooling to RT, the RM was filtered, and the filter cake was washed with EtOH. The filtrate was evaporated under reduced pressure. The residue was treated with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:15:1.5) in DCM to give the title product (40 mg). LCMS (Method 2): Rt = 0.80 min, ES + m / z 488.2 / 490.2 [M+H] + .

[0220] Intermediate 23b Process 1 [ka] N 1 -(1-(5-bromo-2-methoxy-4-nitrophenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N 2 ,N 2 -Dimethylethane-1,2-diamine (Intermediate 23b-1) The title intermediate was prepared in a manner analogous to intermediate 23a-2, starting from intermediate 23a-1 and N',N'-dimethylethane-1,2-diamine. LCMS (Method 2): Rt = 1.18 min, ES + m / z 469.1 / 471.1 / 473.1 [M+H] +

[0221] Process 2 [ka] Methyl 2-((5-(6-chloro-3-((2-(dimethylamino)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)thio)acetate (Intermediate 23b-2) The title intermediate was prepared in a manner similar to intermediate 23a-3, starting from intermediate 23b-1 and methyl 2-sulfanylacetate to afford the title compound (122 mg). LCMS (Method 2): Rt = 1.12 min, ES + m / z 495.1 / 497.1 [M+H] +

[0222] Process 3 [ka] 7-(6-chloro-3-((2-(dimethylamino)ethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Intermediate 23b) The title compound was prepared in a manner analogous to intermediate 23a-4, starting from intermediate 23b-2. LCMS (Method 2): Rt = 1.04 min, ES + m / z 433.2 / 434.2 [M+H] +

[0223] Intermediate 24 [ka] 1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 24) Method 1 A solution of degassed 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (400 mg, 2.02 mmol), Intermediate 2 (733 mg, 2.13 mmol), CsCO (2.31 g, 7.09 mmol), and thiophene-2-carbonyloxycopper (278 mg, 1.46 mmol) in anhydrous DMSO (7 mL) was stirred under nitrogen at 110 °C overnight. After cooling to RT, the RM was filtered. The filtrate was diluted with MeCN (50 mL), and the precipitate thus formed was collected by filtration and triturated with MeOH. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–100% MeOH in EtOAc to give the title product (150 mg).

[0224] Method 2 A mixture of degassed 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (9.4 g, 47.5 mmol), Intermediate 7 (18.6 g, 47.5 mmol), CsCO (54 g, 166.3 mmol), and thiophene-2-carbonyloxycopper (9 g, 47.5 mmol) in DMSO (100 mL) was stirred under argon at 110 °C for 24 h. The RM was quenched with water and extracted with DCM. The combined organic layers were washed with 10% w / w aqueous citric acid, saturated aqueous NaCl, and evaporated to dryness. The residue was purified by chromatography on silica gel eluting with DCM to DCM (1% v / v MeOH + 1% AcOH v / v). The material thus obtained was triturated with ethyl ether to give the title compound (3.14 g). LCMS (Method 1): Rt = 1.22 min, ES + m / z 461.2 / 463.2 [M+H] + .

[0225] Intermediate 25 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 25) The title intermediate was prepared in a manner analogous to Intermediate 24, Method 1, starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and Intermediate 2-1. LCMS (Method 1): Rt = 0.86 min, ES + m / z 360.9 / 362.8 [M+H] + .

[0226] Intermediate 26 [ka] 6-Chloro-1-(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 26) The title intermediate was prepared in a manner analogous to Intermediate 24, Method 1, etc., starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and 6-bromo-7-methoxy-3,4-dihydro-1H-quinolin-2-one. LCMS (Method 1): Rt = 0.77 min, ES + m / z 373.1 / 375.1 [M+H] + .

[0227] Intermediate 27a [ka] 1-(1-(tert-butoxycarbonyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 27a) A mixture of intermediate 3 (1.04 g, 3.04 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (300 mg, 1.52 mmol), thiophene-2-carbonyloxycopper (290 mg, 1.52 mmol), and CsCO (1.48 g, 4.56 mmol) in DMSO (7 mL) was stirred for 72 h at 100 °C under nitrogen. After cooling to RT, the RM was added dropwise to stirring water. The pH was adjusted to 4 (with 1 M aqueous HCl), and the formed precipitate was filtered, washed with water, and dried. The crude material was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM:MeOH:HC0H (90:10:0.3) in DCM to give the title product (330 mg). LCMS (Method 1): Rt = 1.24 min, ES + m / z 458.9 / 460.9 [M+H] + .

[0228] Intermediate 27b [ka] tert-Butyl 6-(6-chloro-3-(methoxycarbonyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 27b) A mixture of intermediate 3 (346 mg, 1.01 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (100 mg, 0.506 mmol), thiophene-2-carbonyloxycopper (97 mg, 0.5 mmol), and CsCO (0.49 g, 1.52 mmol) in DMSO (2.3 mL) was stirred for 72 h at 100 °C under nitrogen. After cooling to RT, iodomethane (126 μL, 2.02 mmol) was added, and the mixture was stirred at RT for an additional 2 h. The RM was quenched with water and extracted three times with DCM. The combined organic layers were dried over NaSO, filtered, and evaporated to dryness. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% cyclohexane / EtOAc (1:1) in cyclohexane to give the title product (118 mg). LCMS (Method 1): Rt = 1.41 min, ES + m / z 473.0 / 475.0 [M+H] + .

[0229] Intermediate 28 [ka] tert-Butyl 7-(3-amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 28) A degassed mixture of Intermediate 2 (408 mg, 1.19 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridin-3-amine (200 mg, 1.19 mmol), CsCO (980 mg, 3.01 mmol), DMCHDA (93.5 μL, 0.59 mmol), and CuI (113 mg, 0.59 mmol) in DMSO (4.9 mL) was stirred overnight at 110 °C under argon. After cooling to RT, the RM was quenched with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (282 mg). LCMS (Method 1): Rt = 1.15 min, ES + m / z 431.9 / 433.9 [M+H] + .

[0230] Intermediate 29 [ka] 6-(3-Amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 29) A degassed solution of 6-bromo-7-methoxy-3,4-dihydro-1H-quinolin-2-one (304 mg, 1.19 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridin-3-amine (100 mg, 0.59 mmol), KCO (246 mg, 1.78 mmol), N,N-dimethylglycine (93.5 μL, 0.59 mmol), and CuI (56.5 mg, 0.30 mmol) in DMSO (3.6 mL) was stirred overnight at 110 °C under argon. After cooling to RT, the RM was quenched with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:5:1) in DCM to give the title product (68.6 mg). LCMS (Method 2): Rt = 0.68 min, ES + m / z 344.1 / 345.9 [M+H] + .

[0231] Intermediate 30 [ka] 6-(6-chloro-3-(methylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 30) The title compound was prepared analogously to Intermediate 29 starting from 6-bromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one and Intermediate 18b. LCMS (Method 2): Rt = 0.79 min, ES + m / z 358.1 / 360.1 [M+H] + .

[0232] Intermediate 31a Process 1 [ka] tert-Butyl 7-(3-((tert-butoxycarbonyl)amino)-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 31a-1) LiHMDS (1.30 M in THF, 463 μL, 0.60 mmol) was added to a solution of intermediate 28 (130 mg, 0.30 mmol) in THF (7 mL) at 0 °C under nitrogen. The RM was stirred for 15 min. A solution of BocO (131 mg, 0.60 mmol) in THF (1 mL) was added dropwise, and the RM was stirred at RT for 3 h. The RM was diluted with water and extracted with EtOAc. The combined organic layers were 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 0–50% EtOAc in cyclohexane. The isolated product was dissolved in methanol (1 mL), KCO (76.5 mg, 0.55 mmol) was added, and the mixture was stirred at RT overnight. The RM was diluted with saturated aqueous NaHCO and extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried over Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to give the title product (107 mg) which was used in the next synthetic step without further purification. LCMS (Method 2): Rt = 1.49 min, ES + m / z 532.3 / 534.3 [M+H] + .

[0233] Process 2 [ka] tert-Butyl 7-(3-((tert-butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 31a) A solution of intermediate 31a-1 (85.0 mg, 0.16 mmol) in dry DMF (1.0 mL) was cooled to 0 °C under argon. NaI (23.9 mg, 0.16 mmol) and NaH (dispersed in mineral oil, 19.2 mg, 0.48 mmol) were added, and the RM was stirred at 0 °C for 30 min. 2-Bromo-N,N-dimethyl-ethanamine hydrobromide (55.8 mg, 0.24 mmol) was added, and stirring was continued at RT for 60 h. The RM was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were passed through a phase separator cartridge, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH / NH4OH (90:4:1) in DCM to give the title product. LCMS (Method 2): Rt = 1.54 min, ES + m / z 603.3 / 605.3 [M+H] + .

[0234] Intermediate 31b [ka] tert-Butyl 7-(3-((tert-butoxycarbonyl)(methyl)amino)-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 31b) The title compound was prepared analogously to intermediate 31a, starting from intermediate 31a-1 and iodomethane. LCMS (Method 2): Rt = 1.54 min, ES + m / z 546.2 / 548.2 [M+H] + .

[0235] Intermediate 32a [ka] tert-Butyl 7-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 32a) To a degassed mixture of Intermediate 2 (657 mg, 1.9 mmol), 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (200 mg, 1.2 mmol), CuI (114 mg, 0.6 mmol), N,N-dimethylglycine (123 mg, 1.2 mmol), and KCO (330 mg, 2.4 mmol) was added DMSO (5 mL). The RM was stirred at 100 °C overnight. After cooling to RT, the RM was diluted with EtOAc (25 mL) and washed with 15% w / w aqueous NHOH (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–15% EtOAc in DCM to give the title product (312 mg). LCMS (Method 2): Rt = 1.32 min, ES + m / z 431.1 / 433.1 [M+H] + .

[0236] Intermediate 32b~32i The following intermediates were prepared from the starting materials indicated in a manner analogous to intermediate 32a. If base, ligand / catalyst, solvent and / or temperature were varied, as further noted. [Table 17] [Table 18]

[0237] Intermediate 32j [ka] 6-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-2,3-dihydroquinolin-4(1H)-one (Intermediate 32j) TFA (173 μL, 2.26 mmol) was added to a solution of intermediate 32h (40.0 mg, 0.09 mmol) in DCM (1.0 mL). The RM was stirred at RT overnight and then concentrated under reduced pressure. The residue was loaded onto an SCX cartridge, washed with methanol, and eluted with 2 M methanolic ammonia to give the title product (32 mg). LCMS (Method 1): Rt = 0.87 min, ES + m / z 342.9 / 344.9 [M+H] +

[0238] Intermediate 33 Process 1 [ka] 1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 33-1) A mixture of 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (300 mg, 1.79 mmol), 1-bromo-5-fluoro-4-methoxy-2-nitro-benzene (448 g, 1.79 mmol) and K2CO3 (742 g, 5.37 mmol) was suspended in DMF (6.0 mL) and stirred at 80 °C for 1 h. After cooling to RT, the RM was diluted with water (80 mL). The formed precipitate was collected by filtration, washed with water (3 × 30 mL), and dried to give the title product (620 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.26 min, ES + m / z 397.1 / 399.1 / 401.1 [M+H] +

[0239] Process 2 [ka] Methyl 2-((5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)thio)acetate (Intermediate 33-2) A mixture of intermediate 33-1 (350 mg, 0.88 mmol), methyl 2-sulfanylacetate (118 μL, 1.3 mmol), and DIPEA (230 μL, 1.3 mmol) in dry acetonitrile (15.0 mL) was stirred at 120 °C in a 100-μL reactor for 3 h. Freshly added methyl 2-sulfanylacetate (16 μL, 0.17 mmol) was added, and the RM was stirred at 120 °C for an additional 2 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0 to 80% (DCM / MeOH (9:1) in DCM) to give the desired product (170 mg). LCMS (Method 1): Rt = 1.16 min, ES + m / z 423.2 / 425.2 [M+H] +

[0240] Process 3 [ka] 7-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Intermediate 33-3) To a stirring solution of intermediate 33-2 (160 mg, 0.38 mmol) in ethanol (5 mL) at 80 °C was added a solution of NH4Cl (81 mg, 1.5 mmol) in water (2 mL) and iron (0.25 g, 4.5 mmol). The RM was stirred at 80 °C for 6 h. After cooling to RT, the RM was diluted with EtOAc (20 mL) and filtered through a bed of diatomaceous earth, washing thoroughly with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–35% DCM / MeOH (95:5) in DCM to give the title product (50 mg). LCMS (Method 1): Rt = 0.96 min, ES + m / z 361.2 / 363.2 [M+H] +

[0241] Process 4 [ka] 7-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazine (Intermediate 33-4) To BH3.THF (1.0 M in THF, 166.3 μL, 0.16 mmol) cooled to 0 °C was added a solution of intermediate 33-3 (30.00 mg, 0.08 mmol) in THF (1 mL), and the RM was stirred at 25 °C for 2 h. A second portion of BH3.THF was added, and the RM was stirred for an additional 2 h. The RM was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 × 10 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH (98:2) in DCM to give the title product (18 mg). LCMS (Method 1): Rt = 1.11 min, ES + m / z 347.2 / 349.2 [M+H] +

[0242] Process 5 [ka] 7-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazine 1,1-dioxide (Intermediate 33) To a cooled solution of intermediate 33-4 (25.0 mg, 67.8 μmol) in dry DCM (1 mL) at 0 °C, m-CPBA (70.0%, 33.4 mg, 0.136 mmol) was added, and the RM was stirred at 0 °C for 1 h. After warming to RT, the RM was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–60% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (13 mg). LCMS (Method 1): Rt = 0.82 min, ES + m / z 378.9 / 380.8 [M+H] +

[0243] Intermediate 34 Process 1 [ka] Diethyl 2-(5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)malonate (Intermediate 34-1) To a mixture of NaH (60% suspension in mineral oil, 80 mg, 2.0 mmol) in DMSO (4.0 mL), diethyl malonate (186 μL, 1.3 mmol) was slowly added, and the RM was stirred at 65° C. After 20 min, intermediate 33-1 (195 mg, 0.49 mmol) was added, and the RM was stirred at 100° C. for 1 h. After cooling to RT, the RM was poured into ice / water and extracted with EtOAc (4 × 10 mL). The combined organic layers were washed with water (10 × 10 mL) and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–45% DCM / MeOH (98:2) in DCM to give the title product (75 mg). LCMS (Method 1): Rt = 1.26 min, ES + m / z 477.2 / 479.2 [M+H] +

[0244] Process 2 [ka] 5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxyindolin-2-one (Intermediate 34-2) To a stirred solution of intermediate 34-1 (75 mg, 0.16 mmol) in acetic acid (4.0 mL) at 90 °C, iron (97 mg, 1.7 mmol) was added portionwise, and the RM was stirred at 90 °C for 80 min. After cooling to RT, the RM was filtered, and the filtrate was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–75% DCM / MeOH / NHOH (90:5:0.5) in DCM to give the title product (21.4 mg). LCMS (Method 1): Rt = 0.82 min, ES + m / z 329.2 / 331.2 [M+H] +

[0245] Process 3 [ka] 5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one (Intermediate 34-3) To a stirring suspension of NaH (60.0%, 14.9 mg, 0.37 mmol) in dry DMF (0.3 mL) was added a solution of intermediate 34-2 (180 mg, 0.37 mmol) in DMF (3 mL), and the RM was stirred for 30 min while allowing the temperature to reach RT. 2-(Chloromethoxy)ethyl-trimethyl-silane (139 μL, 0.75 mmol) was added dropwise at 0 °C. The RM was stirred overnight at RT, then quenched with saturated aqueous NaHCO (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (20 mL), saturated aqueous NaCl (20 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–40% EtOAc / DCM (1:9) in DCM to give the title product (100 mg). LCMS (Method 2): Rt = 1.35 min, ES + m / z 459.2 / 461.2 [M+H] +

[0246] Process 4 [ka] 5'-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6'-methoxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one (Intermediate 34) To a stirred solution of intermediate 34-3 (60.0 mg, 0.12 mmol), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (51.7 mg, 0.14 mmol), and zinc trifluoromethanesulfonate (43.2 mg, 0.12 mmol) in dry DMF (3 mL) was added DBU (53.3 μL, 0.36 mmol). The RM was stirred at RT for 2 h. The RM was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (2 × 10 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–25% EtOAc / DCM (1:9) in DCM to give the title product (48 mg). LCMS (Method 2): Rt = 1.44 min, ES + m / z 485.2 / 487.2 [M+H] +

[0247] Intermediate 35 Process 1 [ka] 1-(Allyloxy)-5-chloro-4-methoxy-2-nitrobenzene (Intermediate 35-1) A suspension of 5-chloro-4-methoxy-2-nitro-phenol (1.00 g, 4.91 mmol), 3-bromoprop-1-ene (509 μL, 5.89 mmol), and KCO (1018 mg, 7.37 mmol) in acetonitrile (10 mL) was stirred at 75 °C overnight. The RM was cooled to RT and diluted with water and DCM. The layers were separated, and the aqueous layer was washed with DCM. The combined organic layers were dried and concentrated to give the crude product, which was used in the next synthetic step without further purification (1.08 g). LCMS (Method 1): Rt = 1.18 min 1 H-NMR (300 MHz, CDCl3) δ: 7.48 (s, 1H), 7.13 (s, 1H), 5.95-6.07 (m, 1H), 5.47 (dq, J = 17.3, 1.3 Hz, 1H), 5.33 (dq, J = 10.4, 1.3 Hz, 1H), 4.62 (dt, J = 5.0, 1.3 Hz, 2H), 3.90 (s, 3H).

[0248] Process 2 [ka] 1-(5-(allyloxy)-2-methoxy-4-nitrophenyl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 35-2) A suspension of 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (700 mg, 4.18 mmol), Intermediate 35-1 (1.08 g, 4.42 mmol), and KCO (1.73 g, 12.5 mmol) in DMSO (10.0 mL) was stirred at 120 °C for 5 h. The RM was cooled to RT and diluted with water. The formed precipitate was collected by filtration, washed with water, and dried to give the desired product (950 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.19 min, ES + m / z 374.9 / 376.9 [M+H] + .

[0249] Process 3 [ka] 5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenol (Intermediate 35-3) To a degassed mixture of intermediate 35-2 (500 mg, 1.33 mmol) and K2CO3 (553 mg, 4.00 mmol) in MeOH (15 mL) was added Pd(PPh3)4 (50.0 mg, 0.04 mmol), and the RM was stirred at 60 °C for 30 min. After cooling to RT, the RM was concentrated, suspended in water, acidified to pH 3, and extracted with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was triturated with DCM / MeOH to give the desired product (200 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.09 min, ES + m / z 335.1 / 337.1 [M+H] + .

[0250] Process 4 [ka] 2-Amino-5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxyphenol (Intermediate 35-4) To a warm reflux of intermediate 35-3 (500 mg, 1.49 mmol) in MeOH (30 mL), a solution of NH4Cl (320 mg, 5.98 mmol) in water (5 mL), and iron (834 mg, 14.9 mmol) were added. The RM was heated at reflux for 2 days. After cooling to RT, the RM was filtered through a pad of diatomaceous earth. The filtrate was evaporated under reduced pressure, and the residue was dissolved in DCM and washed with water. The aqueous phase was back-extracted with DCM (3 × 50 mL), and the combined organic layers were washed with saturated aqueous NaCl and passed through a phase separator. The organic phase was evaporated under reduced pressure to give the desired product (126.9 mg), which was used in the next step without further purification. LCMS (Method 1): Rt = 0.72 min, ES + m / z 305.0 / 306.9 [M+H] + .

[0251] Process 5 [ka] 2-Bromo-N-(4-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-hydroxy-5-methoxyphenyl)-2,2-difluoroacetamide (Intermediate 35-5) A solution of intermediate 35-4 (125 mg, 0.34 mmol), DABAL-Me3 (131 mg, 0.51 mmol), and methyl 2-bromo-2,2-difluoroacetate (71 mg, 0.37 mmol) in THF (3 mL) was stirred at 130 °C for 15 min under nitrogen and microwave irradiation. After cooling to RT, the reaction was carefully quenched with 4 M HCl in 1,4-dioxane (2 mL). The resulting mixture was poured into saturated aqueous NaHCO3 and extracted with DCM. The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–90% DCM / MeOH (20:1) in DCM to give the title product (25 mg). LCMS (Method 1): Rt = 1.09 min, ES + m / z 461.0 / 463.1 / 465.0 [M+H] + .

[0252] Process 6 [ka] 7-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,2-difluoro-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (Intermediate 35) A solution of intermediate 35-5 (24 mg, 52 μmol) and DBU (13.0 μL, 0.10 mmol) in THF (15 mL) was stirred at 110 °C for 16 h. After cooling to RT, the RM was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-50% DCM / MeOH (20:1) in DCM to give the title product (12.4 mg). LCMS (Method 1): Rt = 1.09 min, ES + m / z 381.1 / 383.1 [M+H] + .

[0253] Intermediate 36 Process 1 [ka] 3-(5-chloro-4-methoxy-2-nitrophenoxy)propan-1-ol (Intermediate 36-1) 5-Chloro-4-methoxy-2-nitro-phenol (1.00 g, 4.91 mmol), 3-iodopropan-1-ol (685 μL, 7.37 mmol), and KCO (2.04 mg, 14.7 mmol) were suspended in DMF (15 mL), and the RM was stirred at 70 °C for 5 h. After cooling to RT, the RM was diluted with water (30 mL) and extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with water (40 mL) and saturated aqueous NaCl (40 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–40% DCM / MeOH (99:1) in DCM to give the title product (1.08 g). LCMS (Method 1): Rt = 0.93 min, ES + m / z 262.1 [M+H] + .

[0254] Process 2 [ka] 3-(5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenoxy)propan-1-ol (Intermediate 36-2) A suspension of intermediate 36-1 (1.01 g, 3.86 mmol), 6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (610 mg, 3.64 mmol), and KCO (1.51 g, 10.9 mmol) in DMSO (10.0 mL) was stirred at 120 °C for 5 h. After cooling to RT, the RM was diluted with water. The formed precipitate was collected by filtration, washed with water, and dried to give the title product (700 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.00 min, ES + m / z 393.2 / 395.2 [M+H] + .

[0255] Process 3 [ka] 3-(5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenoxy)propyl methanesulfonate (Intermediate 36-3) To a solution of intermediate 36-2 (200 mg, 0.51 mmol) in DMF (5 mL) cooled to 0° C., methanesulfonyl chloride (59 μL, 0.76 mmol) was added dropwise, and the RM was stirred at RT for 2 h. The RM was poured into water (20 mL), and the formed precipitate was collected by filtration, washed with water, and dried to give the title product (225 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.11 min, ES + m / z 471.1 / 473.1 [M+H] + .

[0256] Process 4 [ka] 8-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (Intermediate 36) To a stirring solution of intermediate 36-3 (210 mg, 0.42 mmol) in ethanol (10 mL) at 80 °C was added a solution of NH4Cl (91 mg, 1.7 mmol) in water (5 mL) and Fe (0.28 g, 5.10 mmol). The RM was stirred at 80 °C overnight. After cooling to RT, the RM was diluted with EtOAc (20 mL), filtered through a bed of diatomaceous earth, and washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH (95:5) in DCM to give the title product (65 mg). LCMS (Method 1): Rt = 0.99 min, ES + m / z 345.2 [M+H] + .

[0257] Intermediate 37a [ka] tert-Butyl 7-(6-chloro-3-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 37a) To a solution of intermediate 24 (100 mg, 0.22 mmol), DIPEA (76 μL, 0.43 mmol), and HATU (91 mg, 0.26 mmol) in DMF (2.0 mL) was added N',N'-dimethylpropane-1,3-diamine (33 μL, 0.26 mmol), and the RM was stirred at RT for 1 h. The RM was diluted with EtOAc (20 mL) and washed with saturated NaHCO3 (4 × 4 mL) and saturated aqueous NaCl (10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–85% DCM / MeOH / NH4OH (95:9:1.5) in DCM to give the title product (63.6 mg). LCMS (Method 1): Rt = 0.92 min, ES + m / z 545.4 / 547.3 [M+H] + .

[0258] Intermediate 37b~37k The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 37a. [Table 19] [Table 20] [Table 21]

[0259] Intermediate 37m Process 1 [ka] 1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 37m-1) To a solution of intermediate 37l (1.0 g, 1.48 mmol) in THF (10 mL), 1 M LiOH (10.6 mL, 11.8 mmol) was added and the RM was stirred at RT for 16 h. The RM was evaporated under reduced pressure, the residue was dissolved in water, and the pH was adjusted to 6.5 using 1 M aqueous HCl. The aqueous phase was extracted with DCM (3 × 10 mL), and the combined organic layers were evaporated to dryness under reduced pressure to give the title product (756 mg). LCMS (Method 1): Rt = 0.99 min, ES + m / z 615.1 / 617.1 [M+H] +

[0260] Process 2 [ka] tert-Butyl 7-(6-chloro-3-((2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 37m) A solution of intermediate 37m-1 (34.0 mg, 55.3 μmol), dimethylamine hydrochloride (9.11 mg, 111 μmol), HATU (25.2 mg, 66.3 μmol), and DIPEA (48.1 μL, 0.28 mmol) in DMF (1 mL) was stirred at RT for 1.5 h. The RM was quenched with water (20 mL) and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl (20 mL), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–70% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (26 mg). LCMS (Method 2): Rt = 0.95 min, ES + m / z 642.4 / 644.4 [M+H] +

[0261] Intermediate 37n Process 1 [ka] N-(azetidin-3-yl)-6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (intermediate 37n-1) A solution of intermediate 37k (100.0 mg, 0.16 mmol) and TFA (362 μL, 4.88 mmol) in DCM (4 mL) was stirred at RT for 4.5 h. The RM was evaporated under reduced pressure. The residue was dissolved in MeOH, passed through an SCX cartridge, washed with methanol, and eluted with methanolic ammonia (7 M) to give the title product (63 mg). LCMS (Method 2): Rt = 0.68 min, ES + m / z 415.2 / 4.17.2 [M+H] +

[0262] Process 2 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)azetidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37n) A solution of intermediate 37n-1 (50 mg, 0.12 mmol), 4-(bromomethyl)tetrahydropyran (33.3 mg, 0.13 mmol), and K2CO3 (33.3 mg, 0.24 mmol) in DMF (1.5 mmol) was stirred at 80 °C for 7 h. A second portion of 4-(bromomethyl)tetrahydropyran was added, and the RM was stirred for an additional 48 h. After cooling to RT, the reaction was quenched with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL) and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–15% DCM / MeOH / NH4OH (90:9:0.5) in DCM to give the title product (48 mg). LCMS (Method 2): Rt = 0.72, ES + m / z 557.2 / 559.2.

[0263] Intermediate 37o [ka] (R)-6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-((4-methylmorpholin-2-yl)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37o) A mixture of intermediate 21-5 (30 mg, 77 μmol), DABAL-Me3 (30 mg, 0.12 mmol), THF (1 mL), and [(2R)-4-methylmorpholin-2-yl]methanamine (15 mg, 0.12 mmol) was heated under argon atmosphere at 130 °C for 45 min under μW irradiation. After cooling to RT, the RM was quenched with 4 M HCl in dioxane (2 mL) and poured into saturated aqueous NaHCO3. The mixture was extracted with DCM, and the combined organic layers were evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH (9:1) in DCM to give the title product (26 mg). LCMS (Method 1): Rt = 0.81 min, ES + m / z 489.2 / 491.2 [M+H] +

[0264] Intermediate 37p [ka] 6 -Chloro-N-(3-(dimethylamino)propyl)-1-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37p) The title compound was prepared in a manner analogous to intermediate 37o, starting from intermediate 27b and N',N'-dimethylpropane-1,3-diamine. LCMS (Method 1): Rt = 0.77 min, ES + m / z 443.0 / 445.0 [M+H] + .

[0265] Intermediate 37q Process 1 [ka] tert-Butyl 7-(3-((2-bromoethyl)carbamoyl)-6-chloro-1H-pyrazolo[4,3-c]oxylidin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 37q-1) Intermediate 37q-1 was prepared in a manner similar to intermediate 37a, starting from intermediate 24 and 2-bromoethylamine hydrochloride. LCMS (Method 2): Rt = 1.38 min, ES + m / z 566.6 / 568.1 / 570.1 [M+H] +

[0266] Process 2 [ka] tert-Butyl 7-(6-chloro-3-((2-(4-methoxypiperidin-1-yl)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]oxylidin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 37q) A solution of intermediate 37q-1 (80.0 mg, 0.14 mmol), 4-methoxypiperidine (19.5 mg, 0.17 mmol), and DIPEA (98.3 μL, 0.57 mmol) in dry DMF (1.3 mL) was stirred overnight at RT under argon. The RM was quenched by the addition of saturated aqueous NH4Cl solution and then extracted with EtOAc (x2). The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on a Si cartridge eluting with a DCM / MeOH mixture (20:1 to 10:1) to give the title product (50.0 mg). LCMS (Method 1): Rt = 0.95 min, ES + m / z 601.0 / 603.2 [M+H] +

[0267] Intermediate 37q~37w The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 37q. [Table 22] [Table 23]

[0268] intermediate 37x Process 1 [ka] N-(2-Bromoethyl)-6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37x-1) A solution of intermediate 37q-1 (215.0 mg, 0.37 mmol) and TFA (1.38 mL, 18.6 mmol) in DCM (2.0 mL) was stirred at 16 °C for 16 h. The RM was neutralized with saturated aqueous NaHCO (20 mL) and the layers were separated. The organic phase was washed with saturated aqueous NaHCO, passed through a phase separator, and evaporated under reduced pressure to give the desired product (223.6 mg), which was used in the next synthetic step without further purification. LCMS (Method 1): Rt = 1.07 min, ES + m / z 466.1 / 468.1 / 470.0 [M+H] +

[0269] Process 2 [ka] 6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(2-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)ethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37x) To a mixture of intermediate 37x-1 (40.0 mg, 81 μmol) in acetone (0.5 mL) was added a solution of 1-oxa-8-azaspiro[4.5]decan-2-one hydrochloride (49 mg, 240 μmol), NaCO (8.6 mg, 81 μmol), and NaI (1.3 mg, 8.1 μmol) in acetone (1.0 mL), and the RM was stirred at 40 °C for 24 h. The RM was evaporated under reduced pressure, and the residue was partitioned between water (10 mL) and DCM (10 mL). After further extraction of the aqueous phase with DCM (3 × 10 mL), the combined organic layers were passed through a phase separator and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NH OH (90:5:0.5) in DCM to give the title product (22 mg). LCMS (Method 1): Rt = 0.71 min, ES + m / z 541.1 / 543.1 [M+H] +

[0270] Intermediate 38a [ka] tert-Butyl 7-(6-chloro-3-((methoxycarbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 38a) To a solution of intermediate 28 (60 mg, 0.14 mmol) in DCM (0.9 mL) cooled to 0 °C, pyridine (15 μL, 0.18 mmol) was added, followed by methyl chloroformate (13 μL, 0.17 mmol). The RM was stirred at 0 °C for 30 min and at RT for 1 h. The RM was quenched with saturated aqueous NaHCO3 and extracted with DCM (4 × 15 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (30.6 mg). LCMS (Method 1): Rt = 1.27 min, ES + m / z 490.1 / 492.0 [M+H] +

[0271] Intermediate 38b [ka] tert-Butyl 7-(6-chloro-3-(((2-(dimethylamino)ethoxy)carbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 38b) To a solution of Intermediate 28 (250 mg, 0.58 mmol) and TEA (242 μL, 1.74 mmol) in DCM (15 mL) cooled to −78 °C was added bis(trichloromethyl)carbonate (172 mg, 0.58 mmol) in one portion. The RM was stirred at −78 °C for 1 h, followed by the addition of a solution of 2-(dimethylamino)ethanol (293 μL, 2.89 mmol) and TEA (161 μL, 1.16 mmol) in DCM (7.5 mL). The RM was stirred at ∼78 °C for an additional 1 h, then warmed to RT and quenched with saturated aqueous NaHCO3. The aqueous phase was further extracted with DCM (3 × 25 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH / NH4OH (90:9:1) in DCM to give the title product (310 mg). LCMS (Method 2): Rt = 1.23 min, ES + m / z 547.3 / 549.2 [M+H] +

[0272] Intermediate 38c~38k The following intermediates were prepared from the starting materials shown in a manner similar to intermediate 38b. If the base, solvent or temperature was varied, this is further indicated. [Table 24] [Table 25]

[0273] intermediate 38l [ka] 2-(Dimethylamino)ethyl (6-chloro-1-(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (Intermediate 38l) A solution of CDI (75 mg, 0.47 mmol), Intermediate 29 (40 mg, 0.12 mmol), and imidazole (24 mg, 0.35 mmol) in 2-Me-THF (1.3 mL) was stirred overnight at 90 °C under argon. 2-(Dimethylamino)ethanol (35 μL, 0.35 mmol) was added, and the RM was stirred at 90 °C for an additional 5 h. After cooling to RT, the RM was diluted with water and extracted with DCM / iPrOH (3 × 15 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, 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 product (19.5 mg). LCMS (Method 2): Rt = 0.94 min, ES + m / z 459.1 / 461.1 [M+H] +

[0274] Intermediate 38m [ka] 2-(Dimethylamino)ethyl (6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (Intermediate 38m) Intermediate 21 (200 mg, 0.53 mmol), T3P (登録商標) A mixture of (50% in EtOAc, 620 μL, 1.1 mmol), azido(trimethyl)silane (141 μL, 1.1 mmol), and TEA (222 μL, 1.6 mmol) in 2-MeTHF (20 mL) was refluxed for 1 h. A solution of 2-(dimethylamino)ethanol (95 mg, 1.1 mmol) in 2-MeTHF (1 mL) was added, and the RM was refluxed for an additional 4 h. After cooling to RT, the RM was diluted with EtOAc (35 mL) and washed with saturated aqueous NaHCO (3 × 10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NH OH (90:9:1.5) in DCM to give the title product (116 mg). LCMS (Method 1): Rt = 0.75 min, ES+ m / z 463.2 / 465.2 [M+H] +

[0275] Intermediate 38n~38x The following intermediates were prepared from the starting materials indicated in a manner analogous to intermediate 38m. [Table 26] [Table 27]

[0276] Intermediate 38y Process 1 [ka] tert-Butyl 7-(6-chloro-3-(((2-(1,3-dioxoisoindolin-2-yl)ethoxy)carbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 38y-1) To a solution of intermediate 28 (100 mg, 0.23 mmol) in DCM (5 mL) cooled to -78 °C, TEA (97 μL, 0.70 mmol) and bis(trichloromethyl)carbonate (68.7 mg, 0.23 mmol) were added, and the RM was stirred at -78 °C for 1 h. 2-(2-Hydroxyethyl)isoindoline-1,3-dione (88 μL, 0.926 mmol) and TEA (65 μL, 0.46 mmol) were added, and the RM was stirred at RT overnight. The RM was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (15 mL). The combined organic layers were washed with saturated aqueous NaCl and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–10% EtOAc in DCM to give the title product (182 mg). LCMS (Method 2): Rt = 1.32 min, ES + m / z 649.3 / 661.3 [M+H] +

[0277] Process 2 [ka] tert-Butyl 7-(3-(((2-aminoethoxy)carbonyl)amino)-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 38y-2) A solution of intermediate 38y-1 (155 mg, 0.24 mmol) and hydrazine hydrate (310 μL, 6.39 mmol) in EtOH (5 mL) was stirred at RT for 2 h. The precipitate was removed by filtration, and the filtrate was partitioned between EtOAc (30 mL) and water (10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), and the solvent was removed under reduced pressure to give the desired product (81.7 mg), which was used in the next synthetic step without further purification. LCMS (Method 2): Rt = 0.92 min, ES + m / z 519.2 / 521.2 [M+H] +

[0278] Process 3 [ka] tert-Butyl 7-(6-chloro-3-(((2-((2-oxotetrahydrofuran-3-yl)amino)ethoxy)carbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 38y) A solution of intermediate 38y-2 (75.0 mg, 0.145 mmol), 3-bromotetrahydrofuran-2-one (14.4 μL, 0.16 mmol), and DIPEA (101 μL, 0.58 mmol) in DMF (3 mL) was stirred at RT for 72 h. The RM was diluted with EtOAc (15 mL) and washed with water (2 × 10 mL) and saturated aqueous NaCl (15 mL). The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–5% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (30 mg). LCMS (Method 2): Rt = 0.95 min, ES + m / z 603.3 / 605.3 [M+H] +

[0279] Intermediate 39a [ka] 3-(6-chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,1-dimethylurea (Intermediate 39a) Intermediate 21 (40.0 mg, 0.11 mmol), T3P (登録商標)A solution of (50.0% solution in DMF, 124 μL, 0.21 mmol), azido(trimethyl)silane (28.2 μL, 0.21 mmol), and TEA (44.4 μL, 0.32 mmol) in 2-MeTHF (0.5 mL) was refluxed overnight. After cooling to RT, the RM was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO (3 × 15 mL) and saturated aqueous NaCl (15 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–30% DCM / MeOH (90:1) in DCM to give the title product (10 mg). LCMS (Method 1): Rt = 1.01 min, ES + m / z 419.1 / 421.1 [M+H] +

[0280] Intermediate 39b [ka] tert-Butyl 7-(6-chloro-3-(3-(3-morpholinopropyl)ureido)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 39b) To a solution of intermediate 28 (50.0 mg, 0.12 mmol) in DCM (3 mL) cooled to -78 °C, DIPEA (48.4 μL, 0.35 mmol) and bis(trichloromethyl)carbonate (34.4 mg, 0.12 mmol) were added, and the RM was stirred for 2 h. A solution of 3-morpholinopropan-1-amine (59.2 μL, 0.40 mmol) and DIPEA (32.3 μL, 0.23 mmol) in DCM (2 mL) was added dropwise, and the RM was stirred at ~78 °C for an additional 2 h. The RM was warmed to RT and diluted with saturated aqueous NaHCO3. The aqueous layer was further extracted with DCM (3 × 15 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. 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 (19.4 mg). LCMS (Method 2): Rt = 1.24 min, ES + m / z 602.3 / 604.3 [M+H] +

[0281] Intermediate 40 Process 1 [ka] tert-Butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 40-1 ) To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.64 mmol) in DCM (10 mL) was added NaHCO (1.68 g) and m-CPBA (1.43 g, 7.89 mmol) at 0 °C, and the RM was stirred at RT for 3 h. The RM was diluted with DCM (10 mL) and saturated aqueous NaHCO (25 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), and the solvent was removed under reduced pressure. The residue was slurried in a mixture of DCM / MeOH and filtered to remove insoluble solids. The filtrate was evaporated under reduced pressure to give the title product (1.11 g). 1 H-NMR (500 MHz, DMSO-d6) δ: 4.39 (s, 2H), 3.87 (bs, 4H), 2.83 (s, 2H), 1.37 (s, 9H).

[0282] Process 2 [ka] 6-Oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate (Intermediate 40-2) A solution of intermediate 40-1 (200 mg, 0.88 mmol) and TFA (9.81 mL, 132.0 mmol) in DCM (10.0 mL) was stirred at RT for 3 hours. The volatiles were evaporated under reduced pressure, and the residue was triturated with diethyl ether to give the title product (198.9 mg). 1 H-NMR (500 MHz, DMSO-d6) δ: 8.80 (bs, 2H), 4.40 (s, 2H), 4.04 (bs, 4H), 2.90 (s, 2H).

[0283] Process 3 [ka] tert-Butyl (2-(7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl)ethyl)carbamate (Intermediate 40-3) A solution of N-Boc-2-aminoacetaldehyde (109.0 mg, 0.68 mmol), intermediate 40-2 (128.0 mg, 0.57 mmol), TEA (79.2 μL, 0.57 mmol), and powdered molecular sieves (4 Å, 200 mg) in methanol (4.0 mL) was stirred at RT for 1 h. Na(CN)BH (143.0 mg, 2.27 mmol) and acetic acid (48.8 μL, 0.85 mmol) were added, and the RM was stirred at RT for 16 h. The RM was quenched with water (10 mL), diluted with EtOAc (10 mL), filtered, and the layers were separated using a phase separator. The organic layer was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH (10:1) in DCM to give the title product. LCMS (Method 2): Rt = 0.75 min, ES + m / z 271.2 [M+H] +

[0284] Process 3 [ka] 2-(2-Aminoethyl)-6-oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate (Intermediate 40) A solution of intermediate 40-3 (50 mg, 0.185 mmol) and TFA (2.06 mL, 27.7 mmol) in DCM (2.0 mL) was stirred at RT for 16 h. The RM was evaporated to dryness and triturated with diethyl ether to give the desired product (93 mg), which was used in the next synthetic step without further purification. LCMS (Method 2): Rt = 0.34 min, ES + m / z 171.2 [M+H] +

[0285] Intermediate 41 Process 1 [ka] Methyl (R)-1-(2-((tert-butoxycarbonyl)amino)ethyl)pyrrolidine-3-carboxylate (Intermediate 41-1) A mixture of (R)-pyrrolidine-3-carboxylate hydrochloride (406 mg, 2.5 mmol), K2CO3 (925 mg, 6.7 mmol), and tert-butyl N-(2-bromoethyl)carbamate (500 mg, 2.2 mmol) in MeCN (2.5 mL) was stirred at 70 °C overnight. After cooling to RT, the RM was filtered and the solvent was evaporated. The crude material was dissolved in EtOAc and washed with water. The aqueous solution was extracted with EtOAc (2 × 15 mL), and the combined organic layers were further washed with water (3 × 15 mL), saturated aqueous NH4Cl (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was passed through a phase separator and the solvent was evaporated to give the title product (422 mg), which was used in the next synthetic step without further purification. 1 H-NMR (300 MHz, CDCl3) δ: 4.95 (brs, 1H), 3.66 (s, 3H), 3.18-3.23 (m, 2H), 2.94-3.04 (m, 1H), 2.82 (t, J = 7.8 Hz, 1H), 2.49-2.72 (m, 5H), 2.01-2.10 (m, 2H), 1.24 (s, 9H).

[0286] Process 2 [ka] Methyl (R)-1-(2-aminoethyl)pyrrolidine-3-carboxylate (Intermediate 41) To a solution of intermediate 41-1 (420 mg, 1.54 mmol) in dry DCM (3 ml) was added TFA (1.77 mL, 23.1 mmol) dropwise at 0 °C. The RM was warmed to RT and stirred for 2 h. The RM was loaded onto a pre-conditioned SCX column, washed with MeOH, and eluted with 2 N methanolic ammonia (50 mL). Evaporation of the methanolic fraction gave the desired product (263 mg). 1H-NMR (300 MHz, CDCl3) δ: 3.66 (s, 3H), 2.95-3.06 (m, 1H), 2.76-2.87 (m, 3H), 2.61-2-68 (m, 2H), 2.43-2.58 (m, 3H), 2.02-2.16 (m, 2H).

[0287] Intermediates 42a-b The following intermediates were prepared from the starting materials shown in a manner analogous to intermediate 37a. [Table 28]

[0288] Intermediate 43 [ka] tert-Butyl 7-(6-chloro-3-(1-methylpiperidine-4-carboxamido)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 43) A solution of intermediate 28 (50.0 mg, 0.12 mmol), TEA (97 μL, 0.70 mmol), and 1-methylpiperidine-4-carbonyl chloride hydrochloride (34.4 mg, 0.17 mmol) in DCM (2 mL) was stirred at RT for 2 h. A second portion of 1-methylpiperidine-4-carbonyl chloride hydrochloride was added, and stirring was continued overnight. The RM was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl (10 mL each). The organic layer was separated using a phase separator, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–40% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the desired product (44 mg). LCMS (Method 2): Rt = 1.21 min, ES + m / z 557.3 / 559.3 [M+H] +

[0289] Intermediate 44 Process 1 [ka] tert-Butyl 6-(3-amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 44-1) Intermediate 27a (500 mg, 1.1 mmol), T3P (登録商標) A solution of (50% in EtOAc, 1.27 mL, 2.2 mmol), azido(trimethyl)silane (289 μL, 2.2 mmol), and TEA (456 μL, 3.3 mmol) in 2-MeTHF (20 mL) was refluxed for 30 min. Water (2.51 mL, 139 mmol) was added, and the RM was refluxed overnight. After cooling to RT, the RM was diluted with EtOAc (25 mL) and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–35% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (279 mg). LCMS (Method 1): Rt = 1.20 min, ES + m / z 430.2 / 432.2 [M+H] +

[0290] Process 2 [ka] tert-Butyl 6-(6-chloro-3-(((2-((2-oxotetrahydrofuran-3-yl)thio)ethoxy)carbonyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 44) A solution of intermediate 44-1 (100 mg, 0.23 mmol), TEA (97.3 μL, 0.70 mmol) in DCM (5 mL) was cooled to −78 °C, and bis(trichloromethyl)carbonate (69.0 mg, 0.23 mmol) was added in one portion. The RM was stirred under the same conditions for 1 h. A solution of intermediate 13 (151 mg, 0.93 mmol) and TEA (64.8 μL, 0.47 mmol) in DCM (2.5 mL) was added to the RM at −78 °C, and stirring was continued for 2 h under cooling and overnight at RT. The reaction was quenched with saturated aqueous NaHCO3, and DCM and water were added. The layers were separated, and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-35% DCM / EtOH / NH4OH (90:4:1) in DCM to give the title product (177 mg). LCMS (Method 2): Rt = 1.28 min, ES + m / z 618.2 / 620.2 [M+H] +

[0291] Intermediate 45a~45d The following intermediate was prepared from the starting material shown in a manner analogous to Step 2 of Intermediate 37q. [Table 29]

[0292] Intermediate 45e [ka] tert-Butyl 7-(6-chloro-3-((2-(2-methyl-6-oxomorpholino)ethyl)carbamoyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 45e) A mixture of intermediate 45a (42.0 mg, 0.07 mmol), K2CO3 (11.4 mg, 0.08 mmol), and ethyl 2-bromoacetate (9.1 μL, 0.08 mmol) in dry MeCN (9 mL) was stirred at RT overnight and then heated in a pressure vial at 110 °C for 9 h. After cooling to RT, the solvent was removed under reduced pressure, and the residue was dissolved in DCM (20 mL), saturated aqueous NaHCO3 (3 × 10 mL), and washed with saturated aqueous NaCl (10 mL). The organic layer was evaporated to give the title product (45 mg), which was used in the next step without further purification. LCMS (Method 2): Rt = 1.25 min, ES + m / z 601.3 / 603.3 [M+H] +

[0293] Intermediate 45f Process 1 [ka] 6-Chloro-N-(2-((2-hydroxy-2-methylpropyl)amino)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 45f-1) A solution of intermediate 45d (80 mg, 0.14 mmol) and TFA (517 μL, 7.0 mmol) in DCM (9.5 mL) was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue was purified on an SCX column by eluting with methanol and methanolic ammonia to give the title compound (55.1 mg), which was used in the next step without further purification. LCMS (Method 1): Rt = 0.70 min, ES + m / z 475.2 / 477.1 [M+H] +

[0294] Process 2 [ka] 6-Chloro-N-(2-(2,2-dimethyl-6-oxomorpholino)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 45f) A solution of intermediate 45f-1 (55 mg, 0.12 mmol) in toluene / acetonitrile was added to a precooled mixture of oxalaldehyde (40%, 15 μL, 0.12 mmol) in toluene (0.3 mL) at 10 °C. The RM was stirred for 3 h at 10 °C and overnight at RT. The RM was diluted with water and extracted with DCM (4 × 10 mL). The combined organic layers were passed through a phase separator, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–50% DCM / MeOH / NH4OH (90:5:0.5) in DCM to give the title product (32 mg). LCMS (Method 2): Rt = 0.99 min, ES + m / z 515.2 / 517.1 [M+H] +

[0295] Preparation of Example Compounds Example 1 [ka] 6-(Difluoromethoxy)-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Example 1) To a degassed solution of Intermediate 32b (33.0 mg, 0.09 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (30.9 mg, 0.13 mmol), and KPO (38.2 mg, 0.18 mmol) in THF (0.5 mL) and water (0.2 mL) was added XPhos Pd G3 (7.62 mg, 9.0 μmol), and the RM was stirred at 75 °C for 2 h. After cooling to RT, the RM was diluted with water and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge by eluting with 0-50% DCM / MeOH / NH4OH (90:9:0.5) in DCM and purified through an SCX column to give the title compound (17 mg). LCMS (Method 4): Rt = 4.42 min, ES + m / z 450.1 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.22 (br d, J = 7.0 Hz, 1H), 9.12 (s, 1H), 8.89 (s, 1H), 8.72 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.16 (m, 1H), 6.88 (s,1H), 6.88 (t, J = 72.4 Hz, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 4.19 (br s, 2H), 3.39 (br s, 2H), 2.61 (s, 3H).

[0296] Examples 2 to 39 The following example compounds were prepared in a manner analogous to Example 1 from the intermediates shown. [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45]

[0297] Example 40 Process 1 [ka] tert-Butyl 6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 40 - Step 1) A degassed mixture of Intermediate 32a (172 mg, 0.40 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (117 mg, 0.48 mmol), KPO (169 mg, 0.80 mmol), and XPhos PdG (17 mg, 20 μmol) in water (1 mL) / THF (2 mL) was stirred under nitrogen at 55° C. for 1.5 h. After cooling to RT, the RM was diluted with water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with water and saturated aqueous NaCl (10 mL each), dried over NaSO, and evaporated under reduced pressure. 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 (158.4 mg). LCMS (Method 2), Rt = 1.22, ES + m / z 514.3.

[0298] Process 2 [ka] 6-Methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Example 40) TFA (0.7 mL, 9.23 mmol) was added to a solution of Intermediate Example 1 - Step 1 (158 mg, 0.31 mmol) in DCM (5.0 mL) and stirred at RT overnight. The solvent was removed under reduced pressure and the residue was loaded onto an SCX cartridge, washed with methanol and eluted with methanolic ammonia (7 M) to give the title product (78.7 mg). LCMS (Method 3), Rt = 2.67 min, ES + m / z 414.1 [M+H] + 1 H-NMR (600 MHz, DMSO-d6) δ: 9.21 (dd, J = 6.9, 1.8 Hz, 1H); 9.09 (d J = 1.2 Hz, 1H); 8.88 (s, 1H); 8.71 (dd, J = 4.0, 1.7 Hz, 1H); 8.14 (d J = 1.2 Hz, 1H); 7.15 (dd, J = 6.9,4.1Hz, 1H); 6.73 (s, 1H); 6.46 (s, 1H); 6.26 (brs, 1H); 4.13 (t, J = 3.3Hz, 2H); 3.62 (s, 3H); 3.36 (m, 2H); 2.60 (s, 3H).

[0299] Examples 41 to 70 The following example compounds were prepared by a two-step procedure similar to Example 40, starting from the intermediate shown. [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]

[0300] Example 71 Process 1 [ka] 6'-Methoxy-5'-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one (Example 71 - Step 1) The title compound was prepared in analogy to Example 40-Step 1 starting from Intermediate 34 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine. LCMS (Method 1), Rt = 1.32, ES +m / z 568.3

[0301] Process 2 [ka] 6'-Methoxy-5'-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (Example 71) An ice-bath cooled solution of Intermediate Example 71, Step 1 (32.0 mg, 0.05 mmol) in dry DCM (1 mL) was treated with TFA (371 μL, 4.85 mmol) and stirred at RT overnight. The RM was evaporated under reduced pressure, and the residue was partitioned between DCM (2 × 10 mL) and NaHCO (15 mL). The combined organic layers were evaporated under reduced pressure, and the residue was dissolved in DCM (1 mL) and treated with 7N methanolic ammonia (200 μL), then stirred at RT for 4 h. The RM was diluted with DCM (8 mL) and washed with saturated aqueous NaHCO (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was evaporated under reduced pressure, and the residue was purified by flash chromatography on a Si cartridge eluting with 0–100% DCM / MeOH / NH OH (90:5:0.5) to give the title product (12.5 mg). LCMS (Method 4): Rt = 3.89 min, ES + m / z 438.2 [M+H] + 1 H-NMR (600 MHz, DMSO-d6) δ: 10.83 (s, 1H), 9.22 (dd, J = 6.9, 1.7 Hz, 1H), 9.12 (d, J = 1.1 Hz, 1H), 8.88 (s, 1H), 8.70 (dd, J = 4.0, 1.7 Hz, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.14-7.16 (m, 2H), 6.86 (s, 1H), 3.78 (s, 3H), 2.63 (s, 3H), 1.58-1.61 (m, 2H), 1.44-1.47 (m, 2H).

[0302] Example 72 Process 1 [ka] 5-Methoxy-6-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Example 72 - Step 1) The title compound was prepared in analogy to Intermediate Example 72-Step 1, starting from Intermediate 19 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine. LCMS (Method 1), Rt = 0.79, ES + m / z 658.5

[0303] Process 2 [ka] 5-Methoxy-6-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzo[d]oxazol-2(3H)-one (Example 72) The title compound was prepared in a similar manner to Example 72 (Step 2), starting from intermediate Example 72-Step 1. LCMS (Method 4): Rt = 3.52 min, ES + m / z 528.2 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ: 11.87 (s, 1H), 9.20 (d, J = 7.1 Hz, 1H), 9.06 (s, 1H), 8.85 (s, 1H), 8.67 (m, 1H), 8.04 (s, 1H), 7.42 (s, 1H), 7.13 (dd, J = 7.5, 3.4 Hz, 1H), 7.02 (s, 1H), 6.68 (t, J = 5.3 Hz, 1H), 3.82 (s, 3H), 3.56-3.63 (m, 4H), 3.44 (q, J = 6.7 Hz, 2H), 2.60-2.65 (m, 2H); 2.42-2.48 (m, 2H, overlap with DMSO); 2.35-2.38 (m, 2H).

[0304] Example 73 Process 1 [ka] tert-Butyl 7-(3-((3-(dimethylamino)propyl)carbamoyl)-6-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 73 - Step 1) To a degassed mixture of intermediate 37a (70 mg, 0.13 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 19 μmol) in DMF (1 mL) was added a solution of intermediate 12 (270 mg, 0.33 mmol) in DMF (1 mL), and the RM was stirred at 110 °C overnight. After cooling to RT, the RM was partitioned between EtOAc (25 mL) and water (15 mL). The aqueous phase was adjusted to pH 9 with 2N aqueous NaOH and extracted with EtOAc (15 mL). The combined organic layers were evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0–90% DCM / MeOH / NH4OH (90:9:1.5) in DCM to give the title product (38 mg). LCMS (Method 1), Rt = 0.86, ES + m / z 628.4

[0305] Process 2 [ka] N-(3-(Dimethylamino)propyl)-6-(imidazo[1,2-b]pyridazin-3-yl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Example 73) The title compound was prepared in a similar manner to Example 40 (Step 2). LCMS (Method 4), Rt = 3.94 min, ES + m / z 528.2 [M+H] + 1 H-NMR (600 MHz, DMSO-d6) δ: 9.51 (s, 1H), 8.76 (br s, 2H), 8.59 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.24 (s, 1H), 7.36 (dd, J = 9.3, 4.4 Hz, 1H), 6.91 (s, 1H), 6.50 (s, 1H), 4.14 (br s, 2H), 3.67 (s, 3H), 3.41-3.35 (m, 4H), 2.40 (br t, J = 7.2 Hz, 2H), 2.23 (s, 6H), 1.78-1.72 (m, 2H).

[0306] Example 74 Process 1 [ka] tert-Butyl 7-(3-((tert-butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-6-((3-methoxypyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 74 - Step 1) A degassed mixture of intermediate 31a (25 mg, 41 μmol), 2-amino-3-methoxypyrazine (6.7 mg, 54 μmol), sodium tert-butoxide (6.0 mg, 62 μmol), and XPhos PdG (3.5 mg, 4.1 μmol) in dioxane (600 μL) was stirred at 100 °C overnight. After cooling to RT, the RM was chromatographed on a Si cartridge eluting with 0–30% DCM / MeOH / NH OH (90:15:1.5) in DCM to give the title product (11 mg). LCMS (Method 2): Rt = 1.59 min, ES + m / z 692.4 [M+H] +

[0307] Process 2 [ka] 3-((3-((2-(dimethylamino)ethyl)amino)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrazin-2(1H)-one (Example 74) A solution of Intermediate Example 74, Step 1 (11.0 mg, 8 μmol), NaI (3.58 mg, 24 μmol), and TMS-Cl (9.0 μL, 72 μmol) in acetonitrile (0.5 mL) was stirred at 85° C. for 2 h. After cooling to RT, the RM was chromatographed on a Si cartridge eluting with 0-100% DCM / MeOH / NHOH (90:15:1.5) in DCM to give the title product (2 mg).

[0308] 1H-NMR (600 MHz, DMSO-d6) δ: 8.74 (d, J = 0.9 Hz, 1H), 8.64 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.68 (s, 1H), 6.52 (m, 1H), 6.42 (s, 1H), 6.12 (s, 1H), 4.11 (t, J = 4.2 Hz, 2H), 3.65 (s, 3H), 2.65 (m, 2H), 2.30 (br s, 6H). LCMS (Method 4): Rt = 4.34, ES + m / z 478.1 [M+H] +

[0309] Examples 75-76 The following example compounds were prepared by a two-step procedure similar to Example 74, starting from the intermediate shown. [Table 63] [Table 64]

[0310] Example 77 [ka] N-(2-(2,2-dimethyl-6-oxomorpholino)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Example 77) The title compound was prepared in a manner analogous to Example 1 from intermediate 45f and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine. LCMS (Method 3), Rt = 4.51 min, ES + m / z 598.3 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.45 (d, J = 1.2 Hz, 1H), 9.24 (dd, J = 6.9, 1.7 Hz, 1H), 8.91 (s, 1H), 8.74 (dd, J = 4.1, 1.7 Hz, 1H), 8.53 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 0.9 Hz, 1H), 7.17 (dd, J = 7.0, 4.3 Hz, 1H), 6.86 (s, 1H), 6.49 (s, 1H), 6.36-6.41 (m, 1H), 4.14 (t, J = 4.3 Hz, 2H), 3.63 (s, 3H), 3.48 (q, J = 6.3 Hz, 2H), 3.36-3.42 (m, 2H), 3.29 (s, 2H), 2.57-2.66 (m, 4H), 1.33 (s, 6H).

[0311] Example 78 Process 1 [ka] 1-(4-(tert-butoxycarbonyl)-6-(difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example 78 - Step 1) The title compound was prepared analogously to Intermediate 24 (Method 1) starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and Intermediate 1. LCMS (Method 1), Rt = 1.22 min, ES + m / z 497.1 / 499.0 [M+H] +

[0312] Process 2 [ka] 1-(4-(tert-Butoxycarbonyl)-6-(difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example 78 - Step 2) To a degassed mixture of Example 78, Step 1 (200 mg, 0.40 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (138 mg, 0.56 mmol), and KPO (0.5 M aqueous solution, 1.61 mL, 0.81 mmol) in THF / water (5.61 mL) was added XPhos Pd G (19 mg, 22 μmol), and the RM was heated at 80° C. for 1 h. The warm reaction mixture was filtered, and the THF was evaporated under reduced pressure. Water was added to the RM until the solid dissolved, filtered, and saturated aqueous NH4Cl was added to form a precipitate that was collected by filtration to give the title product (77 mg), which was used in the next step without further purification. LCMS (Method 1), Rt = 1.01 min, ES + m / z 580.2 [M+H] +

[0313] Process 3 [ka] tert-Butyl 6-(difluoromethoxy)-7-(3-((3-(dimethylamino)propyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 78 - Step 3) The title compound was prepared analogously to Intermediate 37a starting from Example 78-Step 2 and N',N'-dimethylpropane-1,3-diamine. LCMS (Method 1), Rt = 0.86 min, ES + m / z 664.3 [M+H] +

[0314] Process 4 [ka] 1-(6-(Difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-(dimethylamino)propyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Example 78) The title compound was prepared in analogy to Example 40, Step 2, starting from Example 78, Step 3. LCMS (Method 4): Rt = 3.92, ES + m / z 564.2 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.48 (d, J = 1.2 Hz, 1H), 9.24 (dd, J = 7.0, 1.8 Hz, 1H), 8.92 (s, 1H), 8.74 (dd, J = 4.1, 1.7 Hz, 1H), 8.70 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H), 7.18 (dd, J = 7.0, 4.3 Hz, 1H), 7.06 (s, 1H), 6.95 (t, J = 73.9 Hz, 1H), 6.66-6.71 (m, 2H), 4.20 (t, J = 4.3 Hz, 2H), 3.39-3.44 (m, 2H), 3.34-3.38 (m, 2H), 2.28 (t, J = 7.0 Hz, 2H), 2.14 (s, 6H), 1.70 (quin, J = 7.1 Hz, 2H).

[0315] Example 79 Process 1 [ka] 1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylic acid (Example 79 - Step 1) A degassed mixture of intermediate 37m-1 (348 mg, 0.55 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (202 mg, 0.82 mmol), KPO (233 mg, 1.1 mmol), and XPhos PdG (46 mg, 0.055 mmol) in THF / water (2:1, 9 mL) was stirred at 70 °C for 45 min. After cooling to RT, the RM was partitioned between EtOAc (30 mL) and water (30 mL). After adjusting the pH from 9.5 to 6.5, the aqueous layer was extracted with a 4 / 1 DCM / isopropanol mixture (4 × 20 mL). The combined organic layers were passed through a phase separator and evaporated under reduced pressure. The residue was purified by flash chromatography on a Si cartridge eluting with 0-100% DCM / MeOH:HCO2H (90:9:2) in DCM to give the title product (320 mg). LCMS (Method 1): Rt = 0.74 min, ES + m / z 698.4 [M+H] +

[0316] Process 2 [ka] tert-Butyl 7-(3-((2-(4-carbamoylpiperidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 79 - Step 2) To a pre-stirred solution of Example 79, Step 1 (100 mg, 0.14 mmol), HATU (65.4 mg, 0.17 mmol), and DIPEA (74.9 μL, 0.43 mmol) in DMF (2.0 mL) was added NH4Cl (61.3 mg, 0.57 mmol) and DIPEA (99.9 μL, 0.57 mmol), and the RM was stirred at RT for 1 h. A second portion of HATU (15.0 mg, 0.04 mmol) was added, and the mixture was stirred for an additional 1 h. The volatiles were removed 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 (32 mg). LCMS (Method 1): Rt = 0.74 min, ES + m / z 697.4 [M+H] +

[0317] Process 3 [ka] N-(2-(4-Carbamoylpiperidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Example 79) The title compound was prepared in analogy to Step 2 of Example 40, starting from Example 79, Step 2. LCMS (Method 4): Rt = 3.61, ES + m / z 597.2 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.46 (d, J = 0.9 Hz, 1H), 9.23 (dd, J = 7.0, 1.8 Hz, 1H), 8.91 (s, 1H), 8.73 (dd, J = 4.1, 1.7 Hz, 1H), 8.44 (t, J = 5.8 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 7.19 (br s, 1H), 7.17 (dd, J = 7.0, 4.0 Hz, 1H), 6.89 (s, 1H), 6.69 (br s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 4.14 (t, J = 4.3 Hz, 2H), 3.63 (s, 3H), 3.44 (q, J = 6.7 Hz, 2H), 3.39 (m, 2H), 2.93 (m, 2H), 2.48 (m, 2H), 2.00-2.08 (m, 1H), 1.90-1.99 (m, 2H), 1.66 (m, 2H), 1.50-1.58 (m, 2H).

[0318] Example 80 Process 1 [ka] tert-Butyl (R)-6-methoxy-7-(3-((2-(3-(methoxycarbonyl)pyrrolidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 80 - Step 1) The title compound was prepared in analogy to Example 1 from intermediate 42b and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine. LCMS (Method 2): Rt = 1.17 min, ES + m / z 698.3 [M+H] +

[0319] Process 2 [ka] (R)-1-(2-(1-(4-(tert-butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamido)ethyl)pyrrolidine-3-carboxylic acid (Example 80 - Step 2) A solution of Example 80 - Step 1 (574 mg, 0.82 mmol) and LiOH (1.00 M in water, 4.11 mL, 4.11 mmol) in THF (10 mL) was stirred at RT overnight. The RM was diluted with water and washed with EtOAc, then the pH of the aqueous layer was adjusted to 5 and the aqueous layer was extracted with DCM:i-PrOH 8:1 (4 × 15 mL). The combined organic layers were dried over NaSO and evaporated to dryness to give the title compound (553 mg), which was used in the next step without further purification. LCMS (Method 1): Rt = 0.82 min, ES + m / z 684.4 [M+H] +

[0320] Process 3 [ka] tert-Butyl (R)-7-(3-((2-(3-carbamoylpyrrolidin-1-yl)ethyl)carbamoyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Example 80 - Step 2) The title compound was prepared in analogy to Example 79, Step 2, starting from Example 80, Step 1. LCMS (Method 2): Rt = 1.00 min, ES + m / z 683.4 [M+H] +

[0321] Process 4 [ka] (R)—N-(2-(3-carbamoylpyrrolidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Example 80) The title compound was prepared in analogy to Example 40, Step 2, starting from Example 80, Step 3. LCMS (Method 4): Rt = 3.56, ES + m / z 583.1 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ: 9.46 (d, J = 0.9 Hz, 1H), 9.24 (dd, J = 7.0, 1.5 Hz, 1H), 8.91 (s, 1H), 8.74 (dd, J = 4.1, 1.7 Hz, 1H), 8.47 (t, J = 5.8 Hz, 1H), 8.23-8.26 (m, 1H), 7.25 (br s, 1H), 7.17 (dd, J = 7.0, 4.3 Hz, 1H), 6.89 (s, 1H), 6.76 (br s, 1H), 6.49 (s, 1H), 6.36-6.41 (m, 1H), 4.14 (br t, J = 4.1 Hz, 2H), 3.63 (s, 3H), 3.43 (q, J = 6.6 Hz, 2H), 3.37-3.41 (m, 2H), 2.84-2.90 (m, 1H), 2.79 (quin, J = 7.8 Hz, 1H), 2.66-2.73 (m, 1H), 2.56-2.65 (m, 2H), 2.37-2.48 (m, 2H), 1.87 (q, J = 7.3 Hz, 2H).

[0322] Examples 81 to 86 The following example compounds were prepared by a two-step procedure similar to Example 40, starting from the intermediates shown. If base, catalyst, solvent or temperature were varied, this is further indicated. [Table 65] [Table 66] [Table 67]

[0323] Pharmacological activity of compounds (1-86) of the present invention Biochemical potency against JAK1, JAK2, JAK3 and Tyk2 Assay Principles The purpose of this study was to evaluate the ability of compounds to inhibit the activity of all four JAK isoforms in a cell-free environment. Assays for JAK1, JAK2, JAK3, and TYK2 were performed using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. This involves measuring light emission from two labeled binding partners, detected by energy transfer from an excited donor to an acceptor dye. The LANCE Ultra kinase assay was used. In the presence of JAK1, JAK2, JAK3, and TYK2 kinases and ATP (corresponding to Km), a ULight peptide substrate (LANCE Ulight-JAK-1 (Tyr1023) Peptide, Perkin Elmer, TRF0121) was phosphorylated. It was then captured by a Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 Anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), which brings the Eu-chelated donor and ULight acceptor into close proximity. Upon excitation at 320 nm, the Eu chelate transfers its energy to the ULight dye, resulting in fluorescent emission at 665 nm.

[0324] Compound Testing Serial dilutions of compounds in pure DMSO were prepared from a 10 mM DMSO stock solution. Compounds were tested in 11 serial 5-fold dilutions (20 μM to 2 pM) starting from a 20 μM top concentration in a 384-well plate. 200 nL of compound was transferred from the mother plate to the test plate using Mosquito (TTP Labtech). Assays were performed in a 384-well Perkin Elmer test plate with a 20 μL assay volume (kinase reaction) and a 40 μL total volume (stop reagent and antibody detection reagent). 30 / 50 / 20 / 10 nM peptide and 20 / 0.7 / 0.2 / 12 μM ATP in 10 μL of substrate solution (peptide + ATP) were added for JAK1, JAK2, JAK3, and TYK2, respectively. Ten μL of enzyme solution was added to the kinase reaction at concentrations of 0.15 / 0.083 / 0.025 / 0.144 ng / μL for JAK1, JAK2, JAK3, and TYK2, respectively. After shaking and incubation at room temperature for 1.5 hours, 20 μL of stop (10 μL EDTA) and detection mix (10 μL europium-antiphospho-antibody, final: 0.5 nM) were added. After 1 hour of incubation, readings were performed on an EnVision 2104 reader (Perkin Elmer).

[0325] I C 50 Data calculations, curve and QC analysis were performed using Excel tools and GraphPadPrism software, v9. Briefly, individual concentration-effect curves are generated by plotting the logarithm of the test concentration of the test compound (X) versus the corresponding percent inhibition value (Y) using a least-squares (normal) fit. The best-fit IC 50 Values ​​are calculated using the log(inhibitor) normalized response-variable slope equation, where Y=100 / (1+10^((LogIC 50 QC criteria parameters (Z', S:B, R2, HillSlope) are calculated using the formula: (-X)*HillSlope). 50 The curve was confirmed. IC 50Data calculations, curves, and QC analysis were performed using Excel tools and GraphPadPrism software. QC criteria parameters: Z' ≥ 0.5, Hill slope range 0.5-5, S:B > 2.

[0326] The compounds of the present invention exhibit a pIC corresponding to an inhibitory concentration of ≦1 μM. 50 Most of the compounds exhibited inhibitory activity against at least JAK1 of greater than 7.3, and even more preferably greater than 8.3, corresponding to inhibitory concentrations of ≦50 nM, and even more preferably ≦5 nM.

[0327] The data for compounds 1 to 76 are shown in the table below. [Table 68] [Table 69] [Table 70] The compounds are classified in the above table in terms of potency for inhibitory activity against JAK1, JAK2, JAK3 and Tyk2 isoforms according to the following classification criteria: +++:pIC 50 ≧8.3 ++:8.3>pIC 50 ≧7.3 +:pIC 50 <7.3

[0328] Inhibition of IL-13-induced pSTAT6 in BEAS BEAS-2B human cell line was seeded (100,000 cells / well) and incubated for 48 hours at 37°C, 5% CO2, and 95% humidity. Compounds were added and incubated for 30 minutes, followed by the addition of IL-13 as a trigger. After 30 minutes of incubation, cells were lysed and pSTAT6 was determined using the Fastscan phospho-STAT6 (Tyr641) ELISA kit (Cell Signaling). Inhibitors were tested in duplicate at 11 serial 5-fold dilutions (10 μM to 40 pM) starting at 10 μM. IC 50 Data calculations, curves, and QC analysis were performed using Excel tools and GraphPadPrism software. QC criteria parameters were: Z' ≥ 0.35, Hill slope range 0.5-5, S:B > 2. [Table 71] Compounds are classified in the above table in terms of potency for functional activity in the BEAS according to the following classification criteria: §§§§:pIC 50 ≧8.3 §§§:8.3>pIC 50 ≧7.3 §§:7.3>pIC 50 ≧6.3 §:pIC 50 <6.3

[0329] When a numerical limit or range is given herein, the endpoints are included. Also, unless expressly stated, all values ​​and subranges within a numerical limit or range are specifically included. As used herein, the term "a," "an," or "an" means "one or more."

[0330] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.

Claims

1. The single enantiomers, diastereoisomers and mixtures thereof in any ratio of the compounds of formula I 【Chemical 1】 [During the ceremony, R １ is a heteroaryl group selected from the group consisting of imidazo[1,2-b]pyridazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, and 3-oxo-(3,4-dihydropyrazin-2-yl)amino; R ２ is a substituent that connects to the molecular scaffold, 【Chemistry 2】 is the basis of where: V is absent (meaning a bond) or O, S, N(R ６ ), C(O)N(R ６ ), N(R ６ )C(O);N(R ６ )C(O)O;N(R ６ )S(O) ２ ;N(R ６ )C(O)N(R ６ is a divalent group selected from Q is H, (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) alkoxy, -(CH ２ ) ｍ NR ４ R ５ , (C ３ -C ８ ) cycloalkyl, (C ３ -C １０ )heterocycloalkyl; —S—(C ３ -C ６ ) heterocycloalkyl and —N(R ６ )-(C ３ -C ６ ) heterocycloalkyl; wherein said (C ３ -C ８ ) cycloalkyl and (C ３ -C １０ )Heterocycloalkyl is optionally —OH, oxo (i.e., (═O)), (C １ -C １０ ) alkyl, (C １ -C ６ ) alkoxy; halogen, (C １ -C ６ ) haloalkyl, alkanoyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ )Alkoxy(C １ -C ６ ) alkyl, —N(R ６ )(CH ２ ) ｍ C(O)NR ４ R ５ , -(CO)NR ４ R ５ , -(CH ２ ) ｍ NR ４ R ５ , (C ３ -C ８ ) cycloalkyl(C １ -C ６ ) alkyl; (C ３ -C ６ ) heterocycloalkyl(C １ -C ６ ) alkyl, (C ３ -C ６ ) heterocycloalkyl and hydroxyl-(C ３ -C ６ ) heterocycloalkyl; R ３ teeth, 【Chemistry 3】 where the dashed line --- indicates a single or double bond; X is selected from N, S, and C; Y is selected from C, N; Z is selected from C, N, and O; K is absent (meaning a bond) or selected from O, C, S; G is absent (meaning a bond) or selected from C, O; 【Chemistry 4】 is the point of attachment of the substituent to the rest of the molecule 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 and (C ３ -C ６ ) heterocycloalkyl; R ６ are, in each case independently, H, (C １ -C ６ ) alkyl and (C １ -C ６ ) hydroxyalkyl; R ７ is independently in each occurrence -OH, oxo (i.e., =O), (C １ -C ６ ) alkyl, halogen, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, -(CH ２ ) ｍ NR ４ R ５ , (C １ -C ６ ) alkyl-S(O) ２ - and (C １ -C ６ ) alkyl-S(O) ２ N(R ６ )-; R ８ teeth (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkoxy. or a pharmaceutically acceptable salt or solvate thereof.

2. Two-ring part R ３ 【Chemistry 5】 R ３ but 【Chemistry 6】 2. The compound of formula I of claim 1 selected from the group consisting of:

3. Two-ring part R ３ がJ １ ~J １３ 【Chemistry 7】 3. The compound of formula I of claim 2 selected from the group consisting of:

4. R ３ is J1, and R ８ is methoxy; Thus, if the compound has the formula Ia 【Chemistry 8】 [During the ceremony, R １ is pyrazolo[1,5-a]pyrimidin-3-yl or (3-oxo-3,4-dihydropyrazin-2-yl)amino; V is C(O)N(R ６ ), N(R ６ )C(O)O; Q is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, -(CH ２ ) ｍ NR ４ R ５ , (C ３ -C ８ ) cycloalkyl and (C ３ -C １２ )heterocycloalkyl; wherein said (C ３ -C ８ ) cycloalkyl and (C ３ -C １２ )Heterocycloalkyl is optionally oxo (i.e., (=O)), (C １ -C １０ ) alkyl, halogen, (C １ -C ６ ) hydroxyalkyl, —(CO)NR ４ R ５ ;(C ３ -C ８ ) cycloalkyl(C １ -C ６ ) alkyl; (C ３ -C ６ ) heterocycloalkyl; n and m, in each occurrence, are independently 0 or an integer selected from 1, 2, 3, and 4; R ４ and R ５ are the same or different, and independently in each case -H, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl is selected from the group consisting of 4. The compound of formula I of claim 3, represented by: or a pharmaceutically acceptable salt or solvate thereof.

5. V is N(R ６ )C(O)O; Q is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, -(CH ２ ) ｍ NR ４ R ５ and groups 【Chemistry 9】 (C ３ -C ６ ) heterocycloalkyl, wherein X １ is CH ２ ,O,S,NH,NCH ３ , (C=O) and S(=O) ２ Selected from:

5. A compound of formula I according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, in the form of a single enantiomer, a diastereoisomer, and mixtures thereof in any ratio.

6. V is C(O)N(R ６ ) and Q is -(CH ２ ) ｍ NR ４ R ５ and groups 【Chemistry 10】 (C ３ -C ６ ) heterocycloalkyl, wherein X １ is CHR ９ ,O,S,NH,NCH ３ , C.F. ２ , (C １ -C ６ ) alkoxy or (C １ -C ６ )Alkoxy(C １ -C ６ ) alkyl, wherein R ９ is H or -(CO)NR ４ R ５ That is, 5. A compound of formula I according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, in the form of a single enantiomer, a diastereoisomer, and mixtures thereof in any ratio.

7. Q is (C ３ -C ６ ) heterocycloalkyl, —S—(C ３ -C ６ ) heterocycloalkyl or 【Chemistry 11】 -N(R ６ )-(C ３ -C ６ ) heterocycloalkyl.

8. 10. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: single enantiomers, diastereoisomers, and mixtures thereof in any ratio: 6-(difluoromethoxy)-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine, 1-(6-methoxy-2-(methylsulfonyl)isoindolin-5-yl)-3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine, 8-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one, 7-methoxy-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydroquinolin-2(1H)-one, 7-methoxy-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,3-dihydroquinolin-4(1H)-one, 6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazine, 6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one, 6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazine 1,1-dioxide, 7-methoxy-8-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine, 6-methoxy-5-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)indolin-2-one, 2,2-difluoro-6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-methoxy-3-methyl-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydroquinazolin-2(1H)-one, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)azetidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(4,4-difluoropiperidin-1-yl)propyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(2-oxo-1-oxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(dimethylamino)propyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-(1-methylazetidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, (R)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-((4-methylmorpholin-2-yl)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 3-(2-oxomorpholino)propyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(methyl(2-oxotetrahydrofuran-3-yl)amino)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (R)-1-(6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-((4-methylmorpholin-2-yl)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, (S)-1-(6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-N-((4-methylmorpholin-2-yl)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(dimethylamino)propyl)-1-(6-methoxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(dimethylamino)propyl)-1-(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(dimethylamino)propyl)-1-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 7-methoxy-6-(3-(methylamino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydroquinolin-2(1H)-one, 2-(dimethylamino)ethyl (1-(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(dimethylamino)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-morpholinoethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 3-(4-methylpiperazin-1-yl)propyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(piperidin-1-yl)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (R)-1-methylpyrrolidin-3-yl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (S)-1-methylpyrrolidin-3-yl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (R)-2-(3-methoxypyrrolidin-1-yl)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 3-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,1-dimethylurea, 6-methoxy-7-(3-((2-(4-methylpiperazin-1-yl)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one, 7-(3-((2-(dimethylamino)ethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one, 1-(6-methoxybenzo[d]isothiazol-5-yl)-N-(2-morpholinoethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine, 6-methoxy-7-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine, 1-(6-methoxyindolin-5-yl)-3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine, 7-methoxy-6-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,2,3,4-tetrahydroquinoline, N-(3-(dimethylamino)propyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(1-methylazetidin-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, (R)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-((4-methylmorpholin-2-yl)methyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(4-methoxypiperidin-1-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(4-(methoxymethyl)piperidin-1-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(2-oxa-6-azaspiro[3.5]nonan-6-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-((3aS,6aR)-1-oxotetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(3-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(1-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N1-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine, methyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(dimethylamino)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-morpholinoethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 3-(4-methylpiperazin-1-yl)propyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 3-(dimethylamino)propyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 3-morpholinopropyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(1,1-dioxidothiomorpholino)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(4-methylpiperazin-1-yl)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-thiomorpholinoethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, (S)-(4-methylmorpholin-2-yl)methyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(piperidin-1-yl)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-((2-oxotetrahydrofuran-3-yl)thio)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-((2-oxotetrahydrofuran-3-yl)amino)ethyl (1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 2-(dimethylamino)ethyl (1-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate, 1-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-3-(3-morpholinopropyl)urea, 6'-methoxy-5'-(3-methyl-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)spiro[cyclopropane-1,3'-indolin]-2'-one, 5-methoxy-6-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzo[d]oxazol-2(3H)-one, N-(3-(dimethylamino)propyl)-6-(imidazo[1,2-b]pyridazin-3-yl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 3-((3-((2-(dimethylamino)ethyl)amino)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrazin-2(1H)-one, N-(3-(dimethylamino)propyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(3-(4,4-difluoropiperidin-1-yl)propyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-((3-oxo-3,4-dihydropyrazin-2-yl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(2,2-dimethyl-6-oxomorpholino)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-(difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(3-(dimethylamino)propyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(4-carbamoylpiperidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, (R)—N-(2-(3-carbamoylpyrrolidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-N-(2-(2-methyl-6-oxomorpholino)ethyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylpiperidine-4-carboxamide, N-(2-(4-(3-hydroxyoxetan-3-yl)piperidin-1-yl)ethyl)-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, 2-((2-oxotetrahydrofuran-3-yl)thio)ethyl (1-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate.

9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients.

10. 10. A pharmaceutical composition according to claim 9 suitable for administration by inhalation selected from inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations.

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

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

13. 13. The compound or pharmaceutical composition for use according to claim 12 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).

14. 10. A combination of a compound of any of claims 1 to 8 with one or more active ingredients selected from classes currently used in the treatment of respiratory disorders and known to those skilled in the art, such as beta2-agonists, antimuscarinics, corticosteroids, mitogen-activated kinase (P38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinase), nuclear factor kappa-B kinase subunit beta inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, nonsteroidal anti-inflammatory drugs (NSAIDs) and mucus control agents.

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