Heterocyclic derivatives as JANUS kinase inhibitors

Abstract

The present invention relates to compounds of general formula (I) that inhibit JAK family (JAK1, JAK2, JAK3 and TYK2) of non-receptor tyrosine protein kinases; processes for preparing said compounds, pharmaceutical compositions containing them and therapeutic uses thereof. The compounds of the present invention can be used to treat diseases or conditions associated with JAK family non-receptor kinase disorder; particularly for treating various inflammatory diseases including asthma, COPD and other respiratory diseases.

Description

Field of the Invention

[0001] The present invention relates to compounds which are derivatives used as JAK (such as JAK 1) inhibitors for treating various inflammatory diseases including asthma, COPD and other respiratory diseases. Background of the Invention

[0003] The JAK family consists of non-receptor tyrosine protein kinases and has four main members, JAK1, JAK2, JAK3 and TYK2. More than 50 cytokines and growth factors bind to type I and type II receptors that non-covalently associate with different combinations of JAK kinases. Signal transduction triggered by the ligand lies in the tyrosine phosphorylation of the receptor by JAK and the recruitment of one or more STAT proteins. The tyrosine-phosphorylated STAT dimerizes and then translocates through the nuclear membrane into the nucleus to regulate specific genes. JAK has seven homology domains (JAK homology domains, JH). Starting from the carboxyl terminus, JH1 is the first JH, called the kinase domain, and consists of approximately 250 amino acid residues. JH1 encodes the kinase protein that constitutes the kinase domain for phosphorylating substrates; JH2 is a pseudokinase domain that regulates the activity of the kinase domain. JAK3 is expressed in the bone marrow and lymphatic systems as well as in endothelial cells and vascular smooth muscle cells; the other members are expressed in almost all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26; 6(1):402). Many cellular processes are downstream of JAK / STAT signaling: hematopoiesis, immune balance, tissue repair, inflammation, apoptosis and adipogenesis. Different biological responses are regulated by the specific pairing of JAK isoforms. The JAK1 / JAK3 combination mediates the signaling of IL-2, -4, -7, -9, -15 and -21, which is associated with lymphocyte growth / maturation, T cell / NK cell differentiation / steady state, B cell class switch and other inflammatory processes. The combination of JAK1 / TYK2-JAK1 / JAK2 regulates signals related to the innate immune response, such as IL-6 and type I interferon, which are involved in naive T cell differentiation, T cell steady state, granulopoiesis and other inflammatory processes. (Howell MD et al., Front. Immunol. 2019, 10, 2342). JAK2 is usually associated with itself (JAK2 / JAK2), thus controlling the signaling of various cytokines and growth factors, such as IL-3, IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO) and thrombopoietin (TPO) (Hodge et al., Clin Exp Rheumatol 2016; 34(2):318-28).

[0004] Genetically modified mouse models and human diseases have demonstrated the importance of the JAK / STAT pathway in immune adaptation. In particular, overexpression or mutation of some JAK isoforms and aberrant JAK / STAT signaling drive malignancies of hematopoietic and lymphoid tissues as well as inflammatory disorders. Currently, several JAK inhibitors approved by the Food and Drug Administration (FDA) and / or the EU are in clinical use. Two (ruxolitinib and fedratinib) small molecules are used for hematological disorders such as myelofibrosis and polycythemia vera; six JAK inhibitors (tofacitinib, baricitinib, ruxololitinib, filgotinib, upadicitinib, and delgocitinib in Japan) are indicated for immune-mediated disorders such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, atopic dermatitis, ulcerative colitis, and acute graft-versus-host disease. In addition, some of these drugs and others are currently in Phase II and Phase III clinical trials for indications ranging from autoimmune diseases (lupus, vitiligo, etc.), inflammatory bowel disease to non-Hodgkin lymphoma and COVID-19 (Hu X. et al., Sig Transduct Target Ther 2021, 6:402).

[0005] Small molecules targeting JAK / STAT also represent an attractive option for the treatment of fibrotic disorders. Indeed, inflammatory cytokines (IL-4, IL-3, IL-6, IL-11, IL-31, etc.) and growth factors (FGF, VEGF, etc.) involved in the fibrotic process activate the JAK / STAT pathway. Ruxolitinib tested in a bleomycin-induced pulmonary fibrosis mouse model improved fibrotic lesions in the lung and decreased the levels of fibrotic molecular markers (Zhang, Y et al., Ann. Rheum. Dis. 2017, 76, 1467-1475), while tofacitinib acts as a prophylactic agent in experimental skin and lung fibrosis (Wang, W et al., Scleroderma Relat. Disord. 2020, 5, 40-50). In patients, several case reports have been studied. A single-case report confirmed the efficacy and safety of the combination of tofacitinib and nintedanib in the management of aggressive interstitial lung disease with poor prognosis (Conca, W et al., Front. Pharmacol. 2020, 11, 5857619). Baricitinib has been shown to be a safe immunomodulator that reduces the levels of biomarkers of pulmonary fibrosis and inflammation in patients with RA, including the subgroup with interstitial lung disease (D’Alessandro M et al., Int. Immunopharmacol. 2020, 86, 106748).

[0006] In COVID-19, there are some JAK inhibitors that are undergoing clinical trials, namely tofacitinib, baricitinib, and ruxolitinib. Baricitinib and ruxolitinib are associated with a reduced risk of death. They reduce the use of invasive mechanical ventilation and have a marginal impact on the rate of admission to the intensive care unit and the incidence of acute respiratory distress syndrome (ARDS). (Wijaya, I. et al. Clin. Epidemiol. Glob. Health 2021, 11, 100755). Ruxolitinib has also been tested in COVID-19 patients, and it improved clinical symptoms and chest computed tomography images (Cao Y. et al., J. Allergy Clin. Immunol. 2020 146, 137-146).

[0007] Asthma can be included among the numerous immune-mediated diseases, the pathogenesis of which is characterized by the important role of JAK / STAT signaling. Asthma is a chronic inflammatory disease of the airways, which is attributed to the complex interaction between immune responses, genetic susceptibility, and non-specific external stimuli (such as cold, allergens, and exercise), leading to airway hyperresponsiveness, remodeling, and ultimately contributing to airflow limitation. Severe asthma affects 5% to 15% of the adult asthma population (300 million people worldwide) and represents a public health problem associated with increased mortality, increased hospitalizations, significant symptom burden, healthcare costs, and missed work and school (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 in whom the disease remains uncontrolled despite the use of high-dose inhaled corticosteroids (ICS) in combination with long-acting β-agonists or other controller agents. To date, four types of biologics have been licensed for severe asthma, namely omalizumab (anti-IgE antibody), mepolizumab and reslizumab (anti-interleukin [IL]-5 antibodies), benralizumab (anti-IL-5 receptor α antibody), and dupilumab (anti-IL-4 receptor α antibody). Despite their efficacy, many patients continue to experience exacerbations or uncontrolled disease, indicating a need for more new therapies (Israel E, Reddel HK. N Engl J Med 2017;377:965-76).

[0008] Recently, a better understanding of the pathophysiology of asthma has led to a shift from phenotypic classification systems to the introduction of the concept of "endotypes". According to the latter, classification is based on the pathophysiological mechanisms and clinical biomarkers associated with a given patient (Wenzel SE et al., Am J Respir Crit Care Med 2021; 203:809-21). There are two main endotypes in asthma: type 2 and non-type 2. The type 2 pathway is defined by the activation of cytokines derived from Th2 cells and group 2 innate lymphoid cells (ILC2); 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 blood / sputum eosinophilia and elevated fractional 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 and exhibits increased levels of neutrophils or paucigranulocytic features in the airway, with normal levels of airway neutrophils and eosinophils. Type 2-low asthma is not well understood at present, and it may encompass multiple different endotypes. Potential mediators and / or biomarkers of the T2-low endotype under investigation include IL-6, IL-17A / F, IL-23, type I interferons, CXCL10, TNF, alarmin (TSLP, IL-25, IL-33), IL-1β, IL-8, IFN-γ (Hinks TSC et al., ERJ 2021, 57(1)2000528).

[0009] Almost all of the above mediators of the T2 and T2-low endotypes activate the JAK / STAT pathway, which is the rationale for the potential use of JAK inhibitors in both endotypes of severe asthma. The ability of JAK inhibitors to target several cytokines simultaneously may offer advantages over biologics (for non-responder patients) and standard therapies (for patients who remain uncontrolled), considering their administration on top of ICS.

[0010] Although JAK inhibitors have a strong theoretical basis in asthma, safety concerns may arise due to the administration of systemic inhibitors or may limit administration to specific asthmatic subjects (e.g., children). Given that asthma is a lung-restrictive disease, the inhaled administration route of JAK inhibitors can 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. The AstraZeneca pipeline includes AZD-0449 (completed phase I clinical trial) and AZD-4604 (ongoing phase I clinical trial); Theravance Biopharma is starting a new preclinical program for the inhaled JAK inhibitor TD-8236, and Kinaset / Vectura is developing VR588 (ongoing phase I clinical trial) as an inhaled compound. Numerous preclinical studies funded by these companies have demonstrated the efficacy of JAK inhibitors in modulating asthma. At the preclinical stage of drug development, the orally administered JAK1 / 3 inhibitor R256 (currently known as AZD0449) was shown to effectively reduce airway resistance, BAL eosinophilia, mucus production, and, if administered during sensitization, also effectively reduce the TH2 cytokine response (Ashino S et al., J Allergy Clin Immunol 2014;133:1162-74). The iJak-381, administered as a dry powder from Genentech, reduced BAL eosinophilia, CCL11, airway resistance, and Muc5AC in OVA-challenged mice. In addition, it reduced BAL eosinophilia, neutrophilia, CCL11, and CXCL1 in a mouse model exposed to AAH allergen (Dengler HS et al., Sci Transl Med 2018;10:eaao2151). Furthermore, an orally administered JAK inhibitor (such as tofacitinib) formulated for aerosol administration reduced eosinophil counts in a house dust mite murine asthma model (Younis US et al., AAPS PharmSci-Tech 2019;20:167).

[0011] Another respiratory disease that may benefit from pulmonary-restricted JAK inhibition is chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs most commonly caused by cigarette smoke exposure, characterized by largely irreversible and progressive airflow limitation. Although inflammatory cytokines are drivers of chronic airway inflammation and some of them trigger JAK / STAT activation (IL-6, IFN-γ, IL-2, etc.), the role of this pathway in the pathogenesis of COPD is poorly characterized. It has been found that phosphorylated STAT4+ cells (Di Stefano A et al., Eur Respir J. 2004 Jul;24(1):78-85) are increased in COPD compared to healthy non-smoker controls. In another study, phosphorylated STAT3+ and phosphorylated STAT1+ cell counts were higher in lung biopsies from COPD patients than in non-smoker controls, although it was not possible to reproduce the previous data on the phosphorylated STAT4 molecule (Yew-Booth L et al., Eur Respir J 2015;46(3):843-5). These data may also suggest a therapeutic use of JAK inhibitors in COPD disease.

[0012] Given the number of pathological responses mediated by JAK enzymes, there is a continuing need for JAK enzyme inhibitors that can be used to treat many conditions, particularly respiratory diseases.

[0013] Therefore, it remains an important need to discover novel and effective JAK inhibitors suitable for topical administration to the lung for the treatment of asthma and respiratory diseases.

[0014] There is still a strong need for JAK inhibitors and especially inhaled JAK inhibitors that have the potential to provide the compound with improved safety. Although inhaled administration, safety concerns can still arise due to the drug levels reaching the systemic circulation after inhalation of JAKi. In addition to characteristics that are well-suited for inhalation, JAKi should preferably have additional properties that can further limit systemic exposure after inhalation. Summary of the Invention

[0015] Accordingly, an object of the present invention is to provide a compound of formula (I)

[0016]

[0017] wherein R 1 、R 7 、R 8 、X, Y, Z, K, G, n, V and Q are as defined in the detailed description of the invention; or a pharmaceutically acceptable salt thereof, which can be used as a JAK kinase inhibitor.

[0018] Another object of the present invention is to provide pharmaceutical compositions comprising such compounds, methods of using such compounds for treating respiratory diseases, and methods and intermediates useful for preparing such compounds.

[0019] In one aspect, the present invention provides compounds of formula (I) useful as medicaments. In one aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments.

[0020] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating any disease associated with the JAK enzyme mechanism.

[0021] In another aspect, the present invention provides a method for preventing and / or treating any disease associated with the JAK enzyme mechanism as defined above, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0022] In a specific aspect, the compounds of the present invention are used alone or in combination with other active ingredients and can be administered for preventing and / or treating lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung disease and idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS). DETAILED DESCRIPTION OF THE INVENTION

[0024] DEFINITIONS

[0025] The term "pharmaceutically acceptable salt" refers to derivatives of the compounds of formula (I) in which the parent compound is appropriately modified by converting any free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally expected to be pharmaceutically acceptable.

[0026] Thus, suitable examples of such salts can include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acid residues such as carboxyl groups.

[0027] Cations of inorganic bases that can be suitable for preparing the salts of the present invention include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by forming salts by reacting the principal compound acting as a base with inorganic or organic acids include salts such as 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.

[0028] Many organic compounds can form complexes with the solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates" and are another object of the present invention. Polymorphs and crystalline forms of the compounds of formula (I) or their pharmaceutically acceptable salts or solvates are another object of the present invention.

[0029] The term "halogen" or "halo atom" includes fluorine, chlorine, bromine and iodine atoms; it means fluorine, chlorine, bromine, iodine as substituents.

[0030] The term "(C 1 -C 6 )alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. Specific alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, 3-methylbutyl, and the like.

[0031] The expression "(C 1 -C 6 )haloalkyl" refers to the "(C 1 -C 6 )alkyl" as defined above, in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different from each other. Examples include halo-, polyhalo- and perhaloalkyls, in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl or difluoromethyl.

[0032] By analogy, the term "(C 1 -C x )hydroxyalkyl" or "(C 1 -C x )aminoalkyl" refers to the "(C 1 -C x )alkyl" as defined above, in which one or more hydrogen atoms are respectively replaced by one or more hydroxy groups (OH) or amino groups. Thus, "(C 1 -C 6 )hydroxyalkyl" or "(C 1 -C 6 )aminoalkyl" refers to the said hydroxyalkyl or aminoalkyl, in which the number of carbon atoms ranges from 1 to 6.

[0033] The definition of aminoalkyl includes an alkyl group (i.e., a "(C 1 -C 6 )alkyl" group) being replaced by one or more amino groups (-NR 4 R 5 ). Examples of aminoalkyls are monoaminoalkyls such as R 4 R 5 N-(C 1 -C 6 )alkyl, or -(CH 2 ) m NR 4 R 5 . Wherein R 4 and R 5 and m are as defined in the detailed description of the invention.

[0034] Regarding the substituent R as defined above4 and R 5 , which is further explained herein. When R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group, at least one additional ring carbon atom in the heterocyclic group may be replaced by at least one heteroatom or hetero group (such as N, NH, S or O) or may carry an -oxo(=O) substituent. The heterocyclic group may further optionally be substituted at available sites in the ring, i.e., on carbon atoms, or on heteroatoms or hetero groups available for substitution. Thus, examples of the heterocyclic group are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, piperazin-4-yl-2-one, 4-methylpiperazin-1-yl.

[0035] The term "(C 3 -C 10 ) cycloalkyl", likewise "(C 3 -C 6 ) cycloalkyl" refers to a saturated cycloalkyl hydrocarbon group containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and polycyclic ring systems, such as adamantyl.

[0036] The expression "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic system having 6 to 20, preferably 6 to 15, ring atoms, at least one of which is aromatic. The expression "heteroaryl" refers to a monocyclic, bicyclic or tricyclic system having 5 to 20, preferably 5 to 15, ring atoms, at least one of which is aromatic and at least one of which is a heteroatom (such as N, S or O).

[0037] Examples of aryl or heteroaryl monocyclic ring systems include, for example, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, etc.

[0038] Examples of aryl or heteroaryl bicyclic ring systems include naphthyl, biphenylyl, purinyl, pteridinyl, pyrazolopyrimidinyl, benzotriazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indazolyl, benzothienyl, benzodioxanyl, dihydrobenzodioxanyl, indenyl, dihydroindenyl, dihydrobenz[1,4]dioxanyl, 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-naphthyridinyl, etc.

[0039] Examples of aryl or heteroaryl tricyclic ring systems include fluorenyl and benzo-fused derivatives of the above heteroaryl bicyclic ring systems.

[0040] The derived expression "(C 3 -C 10 )heterocycloalkyl", likewise "(C 3 -C 6 )heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic alkyl group having the indicated number of carbon atoms, wherein at least one ring carbon atom is replaced by at least one heteroatom (such as N, NH, S or O) and / or may carry an -oxo(=O) substituent (such as C(=O), S(=O) 2 ). The heterocycloalkyl (i.e., heterocyclic moiety or group) is further optionally substituted at the available sites on the ring, i.e., on the carbon atoms or on the heteroatoms available for substitution.

[0041] Substitution on carbon atoms includes spiro-disubstitution and substitution on two adjacent carbon atoms, thereby forming an additional fused (spiro) 5- to 6-membered heterocycle in both cases.

[0042] The derived expression "hydroxy-(C 3 -C 6 )heterocycloalkyl" refers to substituting the heterocycloalkyl with a hydroxy group at the available sites in the ring, i.e., on the carbon atoms or heteroatoms available for substitution.

[0043] (C 3 -C 6 )heterocycloalkyl is represented by the following examples: oxetanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one-yl, dihydropyrrolyl, 5-oxopyrrolidin-3-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hex-6-yl, 1,1-sulfonylthiomorpholinyl, 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, etc.

[0044] Other examples of the heterocyclic residue 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.

[0045] The term "aryl(C 1 -C 6 )alkyl" refers to an aryl ring attached to a straight-chain or branched-chain alkyl, where the number of constituent carbon atoms is in the range of 1-6, such as phenylmethyl (i.e., benzyl), phenethyl, or phenylpropyl.

[0046] Similarly, the term "heteroaryl(C 1 -C 6 )alkyl" refers to a heteroaryl ring attached to a straight-chain or branched-chain alkyl, where the number of constituent carbon atoms is in the range of 1-6, such as furylmethyl.

[0047] The term "alkanoyl" refers to HC(O)- or alkylcarbonyl (e.g., (C 1 -C 6 )alkylC(O)-), where the group "alkyl" has the meaning defined above. Examples include formyl, acetyl, propionyl, butyryl.

[0048] The term "(C 1 -C 10 )alkoxy" or "(C 1 -C 10 )alkoxy group", similarly "(C 1 -C 6 )alkoxy" or "(C 1 -C 6 )alkoxy group", etc. refers to a straight-chain or branched-chain hydrocarbon of the indicated number of carbon atoms connected to the rest of the molecule through an oxygen bridge. "(C 1 -C 6 )alkylthio" refers to the above hydrocarbon connected through a sulfur bridge.

[0049] The derived expressions "(C 1 -C 6 )haloalkoxy" or "(C 1 -C 6"(haloalkyloxy)" means a haloalkyl group as defined above linked by an oxygen bridge. (C 1 -C 6 ) Examples of haloalkyloxy are difluoromethoxy and trifluoromethoxy.

[0050] Similarly, the derived expressions "(C 3 -C 6 ) heterocycloalkyl-(C 1 -C 6 ) alkyl" and "(C 3 -C 6 ) cycloalkyl-(C 1 -C 6 ) alkyl" mean a heterocycloalkyl group and a cycloalkyl group as defined above linked to the remainder of the molecule by an alkyl group having the indicated number of carbon atoms, such as piperidin-4-yl-methyl and cyclohexylethyl.

[0051] The derived expression "(C 1 -C 6 ) alkoxy(C 1 -C 6 ) alkyl" means an alkoxy group as defined above linked to the remainder of the molecule by an alkyl group having the indicated number of carbon atoms, such as methoxymethyl.

[0052] Similarly, "(C 1 -C 6 ) haloalkyloxy(C 1 -C 6 ) alkyl" means a (C 1 -C 6 ) haloalkyloxy group as defined above linked to the remainder of the molecule by an alkyl group having the indicated number of carbon atoms, such as difluoromethoxypropyl.

[0053] Similarly, "(C 1 -C 6 ) alkoxycarbonyl" means an alkoxy group as defined above linked to the remainder of the molecule by a carbonyl group.

[0054] And "(C 1 -C 6 ) alkoxycarbonyl-(C 1 -C 6 ) alkyl" means an alkoxy group as defined above linked to the remainder of the molecule by a carbonyl group further linked to an alkyl group having the indicated number of carbon atoms, such as methoxycarbonylmethyl.

[0055] And "(C 1 -C 6 ) alkoxycarbonyl-(C 1 -C 6 ) alkylthio thus means a linking group such as methoxycarbonylmethylthio.

[0056] The oxo moiety is represented by (O) as an alternative to other common representations such as (=O). Thus, in terms of the general formula, the carbonyl group is preferably represented as -C(O)- in the present application as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-. Generally, the group within the parentheses is a side group and is not included in the chain, and when considered useful, parentheses are used to help make the linear chemical formula unambiguous; for example, the sulfonyl group -SO 2 - can also be represented as -S(O) 2 - to eliminate ambiguity regarding, for example, the sulfinyl group -S(O)O-.

[0057] When numerically marked, the statement "p is zero" or "p is 0" means that the substituent or group with the label p (e.g., Ip) is absent, that is, there is no substituent other than H when required. Similarly, when the label is attached to a bridging divalent group (e.g., (CH 2 )n), the expression "n is 0 each time it appears..." or "n is 0" means that the bridging group is absent, that is, it is a bond.

[0058] Whenever a basic amino or quaternary ammonium group is present in the compound of formula (I), a physiologically acceptable anion selected from chloride ion, bromide ion, iodide ion, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate may be present. Similarly, in the presence of an acidic group such as a COOH group, the corresponding physiologically cationic salt may also be present, for example, including alkali metal or alkaline earth metal ions.

[0059] When the compounds of formula (I) contain one or more stereocenters, they can exist as optical stereoisomers.

[0060] When the compounds of the present invention have at least one stereocenter, they can accordingly exist as enantiomers. When the compounds of the present invention have two or more stereocenters, they can additionally exist as diastereoisomers. It should be understood that all these single enantiomers, diastereoisomers and any mixtures thereof in any ratio are included within the scope of the present invention. The absolute configuration (R) or (S) of the carbon with the stereocenter is specified based on the priorities of the groups according to the Cahn-Ingold-Prelog nomenclature rules.

[0061] When reported near the chemical name of a compound, "single stereoisomer", "single diastereoisomer" or "single enantiomer" means that the isomer has been isolated as a single diastereoisomer or enantiomer (e.g., by chiral chromatography), but the absolute configuration at the relevant stereocenter has not been determined / specified.

[0062] Atropisomers are generated by the hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow the isolation of conformational isomers (Bringmann G et al., Angew. Chemie Int. Ed. 44(34), 5384 - 5427, 2005. doi:10.1002 / anie.200462661).

[0063] Oki defined atropisomers as conformational isomers that interconvert with a half - life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1 - 82, 1983).

[0064] Atropisomers differ from other chiral compounds in that, in many cases, they can equilibrate thermally, which is usually only chemically possible in other forms of chiral isomerization.

[0065] Separation of atropisomers by chiral resolution methods such as selective crystallization is possible. In atropo - enantioselective or atroposelective synthesis, the formation of one atropisomer comes at the expense of the other. Atroposelective synthesis can be carried out by using chiral auxiliaries such as Corey Bakshi Shibata (CBS) catalysts (asymmetric catalysts derived from proline) or by methods based on thermodynamic equilibrium (when the isomerization reaction favors one atropisomer over the other).

[0066] The racemic forms of the compounds of formula (I), as well as the individual atropisomers (substantially free of their corresponding enantiomers) and stereoisomer - rich mixtures of atropisomers are included within the scope of the present invention.

[0067] The present invention also relates to the corresponding deuterated derivatives of the compounds of formula (I). In the context of the present invention, deuterated derivatives mean that at least one position occupied by a hydrogen atom is occupied by deuterium in an amount higher than its natural abundance. Preferably, the percentage of deuterium at that position is at least 90%, more preferably at least 95%, and even more preferably 99%.

[0068] All preferred groups or embodiments described above and below for the compounds of formula (I) can be combined with each other, and with the necessary modifications, also apply.

[0069] As described above, the present invention provides compounds of general formula (I) for use as JAK inhibitors, methods for their preparation, and pharmaceutical compositions comprising them alone or in combination with one or more active ingredients, mixed with one or more pharmaceutically acceptable carriers.

[0070] In a first aspect, the present invention provides a class of compounds of formula (I)

[0071]

[0072] R 1 is a heteroaryl selected from:

[0073] imidazo[1,2-b]pyridazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, 3-oxo-(3,4-dihydropyrazin-2-yl)amino;

[0074] R 2 is a group of the formula:

[0075]

[0076] i.e., a substituent attached to the molecular skeleton,

[0077] wherein

[0078] V is absent (meaning it is a bond) or is selected from 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;

[0079] Q is selected from 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 the (C 3 -C 8 )cycloalkyl and (C 3 -C 10) The heterocycloalkyl is further optionally substituted by one or more substituents selected from -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, hydroxy-(C 3 -C 6 )heterocycloalkyl;

[0080] R 3 is a bicyclic moiety

[0081] which is a substituent attached to the backbone as shown below:

[0082]

[0083] where the dashed line --- indicates a single or double bond

[0084] X is selected from N, S, C;

[0085] Y is selected from C, N;

[0086] Z is selected from C, N, O;

[0087] K is absent (meaning a bond) or selected from O, C, S;

[0088] G is absent (meaning a bond) or selected from C, O;

[0089] (wherein X, Y, Z, K, and G are each connected in a ring and connected with the correct number of H or substituents according to their valences)

[0090] is the attachment point of the substituent to the rest of the molecule (meaning the bond that attaches the substituent R 1 , R 2 or R 3 to the molecular backbone)

[0091] n and m are each independently 0 or an integer selected from 1, 2, 3, and 4 each time they appear; ((R 7 ) n where n = 0 means that the substituent R 7 is absent, i.e., R 7 is H; n = 0 or m = 0 similarly means that the linking group -(CH 2 ) n - or -(CH 2 ) m is absent, i.e., -(CH 2 ) n - or -(CH 2 ) m - are bonds respectively);

[0092] R 4 and R 5 are the same or different and are selected from:

[0093] -H,

[0094] (C 1 -C 6 )alkyl,

[0095] (C 1 -C 6 )haloalkyl, and

[0096] (C 3 -C 6 )heterocycloalkyl;

[0097] R 6 is independently selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkyl each time it appears;

[0098] R 7 is one or more groups (preferably 1 or 2), independently selected from -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 )-;

[0099] R 8 is selected from:

[0100] (C 1 -C 6 )alkoxy,

[0101] (C 1 -C 6 )haloalkoxy;

[0102] Preferably R 8 is methoxy, fluoromethoxy, difluoromethoxy;

[0103] its individual enantiomers, diastereoisomers and any mixtures thereof in any ratio

[0104] or a pharmaceutically acceptable salt or solvate.

[0105] In a preferred embodiment the bicyclic moiety R 3

[0106]

[0107] is selected from

[0108]

[0109] In a further preferred embodiment the bicyclic moiety R 3 is selected from J 1 -J 13

[0110]

[0111] A particularly preferred group of compounds are those of formula I, wherein

[0112] R 3 is J1 and R 8 is methoxy

[0113] The compounds of the preferred group are represented by formula Ia

[0114]

[0115] wherein

[0116] R 1 is pyrazolo[1,5-a]pyrimidin-3-yl or (3-oxo-3,4-dihydropyrazin-2-yl)amino

[0117] V is a divalent group selected from C(O)N(R 6 ), N(R 6 )C(O)O;

[0118] Q is selected from (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 the (C 3 -C 8 )cycloalkyl and (C 3 -C 12 )heterocycloalkyl are further optionally substituted by one or more substituents selected from oxo (i.e., the group (=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;

[0119] n and m are each independently 0 or an integer selected from 1, 2, 3, and 4;

[0120] R 4 and R 5 are the same or different and are selected from:

[0121] -H,

[0122] (C 1 -C 6Alkyl,

[0123] (C 1 -C 6 ) haloalkyl;

[0124] its individual enantiomers, diastereoisomers and mixtures thereof in any ratio

[0125] or a pharmaceutically acceptable salt or solvate.

[0126] Even more preferred in this group are the compounds of formula Ia

[0127] wherein

[0128] V is N(R 6 )C(O)O;

[0129] Q is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -(CH 2 ) m NR 4 R 5 , and (C 3 -C 6 ) heterocycloalkyl; wherein the (C 3 -C 6 ) heterocycloalkyl is the group wherein X 1 is selected from CH 2 , O, S, NH, NCH 3 , (C=O) and S(=O) 2 .

[0130] Also preferred are the compounds of formula Ia, wherein

[0131] V is C(O)N(R 6 ),

[0132] Q is selected from -(CH 2 ) m NR 4 R 5 and (C 3 -C 6 ) heterocycloalkyl; wherein the (C 3 -C 6 ) heterocycloalkyl is the group wherein X 1 is selected from CHR 9 , O, S, NH, NCH 3 , CF 2 , (C 1 -C 6 ) alkoxy or (C1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, where R 9 is H or -(CO)NR 4 R 5 .

[0133] Also preferred are the compounds of formula Ia, where

[0134] Q is (C 3 -C 6 ) heterocycloalkyl, -S-(C 3 -C 6 ) heterocycloalkyl or -N(R 6 )-(C 3 -C 6 ) heterocycloalkyl, selected from:

[0135]

[0136] wherein preferably the tetrahydro-1H,3H-5λ 2 -furo[3,4-c]pyrrol-1-one is

[0137]

[0138] According to certain embodiments, the present invention provides the compounds of Examples 1 to 86 listed in the following table or their pharmaceutically acceptable salts and solvates.

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] The compounds of the present invention (including all compounds listed above) can be prepared from readily available starting materials using the general methods and procedures described in the experimental section below or by using slightly modified methods readily accessible to those of ordinary skill in the art. Although specific embodiments of the present invention may be shown or described in this application, those skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described in this application or by using other known methods, reagents, and starting materials. When typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Although the optimal reaction conditions may vary depending on the specific reactants or solvents used, those skilled in the art can readily determine these conditions by conventional optimization methods. The preparation methods described below and reported in the following schemes should not be regarded as limiting the scope of the synthetic methods available for preparing the compounds of the present invention.

[0146] In some cases, a step is required to mask or protect sensitive or reactive moieties, and according to the general principles of chemistry, commonly known protecting groups (PG) (Protective group in organic syntheses, 3rd edition, T.W. Greene, P.G.M. Wuts) can be used.

[0147] The compounds of formula (I) (reported again here for clarity, including all compounds listed above) can generally be prepared according to the methods shown in the following schemes. Where the specific details or steps differ from the general scheme, they have been detailed in the specific examples and / or additional schemes.

[0148]

[0149] The compounds of formula (I) can be prepared according to Scheme 1. Compound IV is an intermediate, where the general groups r 1、 r 2 and r 3 can be converted into R 1 、R 2 and R 3 respectively through 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 said procedures can be applied to one or more of those groups (r 1、 r 2 and r 3 ) so as to convert the intermediate IV into the compounds of general formula I, and they are detailed in the experimental section of the specific examples. Obviously, in cases where such transformation is not required (r 1 、r 2 and r 3Corresponding respectively to R 1 , R 2 and R 3 ) Under the following, any general route for preparing Intermediate IV will provide a compound of general formula I.

[0150]

[0151] For synthetic convenience, it may be necessary to protect the rings and / or exocyclic NH moieties that may be present in r 2 and / or r 3 during the synthetic procedure. Suitable protecting groups for protecting the said NH moieties can be carbamate protecting groups such as Boc (tert-butoxycarbonyl) and / or hemiaminals such as SEM (2-(trimethylsilyl)ethoxymethyl). The Boc group can be inserted by reacting the NH derivative with Boc 2 O at room temperature in the presence of a base such as DMAP or pyridine and in an organic solvent such as THF or DMF. The SEM group can be inserted by reacting the NH derivative with SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride) at low temperature such as 0 °C in a suitable organic solvent such as DMF and in the presence of a strong base such as NaH or LiHMDS (lithium hexamethyldisilazide).

[0152] The Boc group can be easily removed by treating the Boc-protected Intermediate IV (or from other convenient upstream intermediates) under acidic conditions with an organic or inorganic strong acid. For example, the Boc group can be cleaved as follows: generally by treating the intermediate with trifluoroacetic acid, pure or mixed with an organic solvent such as DCM, DCE, THF or a similar solvent, at room temperature for several hours (generally 1 to 3 h). The SEM group can be removed by treating Intermediate IV (or from other convenient upstream intermediates) under acidic conditions, similar to the removal of the Boc group. In some cases, the acidic treatment may result in incomplete removal of SEM, so it may be necessary to further treat with concentrated ammonia water to completely remove the formaldehyde adduct resistant to acidic treatment. It should be understood that the insertion and removal of the NH protecting group in r 2 / r 3 can be completed under more convenient circumstances in the synthetic procedure.

[0153] The compound of formula I (or intermediate IV) can be obtained by reacting intermediate II with intermediate III as follows: R is directly introduced through a metal / palladium-catalyzed coupling reaction such as Suzuki coupling, Stille coupling, Buchwald-Hartwig or a similar reaction (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005). 1 (or r 1 ).

[0154] For example, for the introduction of R 1 (when it is pyrazolo[1,5-a]pyrimidin-3-yl), a suitable palladium-catalyzed coupling is Suzuki coupling. Suzuki coupling can be carried out as follows: under heating (generally in the range of 50 - 100 °C), in the presence of a Pd catalyst such as tetrakis(triphenylphosphine)palladium(0), PdCl 2 (dppf) 2 or a ligand-palladium precatalyst such as XPhos-Pd-G3 [(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate], in an organic solvent such as 1,4-dioxane, THF, 1,2-dimethoxyethane, 2-propanol or DMF (aqueous or anhydrous), in the presence of an inorganic base such as an alkaline carbonate (e.g., Cs 2 CO 3 or K 2 CO 3 ) or an inorganic phosphate (e.g., K 3 PO 4 ), react intermediate II with a suitable substituted boric acid or substituted boronic acid pinacol ester (boron pinacolate) derivative (intermediate III, where r 1 is pyrazolo[1,5-a]pyrimidin-3-yl and A is dihydroxyboranyl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) for several hours (generally 1 to 3 h). Substituted boric acids and substituted boronic acid pinacol esters are generally commercially available or can be readily prepared by those skilled in the art starting from commercially available reagents.

[0155] For the introduction of R 1 (when it is imidazo[1,2-b]pyridazin-3-yl), a suitable palladium-catalyzed coupling is Stille coupling, which can be carried out as follows: in the presence of a suitable palladium catalyst (such as Pd(PPh 3 ) 2 Cl 2) In the presence of [substance], in a polar organic solvent (such as DMF or dioxane, with or without additives (such as a base or a lithium salt)), react intermediate II with a suitable stannane reagent (intermediate III, where r 1 is imidazo[1,2 - b]pyridazin - 3 - yl and A is tributylstannyl or trimethylstannyl). Stannanes are generally commercially available or can be readily prepared by those skilled in the art starting from commercially available reagents.

[0156] For the introduction of r 1 (when it is (3 - oxo - 3,4 - dihydropyrazin - 2 - yl)amino), a suitable palladium - catalyzed coupling is the Buchwald - Hartwig coupling. For synthetic convenience, it is necessary to mask the lactam group of (3 - oxo - 3,4 - dihydropyrazin - 2 - yl)amino as an alkoxy imide group (such as methoxy imide group, -C(OMe)=N -) and deprotect it from intermediate IV at the end of the synthesis. Intermediate II and intermediate III (where r 1 is 3 - methoxypyrazin - 2 - amino and A is H) can be reacted to provide intermediate IV (where r 1 is 3 - methoxypyrazin - 2 - amino): Under heating at a high temperature (generally 80 - 120 °C), in the presence of a suitable ligand - palladium ring system such as XPhos - Pd - G3 (2 - dicyclohexylphosphino - 2′,4′,6′ - triisopropyl - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II) methanesulfonate) or RuPhos - Pd - G3 (2 - dicyclohexylphosphino - 2′,6′ - diisopropoxy - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II) methanesulfonate) or usually a suitable Pd source (such as Pd 2 (dba) 3 or Pd(OAc) 2 ) and a suitable phosphine ligand such as a biphenylphosphine ligand class (RuPhos, X - Phos or the like), in the presence of a strong organic base such as sodium tert - butoxide or an inorganic base such as Cs 2 CO 3 in an organic solvent such as 1,4 - dioxane, THF or toluene, for several hours (generally overnight). Where R 1 is (3 - oxo - 3,4 - dihydropyrazin - 2 - yl)amino, the compound of formula I can be prepared as follows: Demethylate the corresponding methoxy - imide derivative by treating the protected precursor with TMS - Cl (trimethylsilyl chloride) and sodium iodide / acetonitrile at 60 - 100 °C for 1 - 5 h; these conditions can also lead to the deprotection of the Boc / SEM groups finally present in r 2 / r 3 .

[0157] The methods described above can provide at least one non - limiting synthetic route for preparing the examples of the present invention starting from the appropriate intermediate II.

[0158] Possible routes for preparing intermediate II are reported in Scheme 2. Intermediate II can be prepared as follows: by N - arylating intermediate V with halide intermediate VI using a copper - catalyzed Ullmann - type reaction. The Ullmann reaction between an NH - heteroaryl and an aryl / heteroaryl halide (bromide or iodide) can be carried out as follows: in the presence of a suitable copper(I) catalyst / cocatalyst such as CuI, Cu 2 O or CuTC (copper thiophenecarboxylate) (either ligand - free or with 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 K 2 CO 3 or Cs 2 CO 3 heating (generally 90 - 150 °C) overnight or longer in a polar organic solvent such as DMSO, DMF or DMA.

[0159] Scheme 2

[0160]

[0161] In another route, intermediate II (referred to as II 3 / R 3 when r i is J2 (for n: 0) and II ii (for n: 1, R 7 : 3 - oxo)) can be synthesized by a multi - step synthesis according to Scheme 3. Intermediate V and intermediate VIIa can undergo aromatic nucleophilic substitution (SNAr) to provide intermediate VIIIa, for example: 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 K 2 CO 3 or Cs 2 CO 3 at RT or higher (up to 120 °C) for several hours (generally 1 to 4 hours). Similarly, intermediate VIIIb and VIIIc can be prepared from V by reacting with VIIb and VIIc respectively.

[0162] Intermediate VIIIa can be reacted with mercaptoethanol (r 5 -SH, r 5The reaction with (ethanol-2-yl) provides intermediate IXa. The C-S coupling can be carried out as follows: Aryl bromide VIIIa and mercaptoethanol are reacted in a suitable catalytic system such as Pd 2 (dba) 3 / Xantphos or another suitable palladium source / 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 a temperature up to 100 °C for several hours (usually 3 - 5 hours).

[0163] Intermediate IXb can be synthesized by performing an aromatic nucleophilic substitution (SNAr) of intermediate VIIIa with methyl 2-thioacetate (r 5 -SH, r 5 is methyl acetate-2-yl): They are heated in an organic solvent such as acetonitrile or dioxane at a high temperature (usually 120 °C) for several hours (usually 3 to 6 hours).

[0164] Scheme 3

[0165]

[0166] Intermediate IXa can be converted to intermediate II through a three-step method involving the following i : 1) nitro reduction, 2) chlorination and cyclization. The nitro reduction can be carried out as follows: Intermediate IXa is treated with a reducing agent such as iron powder or zinc powder by heating in an organic solvent such as methanol or ethanol in the presence of a weak inorganic acid salt such as aqueous ammonium chloride solution at a temperature up to 80 °C for several hours (usually 4 - 5 hours). The subsequent conversion of the alcohol to the corresponding chloride can be achieved by reacting with pure thionyl chloride or oxalyl chloride at low temperature (about 0 °C). The chloride intermediate can be cyclized to provide intermediate II i : by heating (usually 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 in the presence of an additive such as sodium iodide.

[0167] Intermediate IXb can be converted to intermediate II by a method involving nitro reduction and cyclization to an inner amide ii . The nitro reduction of intermediate IXb can be obtained similarly to the description of intermediate IXa. The cyclization can occur spontaneously during the nitro reduction step or be promoted in a separate step by treatment with a strong organic acid such as TFA.

[0168] In an alternative route, intermediate II ii can be converted to intermediate II by reducing the inner amide to the corresponding inner amide with a borane such as BH 3 *THF complex i .

[0169] In yet another approach, Intermediate II i can be converted to Intermediate II as follows iii : In an organic solvent such as DCM, at a temperature of about 0 °C, the sulfide is oxidized to a sulfone using an oxidant such as m-CPBA.

[0170] In yet another manner, in r 3 / R 3 is Intermediate II in the case of J8 (referred to as II in Scheme 3 iv ) can be prepared by a multi-step method starting from Intermediate VIIIa. In the first step, Intermediate VIIIa can undergo aromatic nucleophilic substitution with a malonate such as diethyl malonate by heating the reagent (typically 60 - 70 °C) in an organic solvent such as DMSO or DMF. In the second step, treatment with iron powder in acetic acid as the solvent at a high temperature (e.g., 90 °C) can promote a one-pot nitro reduction, cyclization, and decarboxylation to afford Intermediate II iv .

[0171] In yet another approach, Intermediate II iv can be converted to II by a two-step method involving the following v : 1) NH protection with an SEM group and 2) cyclopropanation with a sulfur vinyl ylide such as vinyldiphenylsulfonium trifluoromethanesulfonate.

[0172] In a different manner, in r 3 / R 3 is Intermediate II in the case of J6 (where n: 0) (referred to as Intermediate II vi ) and in r 3 / R 3 is Intermediate II in the case of J1 (where n: 3, R 7 : 3-oxo, 1,1-difluoro) (referred to as Intermediate II vii ) can be prepared according to Scheme 4.

[0173] Intermediate VIIIb can be converted to Intermediate X by a two-step method involving the following: 1) deallylation and 2) nitro reduction. The deallylation reaction can be carried out as follows: 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, Intermediate VIIIb is treated with an inorganic base such as potassium carbonate or cesium carbonate (typically at 50 - 70 °C). The subsequent nitro reduction can be carried out similarly to the description of the reduction of Intermediate IXa in Scheme 3. Intermediate X can be selectively acylated on the aniline nitrogen to form the corresponding amide: at a high temperature (typically 130 °C) in an organic solvent such as THF by DABAL-Me 3Promote the aminotransfer of methyl 2,2-dibromo-2-fluoroacetate. The subsequent cyclization of the amide intermediate can provide intermediate II vii : Heat (100 - 120 °C) in an organic solvent such as THF or dioxane, and promote the reaction with an organic base such as DBU or DIPEA.

[0174]

[0175] In yet another approach, intermediate II vi can be obtained from intermediate VIIIc through a two-step method involving: r 4 Mesylation of the free hydroxyl group (when r4 is propane-3-ol-1-oxy), and subsequent 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 of the intermediate by heating (about 80 °C) with iron in an organic solvent such as ethanol in the presence of a weak inorganic acid such as aqueous ammonium chloride.

[0176] In a different manner, in r 2 is -NR 6 (CH 2 ) n Q', intermediate II (referred to as IIa) can be prepared according to Scheme 5. If different from Q, Q' is a group that can be easily converted to Q by procedures well-known to those skilled in the art (such as functional group transformation and / or protecting group deprotection that may involve more than one step).

[0177]

[0178] Intermediate XI can be converted to intermediate Va through a multi-step method involving the following: 1) NH protection, 2) C-N coupling with HNR 6 (CH 2 ) n 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 as follows: At about 40 °C, in an organic solvent such as THF, DCM or a mixture, and in the presence of a sulfonic acid such as methanesulfonic acid, heat intermediate XI with dihydropyran for several hours (12 hours or more). The C-N coupling between the THP-protected intermediate XI and HNR 6 (CH 2 ) n -Q' can be carried out as follows: In an organic solvent such as DMF or DMSO, in the presence of a copper(I) catalyst / cocatalyst such as CuI, Cu 2In the presence of O or CuTC (copper thiophenecarboxylate) (without ligand or with a suitable ligand such as proline, N,N-dimethylglycine, dimethylcyclohexane-1,2-diamine (DMCHA)), and in the presence of an inorganic base such as K 2 CO 3 or Cs 2 CO 3 the heterocyclic iodide and the amine are heated (generally at 60 - 100 °C). Finally, the removal of THP can be carried out as follows: at room temperature, in the presence of a silane scavenger such as triethylsilane, in an organic solvent such as DMF or THF, acidic treatment is carried out with an organic acid such as TFA or methanesulfonic acid for several hours (about 2 h). The conversion of intermediate Va to intermediate IIa can be carried out under conditions similar to those described for the conversion of intermediate V to intermediate II in Scheme 2.

[0179] In another manner, intermediate XI and intermediate VIIa can be converted to intermediate XIIa by SNAr, similar to the description of the conversion of V and VIIa to VIIIa in Scheme 3. The conversion of intermediate XIIa to VIIIa' can be completed under conditions similar to those reported for C-N coupling above. Finally, the conversion of VIIIa' to intermediate IIa (when r 3 / R 3 is J2) can be completed under conditions similar to those reported for the conversion of IXb to II ii in Scheme 3.

[0180] In another route, intermediate II can be obtained from the further processing of the r 2 group by generally accepted methods and in accordance with chemical principles. In the following schemes, the most common conversions that can be used to obtain a specific intermediate II are detailed. For clarity, they are labeled with additional letter references.

[0181] Scheme 6

[0182]

[0183] In one of these alternative routes, intermediate IIc (intermediate II when r 2 is -C(O)N(R 6 )-(CH 2 ) n -Q') can be obtained starting from intermediate IIb (intermediate II when r 2 is -C(O)OH) according to Scheme 6 by reaction with HNR 6 (CH 2 ) nQ' is prepared by amide coupling. The amide coupling can be carried out as follows: In an organic solvent such as DMF, DCM or THF, in the presence of a coupling reagent 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 in the presence of an organic base such as DIPEA, TEA or pyridine, react an amine with an acid.

[0184] In a different manner, in the case where intermediate IIb is synthesized as a methyl ester for synthetic convenience, it can be directly converted to an amide: at a high temperature (generally 130 °C) in an organic solvent such as THF, by DABAL-Me 3 to facilitate the aminotransfer reaction with the corresponding amine.

[0185] In yet another approach, intermediate IIc can be prepared from intermediate IIe by alkylating the primary / secondary nitrogen present in the Q' moiety to replace Lg”: In an organic solvent such as DMF, acetone or 1,4-dioxane, in the presence of an organic base such as DIPEA, TEA or an inorganic base such as sodium carbonate and an inorganic iodide such as sodium iodide therewith, treat amine Q' and halide IIe at room temperature or higher (e.g., 40 °C) for several hours to overnight. Intermediate IIe can be obtained from intermediate IIb and HNR 6 (CH 2 ) n Lg” using conditions similar to those reported above for the conversion of intermediate IIb to intermediate IIc in this scheme.

[0186] Intermediate IIb can be prepared starting from a suitable intermediate V (where r 2 is -COOH or -COOMe) using the conditions reported above for the general synthesis of intermediate II in Schemes 2, 3 and 4.

[0187] In yet another approach reported in Scheme 7, intermediate IIg (or IIh) can be prepared from intermediate IIf and HO(CH 2 ) n Q' (or HNR 6 (CH 2 ) nQ'): 1) Isocyanate formation and 2) reaction with an alcohol (or amine) to form the corresponding carbamate (or urea). The intermediate IIf can be reacted with bis(trichloromethyl) carbonate in an organic solvent such as DCM, THF or Me-THF at a low temperature such as dry ice temperature (-78 °C) in the presence of an organic base such as TEA or DIPEA for up to 1 or 2 hours to form the corresponding isocyanate; addition of the intermediate alcohol (or amine) and reaction at room temperature results in the formation of the carbamate of formula IIg (or the urea of formula IIh). An alternative method for forming the isocyanate intermediate from IIf can use carbonyldiimidazole (CDI), heating overnight at a temperature of about 90 °C in an organic solvent such as 2-Me-THF.

[0188] In a different route, the carbamate IIg can be obtained as follows: in an organic solvent such as DCM or THF and in the presence of a base such as pyridine or DIPEA, the amine IIf is reacted with the corresponding chloroformate alcohol ester (Cl-C(O)O(CH 2 ) n Q') reaction.

[0189] Scheme 7

[0190]

[0191] In an alternative method, the intermediates of formula IIg (and IIh) can be obtained from the intermediate IIb and the alcohol intermediate HO(CH 2 ) n Q'(or the amine intermediate HNR 6 (CH 2 ) n Q'): 1) Acyl azide formation and Curtius rearrangement, providing the corresponding isocyanate intermediate; and 2) one-pot reaction of the isocyanate with an alcohol (or amine) to form the corresponding carbamate (or urea). The corresponding acyl azide of intermediate IIb can be prepared as follows: in the presence of a suitable coupling reagent such as an alkyl phosphonic anhydride such as T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution) (containing an organic base such as TEA or DIPEA), and in an organic solvent such as 2-methyl-THF, DMF or toluene, IIb is reacted with an azide source such as azido(trimethyl)silane. The subsequent Curtius rearrangement can be completed as follows: thermal degradation for several hours (generally 1 - 3 hours) at about the solvent reflux temperature (generally 50 °C to 100 °C), providing the corresponding isocyanate; after isocyanate formation, the alcohol intermediate HO(CH 2 ) n Q'(or the amine HNR 6 (CH 2 ) nQ') and continuing the reflux overnight can lead to the formation of the corresponding carbamate of formula IIg (or urea IIh).

[0192] Intermediate IIf can be prepared by starting from a suitable intermediate V (where r 2 is -NH 2 ) using the conditions reported for the general synthesis of intermediate II in Scheme 2, Scheme 3 and subsequent Scheme 4.

[0193] Scheme 8

[0194]

[0195] In the alternative route reported in Scheme 8, intermediate IIa (referred to as Boc-IIa) with the exocyclic NH protected by a Boc group can be prepared by a two-step method involving: 1) Boc insertion of the exocyclic amine and 2) alkylation with Lg-(CH 2 ) n -Q'. Boc protection can be carried out as follows: 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, reacting IIf with Boc 2 O. Alkylation can be carried out as follows: 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, reacting the Boc intermediate with Lg-(CH 2 ) n -Q'.

[0196] In a different route, intermediate II can be obtained by further processing the Q' group to Q” through the functional group transformations summarized in Table 1. The complete details of the transformation are provided in the experimental section. If different from Q, Q” is a group that can be easily transformed into Q by procedures well-known to those skilled in the art (such as functional group transformations and / or deprotection of protecting groups that may involve more than one step).

[0197] Table 1

[0198]

[0199]

[0200] In a different route, intermediate IV can be obtained by further processing the Q' group to Q” through the functional group transformations summarized in Table 2. The complete details of the transformation are provided in the experimental section. If different from Q, Q” is a group that can be easily transformed into Q by procedures well-known to those skilled in the art (such as functional group transformations and / or deprotection of protecting groups that may involve more than one step).

[0201] Table 2

[0202]

[0203]

[0204] As described in detail in the present application, the compounds of the present invention are inhibitors of kinase activity, particularly inhibitors of JAK kinase activity, for the treatment of JAK-dependent diseases.

[0205] In one aspect, the present invention provides a compound according to the present invention, i.e., a compound of formula (I) or a pharmaceutical composition thereof, which is used as a drug, preferably for the prevention and / or treatment of respiratory diseases, particularly pulmonary diseases.

[0206] In another aspect, the present invention provides the use of compound (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of conditions related to the JAK mechanism, particularly for the treatment of conditions such as respiratory diseases and pulmonary diseases.

[0207] In particular, the present invention provides a compound of formula (I) for the prevention and / or treatment of pulmonary diseases selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS).

[0208] In addition, the present invention provides a method for preventing and / or treating conditions related to the JAK mechanism, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

[0209] In particular, the present invention provides a method for prevention and / or treatment, wherein the condition 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).

[0210] Preferably, the use of the compounds of the present invention for the prevention of the aforementioned diseases.

[0211] Equally preferably, the use of the compounds of the present invention for the treatment of the aforementioned diseases.

[0212] Generally, compounds as JAK inhibitors can be used to treat many conditions related to the JAK enzyme mechanism.

[0213] In one embodiment, the conditions that can be treated by the compounds of the present invention are selected from asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF), acute lung injury, and acute respiratory distress syndrome (ARDS).

[0214] In another embodiment, the conditions are selected from asthma and chronic obstructive pulmonary disease (COPD).

[0215] The treatment method of the present invention comprises administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used in this application, an "effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutical active agent means an amount of the compound sufficient to treat the condition of the patient but low enough to avoid serious side effects, and which can still be routinely determined by those skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in a single dose or according to a dosing regimen, wherein multiple doses are administered at different time intervals over a given time period. The typical daily dose can vary depending on the particular route of administration chosen.

[0216] The present invention also provides a pharmaceutical composition in which a compound of formula (I) is admixed with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

[0217] The present invention also relates to the use of the compounds of the present invention and their pharmaceutical compositions for various routes of administration.

[0218] The administration of the compounds of the present invention and their pharmaceutical compositions can be carried out according to the needs of the patient, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intra-sternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally and by ocular administration.

[0219] Various solid oral dosage forms can be used for administering the compounds of the present invention, including tablets, capsule-shaped tablets, capsules, cachets, granules, lozenges and solid forms of bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starch) and known excipients, which include suspending agents, solubilizing agents, buffering agents, binders, disintegrating agents, preservatives, colorants, flavoring agents, lubricants, etc. Sustained-release capsules, tablets and gels are also advantageous.

[0220] Various liquid oral dosage forms can also be used for administering the compounds of the present invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms can also contain suitable known inert diluents (such as water) and suitable known excipients (such as preservatives, wetting agents, sweetening agents, flavoring agents, etc., and reagents for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention can be formulated as injectable compositions in the form of isotonic sterile solutions, for example, for intravenous injection. Other formulations are also possible.

[0221] Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylates, and polyethylene glycols.

[0222] Preparations for vaginal administration can be in the form of creams, gels, pastes, foams, or spray formulations and are known to contain, in addition to the active ingredient, suitable carriers, for example.

[0223] For topical administration, the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear, or nose. Topical administration can also include transdermal administration by means of, for example, transdermal patches.

[0224] The compounds of the present invention can exhibit characteristics suitable for administration by the oral route. Optimizing a drug for oral delivery requires certain characteristics that allow the orally administered compound to be absorbed by the GI tract (gastrointestinal tract) and cleared inadequately to provide good bioavailability (F%), thereby maintaining sufficient concentrations in the plasma and target tissues for a time sufficient to maintain the pharmacological effect. To enhance oral bioavailability, one or more characteristics of the compound need to be optimized such as but not limited to maximizing membrane permeability and reducing metabolic hotspots (optimizing in vitro clearance).

[0225] For the treatment of respiratory diseases, the compounds of the present invention as described above can also preferably be administered by inhalation.

[0226] Certain preferred compounds of the present invention exhibit characteristics suitable for administration by the inhalation route.

[0227] Optimizing a drug for inhalation delivery requires certain characteristics that allow the compound to maintain sufficient local concentration (lung retention) when administered to the lungs to exert the pharmacological effect for a desired duration, with minimal drug absorption in the gastrointestinal tract of the swallowed portion and generally insignificant levels in unwanted compartments (i.e., plasma). For this purpose, one or more characteristics of the compound are optimized such as but not limited to membrane permeability, dissolution rate, and basicity of the compound to enhance its binding to phospholipid-rich lung tissue or lysosomal capture. In certain embodiments, the compounds of the present invention exhibit one or more of the above-described characteristics in the desired range for inhaled compounds. Inhaled JAKi should preferably have additional properties that can further limit systemic exposure after inhalation.

[0228] One way to limit systemic exposure after local administration may be to design a soft-drug, which means introducing in the present invention specific moieties such as cyclic esters or lactones, which favor controlled rapid systemic metabolism (in the liver and / or in the blood) to form metabolites that are predictably less functionally active compared to the parent compound. For this purpose, one approach leads to the optimization of 'appropriately designed lactone derivatives' which can be substrates of hepatic and / or blood esterases and can be beneficial for achieving enhanced in vivo clearance.

[0229] Thus, the preferred compounds of the present invention exhibit one or more of the following characteristics: high biochemical activity against the target, strong functional activity (such as cell-based activity) and rapid clearance in representative tests (stability in liver microsomes and / or hepatocytes, plasma stability), so that they have the ability to provide compounds with improved safety.

[0230] For the treatment of respiratory diseases, the compounds of the present invention as described above can be administered by inhalation.

[0231] Inhalable formulations include inhalable powders, propellant-containing metered aerosols or propellant-free inhalable formulations, and can be administered by suitable inhalation devices, which can be selected from dry powder inhalers, pressurized metered-dose inhalers or nebulizers, respectively.

[0232] For administration as a dry powder, single-dose or multi-dose inhalers known in the prior art can be used. In this case, the powder can be filled in gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0233] A diluent or carrier, such as lactose or any other additive suitable for improving the inhalable fraction, can be added to the powdered compounds of the present invention.

[0234] Inhalation aerosols containing a propellant gas such as hydrofluoroalkane can contain the compounds of the present invention in solution or dispersed form. Propellant-driven formulations can also contain other ingredients, such as co-solvents, stabilizers and optionally other excipients.

[0235] Propellant-free inhalable formulations containing the compounds of the present invention can be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they can be delivered by jet or ultrasonic nebulizers known in the prior art or by soft mist nebulizers, for example It is a registered trademark of Boehringer Ingelheim Pharmaceuticals (Wachtel, H., Kattenbeck, S., Dunne, S. et al. Pulm Ther (2017) 3:19.

[0236] Regardless of the route of administration, the compounds of the present invention can be administered as a single active agent or in combination with other pharmaceutically active ingredients (i.e., as co-therapeutics administered in a fixed-dose combination or in a combination therapy of separately formulated active ingredients).

[0237] The compounds of the present invention can be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used for the treatment of respiratory disorders and known to those skilled in the art, β2-agonists, anticholinergics, corticosteroids, mitogen-activated protein kinase (p38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinases), nuclear factor κ-B kinase subunit β inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modifiers, non-steroidal anti-inflammatory drugs (NSAIDs) and mucolytics).

[0238] The present invention also relates to a kit product comprising a pharmaceutical composition of the compound of the present invention alone or in combination or mixture with one or more pharmaceutically acceptable carriers and / or excipients, and a device, which can be a single-dose or multi-dose dry powder inhaler, metered-dose inhaler or nebulizer.

[0239] The dose of the compounds of the present invention depends on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosing interval, the specific compound used, the efficacy of the compound, the toxicological properties and the pharmacokinetic properties.

[0240] Pharmaceutical compositions comprising the compounds of the present invention suitable for administration by inhalation are in various inhalable forms, such as inhalable powders (DPI), propellant-containing metered aerosols (PMDI) or propellant-free inhalable formulations (e.g., UDV).

[0241] The present invention also relates to a device comprising a pharmaceutical composition containing the compound of the present invention, which can be a single-dose or multi-dose dry powder inhaler, metered-dose inhaler and nebulizer, especially a soft mist nebulizer.

[0242] The following examples illustrate the present invention in more detail.

[0243] During the following description of the exemplary embodiments, the features of the present invention will become apparent. The described exemplary embodiments are given to illustrate the present invention and are not intended to limit the present invention.

[0244] Preparation of Intermediates and Examples

[0245] General Experimental Details

[0246] The chemical name of the compound was generated using Structure To Name Enterprise 10.0 Cambridge software or the latest version.

[0247] When the reaction is carried out at a temperature above the boiling point of the solvent, it is desirable that the reaction be carried out in a closed vessel by conventional heating or by microwave heating.

[0248] Purification by 'chromatography' or 'flash chromatography' means purification using the following: Biotage SP1, or Interchim puriFlash purification system, or Biotage Isolera Four purification system equipped with a Biotage Dalton 2000 mass detector, or equivalent MPLC, using a pre-packed polypropylene column containing a stationary phase (column). If the product is purified using an Si column, it means an Interchim (or equivalent) pre-packed polypropylene column containing unbonded activated silica with spherical particles having an average size of 15 μm; or (or equivalent) pre-packed polypropylene column containing unbonded activated silica with irregular particles having an average size of 50 μm. The fractions containing the desired product are pooled (identified by TLC and / or LCMS analysis) and concentrated in vacuo. Purification by 'RP chromatography' or 'RP flash chromatography' means purification on an MPLC apparatus with a C18-functionalized silica column such as Biotage Sfar C 18 or equivalent equipment. In the case of using an SCX-2 column, 'SCX-2 column' means Bond pre-packed polypropylene column containing an uncapped propylsulfonic acid-functionalized silica strong cation exchange sorbent. When preparative HPLC-MDAP is used for purification (MDAP: mass-directed automated purification), the fractions containing the desired product are pooled, the solvent is removed by evaporation, or lyophilized.

[0249] NMR methods

[0250] NMR spectra were obtained using a Bruker Avance III 600 (5 mm RT inverse probe), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probe), or Bruker DPX 300 spectrometer, applying standard Bruker pulse sequences. Alternatively, NMR spectra were recorded using a Varian MR-400Mhz spectrometer operating at 400 MHz or a Varian Unity Inova 400 spectrometer operating at 400 MHz with a 5 mm inverse detection triple resonance probe. DMSO-d 6 or CDCl3 Used as a solvent. Chemical shifts are provided relative to the internal standard tetramethylsilane or the residual peak of the solvent. All experiments were recorded at 298 K, unless otherwise described. Coupling constants (J values) are given in Hertz (Hz), and the multiplicity is reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, nd = not determined.

[0251] LCMS method

[0252] Method 1

[0253] Acquity UPLC coupled with an SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter), mobile phase A: 0.1% formic acid / water, mobile phase B: 0.1% formic acid / acetonitrile;

[0254] Gradient - Time Flow Rate (mL / min) A％ B％ 0.00 0.9 97 3 1.50 0.9 3 97 1.90 0.9 3 97 2.00 0.05 97 3

[0255] Column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scanning positive and negative electrospray (ES + / ES-), scan range: 100 to 1000 AMU.

[0256] Method 2

[0257] Acquity UPLC coupled with an SQD mass spectrometer; column: Acquity UPLC BEH C 18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter), mobile phase A: 10 mM aqueous ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile;

[0258] Gradient - Time Flow Rate (mL / min) A％ B％ 0.00 0.9 97 3 1.50 0.9 3 97 1.90 0.9 3 97 2.00 0.05 97 3

[0259] Column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: ionization mode: alternating scanning positive and negative electrospray (ES + / ES-), scan range: 100 to 1000 AMU.

[0260] Method 3

[0261] Acquity UPLC coupled with an SQD mass spectrometer; column: Acquity UPLC BEH C18 (50 mm x 2.1 mm i.d., 1.7 μm packing diameter), mobile phase A: 0.1% v / v formic acid / water, mobile phase B: 0.1% v / v formic acid / acetonitrile;

[0262] Gradient - Time Flow Rate (mL / min) A％ B％ 0.00 0.6 97 3 0.50 0.6 97 3 7.00 0.6 3 97 7.50 0.05 97 3

[0263] Column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: Ionization mode: Alternating scan of positive and negative electrospray (ES + / ES-), scan range: 100 to 1500 AMU.

[0264] Method 4

[0265] AGILENT LC 1260Infinity with SFC and Agilent 6540UHD accurate mass Q-TOF LC / MS; Column: Acquity UPLC BEH C 18 (100 mm x 2.1 mm inner diameter, 1.7 μm packing diameter), Mobile phase A: 0.05% ammonia water, Mobile phase B: acetonitrile;

[0266] Gradient - Time Flow Rate (mL / min) A％ B％ 0.00 0.5 97 3 8.00 0.5 0 100 10.00 0.5 97 3 12.00 0.05 97 3

[0267] Column temperature: 40 °C; UV detection: 210 nm to 350 nm; MS conditions: Ionization mode: Alternating scan of positive and negative electrospray (ES + / ES-), scan range: 100 to 1000 AMU.

[0268] Method 5

[0269] Shimadzu LCMS-2020 single quadrupole liquid chromatography mass spectrometer; Column: AcquityUPLC BEH C 18 (100 mm x 2.1 mm inner diameter, 1.7 μm packing diameter), Mobile phase A: 0.1% formic acid / water, Mobile phase B: 0.1% formic acid / acetonitrile;

[0270] Gradient - Time Flow Rate (mL / min) A％ B％ 0.10 0.5 80 20 2.00 0.5 5 95 2.70 0.5 5 95 2.80 0.5 80 20 3.00 0.5 80 20

[0271] Column temperature: 25 °C; UV detection: 215 nm and 254 nm; MS conditions: Ionization mode: Alternating scan of positive and negative electrospray (ES + / ES-), scan range: 100 to 1000 AMU.

[0272] HPLC-MDAP

[0273] Method 1

[0274] Agilent 1290Infinity II purification system; Column: Waters (C18, 100 mm x 19 mm inner diameter, 5 μm), Mobile phase A: 0.1% (v / v) formic acid / water, Mobile phase B: acetonitrile;

[0275] Gradient - Time Flow Rate (mL / min) A％ B％ 0.00 30 90 10 0.80 30 90 10 5.00 30 70 30 6.01 30 0 100 6.95 30 0 100 6.96 30 10 90

[0276] Abbreviations used:

[0277] AIBN = azobisisobutyronitrile; aq. = aqueous / water solution; Boc 2 O = di-tert-butyl dicarbonate; CDI = carbonyldiimidazole; DABAL-Me 3 = bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC = dicyclohexylcarbodiimide; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMCHDA = trans-N,N′-dimethylcyclohexane-1,2-diamine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; 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; sat. = saturated; 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.

[0278] In the following methods, some of the starting materials are identified by the numbers indicated in the "Intermediate" or "Example" step numbers. This is provided only for the assistance of those skilled in the art of chemistry.

[0279] "Similar" or "analogous" procedures mean that the above procedures may involve minor variations such as reaction temperature, reagent / solvent amount, reaction time, work-up conditions, and / or chromatographic purification conditions.

[0280] In the examples, the stereochemistry of the compounds has been assigned based on the following assumption in the cases indicated: the absolute configuration at the resolved stereocenters of the starting materials is maintained throughout any subsequent reaction conditions.

[0281] Unless otherwise stated, if the absolute configuration (R) or (S) is reported in the compound name, the ee% must be considered equal to or greater than 90%.

[0282] Preparation of Intermediate

[0283] Intermediate 1

[0284] Step 1

[0285]

[0286] 4-(Difluoromethoxy)-2-nitrophenol (Intermediate 1-1)

[0287] 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 reaction mixture (RM) was stirred at 0 °C for 3 hours. The RM was poured onto an ice / water mixture and extracted with DCE (10 mL). The organic layer was separated, dried and evaporated in vacuo to give the desired product (630 mg), which was used in the subsequent step without further purification.

[0288] LCMS (Method 1): Rt = 0.40 min

[0289] 1 1H-NMR (500 MHz, DMSO-d 6 ) 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).

[0290] Step 2

[0291]

[0292] 1-(2-Bromoethoxy)-4-(difluoromethoxy)-2-nitrobenzene (Intermediate 1-2)

[0293] A mixture of Intermediate 1-1 (630 mg, 3.07 mmol) and K 2 2CO 3 (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 organics were washed with saturated aqueous NaHCO 3 3, dried and concentrated in vacuo. The crude material was purified by flash chromatography on a Si column, eluting with 0 - 20% DCM / MeOH / NH 4 4OH (90:9:0.5) in DCM to give the title product (466 mg).

[0294] LCMS (Method 1): Rt = 1.15 min, no MS data

[0295] 1 H-NMR (500 MHz, DMSO-d 6 ) 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 = 5.4 Hz, 2H).

[0296] Step 3

[0297]

[0298] 6-(Difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 1-3)

[0299] Dissolve Intermediate 1-2 (466 mg, 0.78 mmol) in ethanol (42 mL) and heat at 80 °C, then add an aqueous solution of NH 4 Cl (166 mg, 3.10 mmol) in water (5 mL) and subsequently add iron (434 mg, 7.80 mmol). Stir the RM at 80 °C for 3 h. After cooling to RT, dilute the RM with water and extract twice with DCM. The combined organic layers are dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified by flash chromatography on a Si column, eluting with 0 - 20% EtOAc / cyclohexane, to afford the title product (88 mg).

[0300] LCMS (Method 1): Rt = 0.99 min, ES + m / z 202.1 [M+H] + .

[0301] Step 4

[0302]

[0303] 7-Bromo-6-(difluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 1)

[0304] To a solution of Intermediate 1-3 (44.0 mg, 0.22 mmol) in EtOAc (1 mL) cooled to 0 °C, add NBS (38.9 mg, 0.22 mmol) and stir the RM at RT for 5 h. Dilute the RM with EtOAc and wash with saturated NaHCO 3Aqueous quenching. The layers were separated and the aqueous layer was additionally extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, separated by a phase separator and concentrated in vacuo to afford the desired product (63 mg), which was used in the subsequent synthetic step without further purification.

[0305] LCMS (Method 1): Rt = 1.14 min, ES + m / z 280.0 / 282.1 [M+H] + 。

[0306] Intermediate 2

[0307] Step 1

[0308]

[0309] 7-Bromo-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Intermediate 2-1)

[0310] 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 in portions over 15 min. The RM was stirred at 0 °C for an additional 30 min and quenched with K 2 CO 3 aqueous solution (10% w / w; 60 mL). The organic layer was separated, washed with saturated aqueous NaCl solution and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-30% EtOAc / cyclohexane to afford the title product (3.5 g).

[0311] LCMS (Method 1): Rt = 0.97 min, ES + m / z 243.9 / 245.9 [M+H] + 。

[0312] Step 2

[0313]

[0314] tert-Butyl 7-bromo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 2)

[0315] THF (15 mL) was added to Intermediate 2-1 (1.4 g, 5.74 mmol), DMAP (840.9 mg, 6.88 mmol) and Boc 2A mixture of O (2.80 g, 13.19 mmol) was then stirred with RM overnight at RT. The RM was partitioned between EtOAc (50 mL) / water (30 mL). The organic layer was washed with 2 M aqueous citric acid solution (2 x 20 mL), saturated aqueous NaCl solution (20 mL) and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 10% EtOAc / cyclohexane to afford the title compound (1.26 g).

[0316] LCMS (Method 1): Rt = 1.27 min

[0317] 1 H-NMR (300 MHz, CDCl 3 ) 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).

[0318] Intermediate 3

[0319] Step 1

[0320]

[0321] tert-Butyl 7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 3-1)

[0322] A solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (500 mg, 3.06 mmol), DMAP (449 mg, 3.68 mmol) and Boc 2 O (1.54 g, 7.05 mmol) in THF (10 mL) was stirred overnight at RT. An additional (1) equivalent of Boc 2 O was added and the stirring was 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 solution (2 x 15 mL), saturated aqueous NaCl solution (20 mL) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 10% EtOAc / cyclohexane to afford the title product (228 mg).

[0323] LCMS (Method 1): Rt = 1.35 min

[0324] 1 H-NMR (300 MHz, DMSO-d 6)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).

[0325] Step 2

[0326]

[0327] tert-Butyl 6-bromo-7-methoxy-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 3)

[0328] Cool a solution of Intermediate 3-1 (228 mg, 0.86 mmol) in EtOAc (10 mL) to 0 °C. Add 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (124 mg, 43.3 mmol) portionwise over 15 minutes. Stir the RM at 0 °C for 20 minutes, then quench with 10% (w / w) K 2 CO 3 aqueous solution (20 mL). Separate the organic layer, wash with saturated NaCl aqueous solution (20 mL) and concentrate in vacuo. Purify the residue by flash chromatography on a Si column, eluting with 0 - 15% EtOAc / cyclohexane to afford the title product (240 mg).

[0329] LCMS (Method 1): Rt = 1.46 minutes, ES + m / z 285.9 / 287.9 [M+H] + .

[0330] Intermediate 4

[0331]

[0332] 7-Bromo-8-methoxy-1,3,4,5-tetrahydro-2H-benzo[b]azepin -2-one (Intermediate 4)

[0333] Add 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (123 mg, 0.43 mmol) portionwise over 10 minutes at 0 °C to a solution of 8-methoxy-1,3,4,5-tetrahydro-1-benzazepin -2-one (165 mg, 0.86 mmol) in EtOAc (4 mL). Stir the RM at RT overnight. Quench the RM with saturated NaHCO 3Quenched with aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, separated by a phase separator and concentrated in vacuo to afford the title product (230 mg), which was used in the subsequent synthetic step without further purification.

[0334] LCMS (Method 1): Rt = 0.93, ES + m / z 270.0 / 272.0 [M+H] + 。

[0335] Intermediate 5

[0336] Step 1

[0337]

[0338] tert-Butyl 7-methoxy-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 5-1)

[0339] 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 Boc 2 O (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 solution, separated by a phase separator and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-10% EtOAc / cyclohexane to afford the title product (138 mg).

[0340] LCMS (Method 1): Rt = 1.11 min

[0341] 1 H-NMR (500 MHz, DMSO-d 6 ) 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).

[0342] Step 2

[0343]

[0344] tert-Butyl 6-bromo-7-methoxy-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 5)

[0345] A solution of intermediate 5-1 (100.0 mg, 0.36 mmol) in EtOAc (2.0 mL) was cooled to 0 °C, and then NBS (64.2 mg, 0.36 mmol) was added. The RM was warmed to RT and heated at 65 °C for 30 h. After cooling to RT, the RM was diluted with saturated NaHCO 3 aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with saturated NaCl aqueous solution and passed through a phase separator. The solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-40% EtOAc / cyclohexane, to afford the title product (153 mg).

[0346] LCMS (method 1): Rt = 1.30 min.

[0347] 1 1H-NMR (500 MHz, DMSO-d 6 ) 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).

[0348] Intermediate 6

[0349] Step 1

[0350]

[0351] tert-Butyl 6-methoxyindoline-1-carboxylate (Intermediate 6-1)

[0352] A solution of 6-methoxyindoline (1.0 g, 6.70 mmol), Boc 2 O (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 solution (2 x 50 mL), saturated NaHCO 3 aqueous solution (50 mL) and saturated NaCl aqueous solution (50 mL). The organic phase was evaporated to dryness in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-15% EtOAc / cyclohexane, to afford the title product (1.16 g).

[0353] LCMS (method 1): Rt = 1.25 min, ES + m / z 250.0 [M+H] + .

[0354] Step 2

[0355]

[0356] tert-Butyl 5-bromo-6-methoxyindoline-1-carboxylate (Intermediate 6)

[0357] 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (0.66 g, 2.3 mmol) was added portionwise to a solution of Intermediate 6-1 (1.16 g, 4.65 mmol) in EtOAc (70 mL) at 0 °C over 15 minutes. The RM was stirred at RT for 2 hours and then quenched with 10% w / w K 2 CO 3 aqueous solution (75 mL). The organic layer was separated, washed with saturated NaCl aqueous solution (35 mL) and concentrated in vacuo to afford the desired product (1.52 g), which was used in the subsequent synthetic step without further purification.

[0358] LCMS (Method 1): Rt = 1.40 minutes, ES + m / z 228.0 / 230.0 [M+H] + .

[0359] Intermediate 7

[0360] Step 1

[0361]

[0362] tert-Butyl 6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 7-1)

[0363] The title compound was prepared in a similar manner to Intermediate 3 - Step 1, starting from 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine.

[0364] LCMS (Method 5): Rt = 2.5 minutes

[0365] 1 H-NMR (300 MHz, DMSO-d 6 ) 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).

[0366] Step 2

[0367]

[0368] tert-Butyl 7-iodo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 7)

[0369] 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 mixture was stirred at 40 °C overnight. The reaction mixture was quenched in cold water and extracted with EtOAc. The combined organic layers were evaporated to dryness and the residue was purified by chromatography on silica gel, eluting with a gradient of DCM-hexane from 1:1 to 3:2, to afford the title compound (7.38 g).

[0370] LCMS (Method 1): Rt = 2.8 min

[0371] 1 1H-NMR (300 MHz, DMSO-d 6 ) 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).

[0372] Intermediate 8

[0373] Step 1

[0374]

[0375] 5-Methoxybenzo[d]oxazol-2(3H)-one (Intermediate 8-1)

[0376] CDI (2.40 g, 14.8 mmol) was added portionwise over 1 h to a refluxing solution of 2-amino-4-methoxyphenol (1.00 g, 14.4 mmol) in THF (20 mL), and the mixture was refluxed for an additional 1 h. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water (3 x 30 mL) and saturated aqueous NaCl (2 x 30 mL). The organic layer was dried over MgSO 4 and the solvent was removed in vacuo. The crude material was purified by flash chromatography on a Si column, eluting with 0 - 80% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM, to afford the title product (700 mg).

[0377] LCMS (Method 1): Rt = 0.70 min, ES + m / z 166.1 [M+H] + .

[0378] Step 2

[0379]

[0380] 6-Iodo-5-methoxybenzo[d]oxazol-2(3H)-one (Intermediate 8-2)

[0381] 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 x 20 mL). The combined organic layers were washed with water (3 x 20 mL) and saturated aqueous NaCl solution (2 x 10 mL). The organic phase was evaporated in vacuo to afford the title product (626 mg), which was used in the subsequent synthetic step without further purification.

[0382] LCMS (Method 1): Rt = 0.93 min, ES + m / z 291.9 [M+H] + 。

[0383] Step 3

[0384]

[0385] 6-Iodo-5-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Intermediate 8)

[0386] 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 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 to reach RT. The RM was quenched with saturated NaHCO 3 aqueous solution (15 mM) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (20 mL), saturated aqueous NaCl solution (20 mL), dried over MgSO 4 and concentrated in vacuo to afford the desired product (300 mg), which was used in the subsequent synthetic step without further purification.

[0387] LCMS (Method 1): Rt = 1.49 min.

[0388] 1 H-NMR (300 MHz, DMSO-d 6)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).

[0389] Intermediate 9

[0390] Step 1

[0391]

[0392] 1-Bromo-4,5-bis(bromomethyl)-2-methoxybenzene (Intermediate 9-1)

[0393] Dissolve 1-bromo-2-methoxy-4,5-dimethyl-benzene (200 mg, 0.93 mmol) in α,α,α-trifluorotoluene (10.0 mL). Add NBS (331 mg, 1.86 mmol) and AIBN (30.5 mg, 0.19 mmol) and stir the RM at 90 °C for 3 h. After cooling to RT, dilute the RM with EtOAc, wash with water and saturated NaCl aqueous solution, dry over a phase separator and remove the solvent in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 30% EtOAc / cyclohexane to afford the title product (246 mg).

[0394] LCMS (Method 1): Rt = 1.34 min.

[0395] 1 H-NMR (300 MHz, DMSO-d 6 )δ: 7.74 (s, 1H), 7.26 (s, 1H), 4.80 (s, 2H), 4.79 (s, 2H), 3.87 (s, 3H).

[0396] Step 2

[0397]

[0398] 5-Bromo-6-methoxy-2-(methylsulfonyl)isoindoline (Intermediate 9)

[0399] 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 mixture was stirred for 1 h. A solution of intermediate 9-1 (240 mg, 0.64 mmol) / DMF (10.0 mL) was added dropwise. The resulting solution was stirred at 50 °C for 3 h and overnight at RT. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous NaCl, separated by a phase separator and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 30% EtOAc / cyclohexane to afford the title product (160 mg).

[0400] LCMS (Method 1): Rt = 1.34 min.

[0401] 1 1H-NMR (300 MHz, DMSO-d 6 ) 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).

[0402] Intermediate 10

[0403] Step 1

[0404]

[0405] 5-Bromo-2-(tert-butylthio)-4-methoxybenzaldehyde (Intermediate 10-1)

[0406] 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 K 2 2CO 3 (949 mg, 6.87 mmol) in DMF (15 mL) was stirred at 80 °C for 3 h. The reaction mixture was cooled to RT and poured into water (30 mL). The precipitate formed was collected by filtration, washed with water (2 x 10 mL) and dried at 45 °C for 3 h to afford the title product (1 g).

[0407] LCMS (Method 1): Rt = 1.40 min.

[0408] 1 1H-NMR (300 MHz, CDCl 3 ) δ: 10.6 (s, 1H), 8.20 (s, 1H), 7.08 (s, 1H), 3.98 (s, 3H), 1.32 (s, 9H).

[0409] Step 2

[0410]

[0411] 5-Bromo-2-(tert-butylthio)-4-methoxybenzaldoxime (Intermediate 10-2)

[0412] A mixture 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 the residual solid and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc (25 mL), washed with water (15 mL), saturated aqueous NaCl solution (15 mL), dried over MgSO 4 and the solvent was removed in vacuo to afford the desired product (997 mg), which was used in the subsequent synthetic step without further purification.

[0413] LCMS (Method 1): Rt = 1.26 min.

[0414] 1 H-NMR (300 MHz, DMSO-d 6 ) 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).

[0415] Step 3

[0416]

[0417] 5-Bromo-6-methoxybenzo[d]isothiazole (Intermediate 10)

[0418] 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 in a μW reactor at 110 °C for 30 min. A second equivalent of TsOH was added and the RM was stirred for an additional 1 h at 120 °C in the μW reactor for two cycles. After cooling to RT, the precipitate formed was collected by filtration and dried at 45 °C to afford the desired product (280 mg).

[0419] LCMS (Method 1): Rt = 1.10 min.

[0420] 1 H-NMR (500 MHz, DMSO-d 6 ) δ: 8.92 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 3.96 (s, 3H).

[0421] Intermediate 11

[0422] Step 1

[0423]

[0424] (4 - Bromo - 2 - formyl - 5 - methoxyphenyl)methyl carbamate (Intermediate 11 - 1)

[0425] 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 in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 25% DCM / MeOH (9:1) in DCM, to afford the title product (190 mg).

[0426] LCMS (Method 1): Rt = 1.16 min, ES + m / z 288.0 / 290.0 [M + H] +

[0427] Step 2

[0428]

[0429] 6 - Bromo - 7 - methoxy - 3 - methyl - 3,4 - dihydroquinazolin - 2(1H) - one (Intermediate 11)

[0430] A solution of Intermediate 11 - 1 (185 mg, 0.64 mmol) and methylamine in methanol solution (9.8 M, 97 μL, 0.95 mmol) in AcOH (2 mL) was stirred in a μW reactor at 130 °C for 15 min. 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 in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM, to afford the title product (154 mg).

[0431] LCMS (Method 1): Rt = 0.88 min, ES + m / z 271.1 / 273 [M + H] +

[0432] Intermediate 12

[0433]

[0434] 3-(Tributylstannyl)imidazo[1,2-b]pyridazine (Intermediate 12)

[0435] 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 THF solution, 4.7 mL, 6.1 mmol) was added dropwise over 5 minutes. The RM was stirred at 0 °C for 15 minutes, then tributyltin chloride (685 μL, 2.5 mmol) was added dropwise, and the RM was stirred at RT for an additional 30 minutes. The RM was cooled in an ice bath and quenched with water (5 mL), saturated aqueous NH4Cl solution (10 mL) was added, and the mixture was extracted with EtOAc (15 mL). The organic layer was washed with saturated aqueous NaCl solution (10 mL), dried over MgSO 4 and evaporated in vacuo. The residue was purified by chromatography on neutral alumina (Al 2 O 3 ), eluting with a mixture of cyclohexane and EtOAc, to give the title product (285 mg).

[0436] LCMS (Method 2): Rt = 1.82 minutes, ES + m / z (most abundant isotope) 410.0 [M+H] +

[0437] Intermediate 13

[0438]

[0439] 3-((2-Hydroxyethyl)thio)dihydrofuran-2(3H)-one (Intermediate 13)

[0440] A solution of 3-bromotetrahydrofuran-2-one (822 μL, 9.09 mmol), 2-mercaptoethanol (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 in vacuo, and the residue was purified by flash chromatography on a Si column, eluting with 0 - 50% EtOAc / DCM, to give the title product (1.43 g).

[0441] 1 1H-NMR (300 MHz, CDCl 3)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).

[0442] Intermediate 14

[0443]

[0444] 3 - ((2 - Hydroxyethyl)(methyl)amino)dihydrofuran - 2(3H) - one (Intermediate 14)

[0445] A solution of 3 - bromotetrahydrofuran - 2 - one (782 μL, 8.65 mmol) and 2 - (methylamino)ethanol (1.39 mL, 17.3 mmol) in THF (4 mL) was stirred overnight at RT. The solvent was removed in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH (9:1) in DCM to afford the title product (295 mg).

[0446] 1 H - NMR (300 MHz, CDCl 3 )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).

[0447] Intermediate 15

[0448] Step 1

[0449]

[0450] Ethyl 1 - (2 - ((tert - butoxycarbonyl)amino)ethyl)piperidine - 4 - carboxylate (Intermediate 15 - 1)

[0451] At 65 °C, tert - butyl N - (2 - bromoethyl)carbamate (3 g, 13.0 mmol), ethyl piperidine - 4 - carboxylate (2.1 mL, 13.0 mmol) and K 2 CO 3A suspension of [[ID=]], 3 in DMF (30.0 mL) was stirred for 24 h. After cooling to RT, the RM was diluted with water (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organics were washed with saturated NaHCO

[0452] aqueous solution (80 mL) and saturated NaCl aqueous solution (50 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM:MeOH (93:7) in DCM to afford the title product (3.24 g). + LCMS (Method 2): Rt = 1.05 min, ES + .

[0453] Step 2

[0454]

[0455] Ethyl 1-(2-aminoethyl)piperidine-4-carboxylate (Intermediate 15)

[0456] 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 overnight at RT. The volatiles were removed in vacuo and the crude product was passed through an SCX column, washed with EtOH (500 mL) and eluted with 15% aq. NH 3 / EtOH (100 mL) to afford the title product (1.16 g).

[0457] 1 H-NMR (300 MHz, CDCl 3 ) 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).

[0458] Intermediate 16

[0459]

[0460] 4-(3-Hydroxypropyl)morpholin-2-one (Intermediate 16)

[0461] A mixture of 3-(2-hydroxyethylamino)propan-1-ol (393 mg, 3.30 mmol), methyl 2-bromoacetate (344 μL, 3.63 mmol) and K 2 CO 3 (502 mg, 3.63 mmol) in anhydrous acetonitrile (14 mL) was stirred overnight at RT. The RM was filtered and concentrated in vacuo. 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 in vacuo, providing the desired product (120 mg), which was used in the subsequent synthetic step without further purification.

[0462] 1 H-NMR (300 MHz, CDCl 3 ) 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 (quintet, J = 5.5 Hz, 2H).

[0463] Intermediate 17

[0464]

[0465] 6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 17)

[0466] Dihydropyran (9.79 mL, 107 mmol) and methanesulfonic acid (464 μL, 7.16 mmol) were added to 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (10 g, 35.8 mmol) / DCM (100 mL) and THF (50 mL). The RM was stirred at 40 °C for 4 h and then overnight at RT. The RM was evaporated to dryness and the residue was purified by flash chromatography on a Si column, eluting with 0 - 40% EtOAc / cyclohexane, providing the title product (7.5 g).

[0467] LCMS (Method 2): Rt = 1.22 min, ES + m / z 364.0 / 366.0 [M+H] + .

[0468] Intermediate 18a

[0469] Step 1

[0470]

[0471] 6-Chloro-N-(2-morpholinoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18a-1)

[0472] At 100 °C under nitrogen, a degassed mixture of Intermediate 17 (900 mg, 2.48 mmol), 2-morpholinoethylamine (1.30 mL, 12.7 mmol), K 2 CO 3 (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 for 2 h. After cooling to RT, the RM was diluted with water (30 mL) and extracted with EtOAc (4 x 15 mL). The combined organics were washed with 10% w / w aqueous ammonia (2 x 15 mL), water (2 x 20 mL) and saturated aqueous NaCl (40 mL). The organic phase was evaporated in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 80% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM to afford the title product (750 mg).

[0473] LCMS (Method 2): Rt = 0.94 min, ES + m / z 366.3 / 368.3 [M+H] + .

[0474] Step 2

[0475]

[0476] 6-Chloro-N-(2-morpholinoethyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18a)

[0477] 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 x 20 mL) and the combined organic layers were evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM to afford the title product (250 mg).

[0478] LCMS (Method 1): Rt = 0.42 min, ES +m / z 282.0 / 283.9 [M+H] +

[0479] Intermediate 18b

[0480] Step 1

[0481]

[0482] 6-Chloro-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18b-1)

[0483] The title product was prepared in a similar manner 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.

[0484] LCMS (Method 2): Rt = 0.94 min, ES + m / z 267.1 / 269.1 [M+H] + .

[0485] Step 2

[0486]

[0487] 6-Chloro-N-methyl-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 18b)

[0488] The title compound was prepared similarly to Intermediate 18a (Step 2), starting from Intermediate 18b-1.

[0489] LCMS (Method 2): Rt = 0.51 min, ES + m / z 183.1 / 185.1 [M+H] +

[0490] Intermediate 19

[0491]

[0492] 6-(6-Chloro-3-((2-morpholinoethyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-methoxy-3-((2-(trimethylsilyl)ethoxy)methyl)benz[d]oxazol-2(3H)-one (Intermediate 19)

[0493] Under nitrogen at 100 °C, degassed Intermediate 18a (102 mg, 0.36 mmol), Intermediate 8 (85.0 mg, 0.18 mmol), K 2 CO3 (151 mg, 1.09 mmol), proline (6.27 mg, 0.05 mmol) and CuI (6.9 mg, 36 μmol) in DMF (2 mL) were stirred for 8 h. After cooling to RT, the RM was diluted with water (10 mL) and extracted with EtOAc (5 x 5 mL). The combined organic layers were washed with 10% w / w aqueous ammonia (2 x 10 mL), water (2 x 20 mL) and saturated aqueous NaCl solution (30 mL). The organic phase was evaporated in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 80% DCM / MeOH / NH 4 OH (90:5:0.5) to afford the title product (15 mg).

[0494] LCMS (Method 1): Rt = 1.07 min, ES + m / z 575.4 / 577.4 [M+H] + 。

[0495] Intermediate 20

[0496]

[0497] 6-Chloro-1-(6-methoxybenzo[d]isothiazol-5-yl)-N-(2-morpholinoethyl)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 20)

[0498] The degassed 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 K 2 CO 3 (118 mg, 0.85 mmol) in DMSO (2.5 mL) were heated overnight at 100 °C under nitrogen. After cooling to RT, the RM was diluted with EtOAc (15 mL) and washed with water (2 x 10 mL) and saturated aqueous NaCl solution (10 mL). The RM was evaporated in vacuo and the residue was purified by flash chromatography on a Si column eluting with 0 - 80% DCM / MeOH / NH 4 OH (90:5:0.5) to afford the title product (105 mg).

[0499] LCMS (Method 1): Rt = 0.99 min, ES + m / z 445.2 / 447.2 [M+H] +

[0500] Intermediate 21

[0501] Step 1

[0502]

[0503] Methyl 1-(5-bromo-2-methoxy-4-nitrophenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-1)

[0504] 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. Methyl iodide (3.78 mL, 60.7 mmol) was added and the RM was stirred overnight at RT. The RM was quenched in water (200 mL), and the precipitate formed was collected by filtration and dried. The crude material was triturated in EtOAc and washed with EtOAc to afford the title product (5.83 g), which was used in the subsequent synthetic step without further purification.

[0505] LCMS (Method 1): Rt = 1.08 min, ES + m / z 426.9 / 428.9 / 430.9 [M+H] + .

[0506] Step 2

[0507]

[0508] Methyl 6-chloro-1-(5-((2-hydroxyethyl)thio)-2-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-2)

[0509] The degassed 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 2 (dba) 3 (330 mg, 0.57 mmol) in 1,4-dioxane (100 mL) were stirred under argon at 100 °C for 3 h. After cooling to RT, the reaction was quenched with water. The precipitate formed was collected by filtration, washed with a small amount of EtOAc and dried to afford the title compound (5.3 g), which was used in the subsequent synthetic step without further purification.

[0510] LCMS (Method 1): Rt = 1.08 minutes, ES + m / z 439.0 / 441.0 [M+H] + 。

[0511] Step 3

[0512]

[0513] Methyl 1-(4-amino-5-((2-hydroxyethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-3)

[0514] A solution of Intermediate 21-2 (5.3 g, 12 mmol) in MeOH (200 mL) was stirred at 80 °C, and then an aqueous solution of NH 4 Cl (6.5 g, 121 mmol) in water (20 mL) and iron powder (6.7 g, 121 mmol) were subsequently added. The RM was stirred at 80 °C for 4.5 hours, then filtered while hot, and the filtrate was concentrated in vacuo. The crude material was diluted with saturated NaHCO 3 aqueous solution, the resulting suspension was sonicated, and the solid was collected by filtration. The solid material was washed with water several times and dried to give the title product (3.13 g).

[0515] LCMS (Method 1): Rt = 0.92 minutes, ES + m / z 409.1 / 411.1 [M+H] + 。

[0516] Step 4

[0517]

[0518] Methyl 1-(4-amino-5-((2-chloroethyl)thio)-2-methoxyphenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Intermediate 21-4)

[0519] 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 hours, then the volatiles were removed in vacuo and the residue was treated with saturated NaHCO 3 aqueous solution. The resulting slurry was sonicated and the solid was collected by filtration, washed with water, and dried. The crude obtained was purified by flash chromatography on a Si column, eluting with 0-10% EtOAc / DCM to give the title product (2.7 g).

[0520] LCMS (Method 1): Rt = 1.24 minutes, ES +m / z 427.0 / 429.0 / 431.0[M+H] + 。

[0521] Step 5

[0522]

[0523] 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)

[0524] At 90 °C, a mixture of Intermediate 21-4 (2.70 g, 6.32 mmol), K 2 CO 3 (2.62 g, 19 mmol) and NaI (189 mg, 1.26 mmol) in DMF (80 mL) was stirred 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 column, eluting with 0 - 100% DCM / acetonitrile (9:1) in DCM, to afford the title product (730 mg).

[0525] LCMS (Method 1): Rt = 1.13 min, ES + m / z 391.1 / 393.1[M+H] + 。

[0526] Step 6

[0527]

[0528] 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)

[0529] Intermediate 21-5 (730 mg, 1.87 mmol) was suspended in THF (15 mL), and LiOH solution (1.0 M in water, 9 mL, 9 mmol) was added. The RM was stirred at 40 °C for 2.5 h. The organic solvent was removed in vacuo, and the residue was diluted with water. The pH was adjusted to 2.5 with 1 M aqueous HCl. The formed precipitate was filtered, washed several times with water and dried, to afford the title compound (698 mg).

[0530] LCMS (Method 1): Rt = 0.95 min, ES + m / z 377.1 / 379.0[M+H] + 。

[0531] Intermediate 22

[0532] Step 1

[0533]

[0534] 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)

[0535] The intermediate was prepared similarly to Intermediate 21-2, starting from Intermediate 21-1 and methyl 2-thioalkylacetate.

[0536] LCMS (Method 1): Rt = 1.18 min, ES + m / z 467.1 / 469.1 [M+H] + .

[0537] Step 2

[0538]

[0539] 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)

[0540] A solution of Intermediate 22-1 (265 mg, 0.51 mmol) in ethanol (6.0 mL) was stirred at 80 °C, then a solution of NH 4 Cl (109 mg, 2.0 mmol) in water (3.0 mL) and iron (340 mg, 6.1 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. After cooling to RT, the reaction mixture was filtered and the filter was further washed with EtOAc. The combined organic layers were evaporated in vacuo to afford the desired product (1.03 g), which was used in the subsequent synthetic step without further purification.

[0541] LCMS (Method 1): Rt = 1.09 min, ES + m / z 437.2 / 439.1 [M+H] + .

[0542] Step 3

[0543]

[0544] 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)

[0545] To a suspension of Intermediate 22-2 (1.0 g, 1.7 mmol) in DCM (12.0 mL) was added TFA (1.3 mL, 17.0 mmol). The RM was stirred at RT for 24 h. The RM was evaporated in vacuo and the residue was purified by flash chromatography on a Si column eluting with 0 - 60% DCM / MeOH (20:1) in DCM to afford the title product (341.5 mg).

[0546] LCMS (Method 1): Rt = 0.99 min, ES + m / z 405.2 / 407.1 [M+H] + 。

[0547] Step 4

[0548]

[0549] 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)

[0550] To a suspension of Intermediate 22-3 (340 mg, 0.84 mmol) in THF (10 mL) was added aqueous LiOH (1.0 M, 7.5 mL, 7.5 mmol). The RM was stirred at RT for 2 h. The THF was removed in vacuo. The residue was diluted with water and acidified to pH 2.5 with 1 M aqueous HCl. The precipitate formed was collected by filtration, washed with water and dried to afford the title product (320 mg).

[0551] LCMS (Method 2): Rt = 0.48 min, ES + m / z 391.0 / 393.0 [M+H] + 。

[0552] Intermediate 23a

[0553] Step 1

[0554]

[0555] 1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (Intermediate 23a-1)

[0556] At 65 °C, 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 K 2 CO 3A mixture of [[ID=]] (2.23 g, 16.1 mmol) in DMF (30 mL) was stirred for 2 h. The reaction was repeated on a 17.4 mmol scale and combined with the previous reaction after cooling to RT. The combined RM was poured into water (400 mL), and the precipitate was collected by filtration. The collected solid was washed thoroughly with water and azeotroped with toluene to afford the title product (11.1 g).

[0557] LCMS (Method 2): Rt = 1.36 min, ES + m / z 508.9 / 510.9 / 512.8 [M+H] + 。

[0558] Step 2

[0559]

[0560] 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)

[0561] At 75 °C, a degassed mixture of Intermediate 23a-1 (800 mg, 1.57 mmol), 2-(4-methylpiperazin-1-yl)ethylamine (366 μL, 2.83 mmol), proline (90.4 mg, 0.79 mmol), K 2 CO 3 (1.3 g, 9.42 mmol) and CuI (89.7 mg, 0.47 mmol) in anhydrous DMSO (6 mL) was stirred for 5 h. A second equivalent of CuI and proline were added. After cooling to RT, the solvent was removed in vacuo. 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 solution (20 mL) and concentrated in vacuo. The residue was purified by flash chromatography on a Si column twice, eluting with DCM / MeOH / NH 4 OH (90:15:1.5) to afford the title product (243 mg).

[0562] LCMS (Method 2): Rt = 1.08 min, ES + m / z 524.1 / 526.1 / 528.1 [M+H] + 。

[0563] Step 3

[0564]

[0565] 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)

[0566] A solution of Intermediate 23a-2 (240 mg, 0.46 mmol), DIPEA (199 μL, 1.1 mmol) and methyl 2-thioacetate (102 μL, 1.1 mmol) in anhydrous acetonitrile (14 mL) was stirred overnight at 120 °C. The solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-100% DCM / MeOH / NH 4 OH (90:15:1.5) in DCM to afford the title product (87 mg).

[0567] LCMS (Method 2): Rt = 0.97 min, ES + m / z 550.2 / 552.2 [M+H] + .

[0568] Step 4

[0569]

[0570] 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)

[0571] A solution of Intermediate 23a-3 (85 mg, 0.15 mmol) in EtOH (20 mL) was stirred at 80 °C, then a solution of NH 4 Cl (70 mg, 1.3 mmol) in water (5 mL) and iron (0.16 g, 2.9 mmol) were added. The reaction mixture (RM) was stirred at 80 °C for 4.5 h. A second equivalent of iron and NH 4 Cl were added and the RM was stirred at 80 °C for an additional 1 h. The RM was quenched with 2N HCl (1 mL) aqueous solution and stirred at 80 °C for 2 h. After cooling to RT, the RM was filtered and the cake was washed with EtOH. The filtrate was evaporated in vacuo. The residue was treated with saturated NaHCO 3 aqueous solution (10 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL), dried over Na 2 SO 4 and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-100% DCM / MeOH / NH 4Elution with OH(90:15:1.5) gave the title product (40 mg).

[0572] LCMS (Method 2): Rt = 0.80 min, ES + m / z 488.2 / 490.2 [M+H] + .

[0573] Intermediate 23b

[0574] Step 1

[0575]

[0576] N 1 -(1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N 2 ,N 2 -dimethyl ethane-1,2-diamine (Intermediate 23b-1)

[0577] The title intermediate was prepared in a similar manner to Intermediate 23a-2, starting from Intermediate 23a-1 and N',N'-dimethyl ethane-1,2-diamine.

[0578] LCMS (Method 2): Rt = 1.18 min, ES + m / z 469.1 / 471.1 / 473.1 [M+H] +

[0579] Step 2

[0580]

[0581] 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)

[0582] The title intermediate was prepared in a similar manner to Intermediate 23a-3, starting from Intermediate 23b-1 and methyl 2-thioacetate, giving the title product (122 mg).

[0583] LCMS (Method 2): Rt = 1.12 min, ES + m / z 495.1 / 497.1 [M+H] +

[0584] Step 3

[0585]

[0586] 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)

[0587] The title compound was prepared in a similar manner to Intermediate 23a-4, starting from Intermediate 23b-2.

[0588] LCMS (Method 2): Rt = 1.04 min, ES + m / z 433.2 / 434.2 [M+H] +

[0589] Intermediate 24

[0590]

[0591] 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)

[0592] Method 1

[0593] Under nitrogen at 110 °C, a degassed mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (400 mg, 2.02 mmol), Intermediate 2 (733 mg, 2.13 mmol), Cs 2 CO 3 (2.31 g, 7.09 mmol) and copper(II) thiophene-2-carboxylate (278 mg, 1.46 mmol) in anhydrous DMSO (7 mL) was stirred overnight. After cooling to RT, the RM was filtered. The filtrate was diluted with MeCN (50 mL) to filter and collect the formed precipitate and triturated with MeOH. The crude material was purified by flash chromatography on a Si column, eluting with 0-100% MeOH / EtOAc, to afford the title product (150 mg).

[0594] Method 2

[0595] Under argon at 110 °C, a degassed mixture of 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), Cs 2 CO 3A mixture of [[ID=]],

[0596] LCMS (Method 1): Rt = 1.22 min, ES + m / z 461.2 / 463.2 [M+H] + 。

[0597] Intermediate 25

[0598]

[0599] 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)

[0600] The title intermediate was prepared in a manner similar to that of Intermediate 24, Method 1, starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and Intermediate 2-1.

[0601] LCMS (Method 1): Rt = 0.86 min, ES + m / z 360.9 / 362.8 [M+H] + 。

[0602] Intermediate 26

[0603]

[0604] 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)

[0605] The title intermediate was prepared in a manner similar to that of Intermediate 24, Method 1, 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.

[0606] LCMS (Method 1): Rt = 0.77 min, ES + m / z 373.1 / 375.1 [M+H] + 。

[0607] Intermediate 27a

[0608]

[0609] 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)

[0610] At 100 °C under nitrogen, 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-carbonyloxy copper (290 mg, 1.52 mmol) and Cs 2 CO 3 (1.48 g, 4.56 mmol) in DMSO (7 mL) was stirred for 72 h. After cooling to RT, RM was added dropwise to water with stirring. 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 column, eluting with 0 - 50% DCM:MeOH:HCO 2 H (90:10:0.3) to give the title product (330 mg).

[0611] LCMS (Method 1): Rt = 1.24 min, ES + m / z 458.9 / 460.9 [M+H] + .

[0612] Intermediate 27b

[0613]

[0614] 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)

[0615] At 100 °C under nitrogen, 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-carbonyloxy copper (97 mg, 0.5 mmol) and Cs 2 CO 3The mixture of [[ID=]] (0.49 g, 1.52 mmol) in DMSO (2.3 mL) was stirred for 72 h. After cooling to RT, methyl iodide (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 Na 2 SO 4 , filtered, and evaporated to dryness. The residue was purified by flash chromatography on a Si column, eluting with 0 - 10% cyclohexane / EtOAc (1:1) in cyclohexane, to afford the title product (118 mg).

[0616] LCMS (Method 1): Rt = 1.41 min, ES + m / z 473.0 / 475.0 [M + H] + .

[0617] Intermediate 28

[0618]

[0619] 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)

[0620] Under argon at 110 °C, a mixture of degassed Intermediate 2 (408 mg, 1.19 mmol), 6-chloro-1H-pyrazolo[4,3-c]pyridin-3-amine (200 mg, 1.19 mmol), Cs 2 CO 3 (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. After cooling to RT, the RM was quenched with saturated aqueous NaHCO 3 (50 mL) and extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na 2 SO 4 , and the solvent was removed in vacuo. The crude residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM, to afford the title product (282 mg).

[0621] LCMS (Method 1): Rt = 1.15 min, ES + m / z 431.9 / 433.9 [M + H] + .

[0622] Intermediate 29

[0623]

[0624] 6-(3-Amino-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 29)

[0625] Under argon at 110 °C, 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), K 2 CO 3 (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. After cooling to RT, the RM was quenched with saturated NaHCO 3 aqueous solution (50 mL) and extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with saturated NaCl aqueous solution, dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:5:1) in DCM to afford the title product (68.6 mg).

[0626] LCMS (Method 2): Rt = 0.68 min, ES + m / z 344.1 / 345.9 [M+H] + .

[0627] Intermediate 30

[0628]

[0629] 6-(6-Chloro-3-(methylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 30)

[0630] The title compound was prepared similarly to Intermediate 29, starting from 6-bromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one and Intermediate 18b.

[0631] LCMS (Method 2): Rt = 0.79 min, ES +m / z 358.1 / 360.1 [M+H] + 。

[0632] Intermediate 31a

[0633] Step 1

[0634]

[0635] 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)

[0636] To a solution of Intermediate 28 (130 mg, 0.30 mmol) in THF (7 mL) at 0 °C under nitrogen was added LiHMDS (1.30 M in THF, 463 μL, 0.60 mmol). The RM was stirred for 15 minutes. A solution of Boc 2 O (131 mg, 0.60 mmol) in THF (1 mL) was added dropwise and the RM was stirred at RT for 3 hours. The RM was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-50% EtOAc / cyclohexane. The separated product was dissolved in methanol (1 mL), K 2 CO 3 (76.5 mg, 0.55 mmol) was added and the mixture was stirred at RT overnight. The RM was diluted with saturated aqueous NaHCO 3 and extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl, dried over Na 2 SO 4 and the solvent was removed in vacuo, providing the title product (107 mg), which was used in the subsequent synthetic step without further purification.

[0637] LCMS (Method 2): Rt = 1.49 minutes, ES + m / z 532.3 / 534.3 [M+H] + 。

[0638] Step 2

[0639]

[0640] 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)

[0641] A solution of Intermediate 31a-1 (85.0 mg, 0.16 mmol) in anhydrous DMF (1.0 mL) was cooled to 0 °C under argon. NaI (23.9 mg, 0.16 mmol) and NaH (60% mineral oil dispersion, 19.2 mg, 0.48 mmol) were added and the RM was stirred at 0 °C for 30 minutes. 2-Bromo-N,N-dimethyl-ethylamine hydrobromide (55.8 mg, 0.24 mmol) was added and the RM was stirred at RT for 60 hours. The RM was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organics were passed through a phase separator column and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:4:1) to afford the title product.

[0642] LCMS (Method 2): Rt = 1.54 minutes, ES + m / z 603.3 / 605.3 [M+H] + .

[0643] Intermediate 31b

[0644]

[0645] 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)

[0646] The title compound was prepared similarly to Intermediate 31a, starting from Intermediate 31a-1 and methyl iodide.

[0647] LCMS (Method 2): Rt = 1.54 minutes, ES + m / z 546.2 / 548.2 [M+H] + .

[0648] Intermediate 32a

[0649]

[0650] 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)

[0651] 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 K 2 CO 3 (330 mg, 2.4 mmol) in DMSO (5 mL) was added. 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 NH 4 OH aqueous solution (3 x 15 mL) and saturated NaCl aqueous solution (15 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-15% EtOAc / DCM, to afford the title product (312 mg).

[0652] LCMS (Method 2): Rt = 1.32 min, ES + m / z 431.1 / 433.1 [M+H] + .

[0653] Intermediates 32b to 32i

[0654] The following intermediates were prepared in a similar manner to Intermediate 32a, starting from the indicated starting materials. If the base, ligand / catalyst, solvent and / or temperature were varied, this is stated separately.

[0655]

[0656]

[0657] Intermediate 32j

[0658]

[0659] 6-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-2,3-dihydroquinolin-4(1H)-one (Intermediate 32j)

[0660] 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 reaction mixture was stirred overnight at RT and then concentrated in vacuo. The residue was loaded onto an SCX column, washed with methanol, and eluted with 2 M ammonia in methanol to afford the title product (32 mg).

[0661] LCMS (Method 1): Rt = 0.87 min, ES + m / z 342.9 / 344.9 [M+H] +

[0662] Intermediate 33

[0663] Step 1

[0664]

[0665] 1-(5-Bromo-2-methoxy-4-nitrophenyl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 33-1)

[0666] 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 K 2 CO 3 (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 reaction mixture was diluted with water (80 mL). The precipitate formed was collected by filtration, washed with water (3 x 30 mL) and dried to afford the title product (620 mg), which was used in the subsequent synthetic step without further purification.

[0667] LCMS (Method 1): Rt = 1.26 min, ES + m / z 397.1 / 399.1 / 401.1 [M+H] +

[0668] Step 2

[0669]

[0670] Methyl 2-((5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)thio)acetate (Intermediate 33-2)

[0671] Intermediate 33-1 (350 mg, 0.88 mmol), methyl 2-thioacetate (118 μL, 1.3 mmol) and DIPEA (230 μL, 1.3 mmol) in anhydrous acetonitrile (15.0 mL) were stirred in a μM reactor at 120 °C for 3 h. A fresh (1) equivalent of methyl 2-thioacetate (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 in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 80% in DCM (DCM / MeOH (9:1)) to afford the desired product (170 mg).

[0672] LCMS (Method 1): Rt = 1.16 min, ES + m / z 423.2 / 425.2 [M+H] +

[0673] Step 3

[0674]

[0675] 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)

[0676] To a stirred solution of Intermediate 33-2 (160 mg, 0.38 mmol) in ethanol (5 mL) at 80 °C was added a solution of NH 4 Cl (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), filtered through a bed of diatomaceous earth and washed thoroughly with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 35% in DCM (DCM / MeOH (95:5)) to afford the title product (50 mg).

[0677] LCMS (Method 1): Rt = 0.96 min, ES + m / z 361.2 / 363.2 [M+H] +

[0678] Step 4

[0679]

[0680] 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)

[0681] To BH cooled to 0 °C 3 . A THF solution (1.0 M, in THF, 166.3 μL, 0.16 mmol) was added to 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 equivalent of BH 3 .THF was added, and the RM was stirred for another 2 h. The RM was quenched with saturated NH 4 Cl aqueous solution (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (3 x 10 mL) and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH (98:2) in DCM, to afford the title product (18 mg).

[0682] LCMS (Method 1): Rt = 1.11 min, ES + m / z 347.2 / 349.2 [M+H] +

[0683] Step 5

[0684]

[0685] 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)

[0686] To a solution of Intermediate 33-4 (25.0 mg, 67.8 μmol) in anhydrous DCM (1 mL) cooled to 0 °C was added m-CPBA (70.0%, 33.4 mg, 0.136 mmol), 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 NaHCO 3 aqueous solution. The organic phase was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 60% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM, to afford the title product (13 mg).

[0687] LCMS (Method 1): Rt = 0.82 min, ES + m / z 378.9 / 380.8 [M+H] +

[0688] Intermediate 34

[0689] Step 1

[0690]

[0691] Diethyl 2-(5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenyl)malonate (Intermediate 34-1)

[0692] To a mixture of NaH (60% mineral oil suspension, 80 mg, 2.0 mmol) in DMSO (4.0 mL) was slowly added diethyl malonate (186 μL, 1.3 mmol), and the reaction mixture (RM) was stirred at 65 °C. After 20 minutes, Intermediate 33-1 (195 mg, 0.49 mmol) was added, and the RM was stirred at 100 °C for 1 hour. After cooling to RT, the RM was poured into ice / water and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with water (10 x 10 mL) and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 45% DCM / MeOH (98:2) in DCM, to afford the title product (75 mg).

[0693] LCMS (Method 1): Rt = 1.26 min, ES + m / z 477.2 / 479.2 [M+H] +

[0694] Step 2

[0695]

[0696] 5-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxyindolin-2-one (Intermediate 34-2)

[0697] To a stirred solution of Intermediate 34-1 (75 mg, 0.16 mmol) in acetic acid (4.0 mL) at 90 °C was added iron (97 mg, 1.7 mmol) portionwise, and the RM was stirred at 90 °C for 80 minutes. After cooling to RT, the RM was filtered, the filtrate was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic matter was washed with saturated NaHCO 3 aqueous solution (10 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 75% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM, to afford the title product (21.4 mg).

[0698] LCMS (Method 1): Rt = 0.82 min, ES + m / z 329.2 / 331.2 [M+H] +

[0699] Step 3

[0700]

[0701] 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)

[0702] To a stirred suspension of NaH (60.0%, 14.9 mg, 0.37 mmol) in anhydrous DMF (0.3 mL) was added a solution of Intermediate 34-2 (180 mg, 0.37 mmol) in DMF (3 mL). The RM was stirred for 30 min 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 and then quenched with saturated NaHCO 3 aqueous solution (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (20 mL), saturated aqueous NaCl solution (20 mL) and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-40% EtOAc / DCM (1:9) in DCM to afford the title product (100 mg).

[0703] LCMS (Method 2): Rt = 1.35 min, ES + m / z 459.2 / 461.2 [M+H] +

[0704] Step 4

[0705]

[0706] 5'-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6'-methoxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopropane-1,3'-indoline]-2'-one (Intermediate 34)

[0707] To a stirred mixture 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 anhydrous 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 NH 4 Cl (10 mL) aqueous solution and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), dried over Na 2 SO 4 and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-25% EtOAc / DCM (1:9) in DCM, to afford the title product (48 mg).

[0708] LCMS (method 2): Rt = 1.44 min, ES + m / z 485.2 / 487.2 [M+H] +

[0709] Intermediate 35

[0710] Step 1

[0711]

[0712] 1-(Allyloxy)-5-chloro-4-methoxy-2-nitrobenzene (Intermediate 35-1)

[0713] A suspension of 5-chloro-4-methoxy-2-nitrophenol (1.00 g, 4.91 mmol), 3-bromoprop-1-ene (509 μL, 5.89 mmol), and K 2 CO 3 (1018 mg, 7.37 mmol) in acetonitrile (10 mL) was stirred overnight at 75 °C. The RM was cooled to RT, diluted with water and DCM. The layers were separated and the aqueous layer was washed with DCM. The combined organics were dried and concentrated to afford the crude product, which was used in the subsequent synthetic step without further purification (1.08 g).

[0714] LCMS (method 1): Rt = 1.18 min

[0715] 1 H-NMR (300 MHz, CDCl 3)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).

[0716] Step 2

[0717]

[0718] 1-(5-(Allyloxy)-2-methoxy-4-nitrophenyl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 35-2)

[0719] 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 K 2 CO 3 (1.73 g, 12.5 mmol) in DMSO (10.0 mL) was stirred for 5 h. The RM was cooled to RT and diluted with water. The precipitate formed was collected by filtration, washed with water, and dried to afford the desired product (950 mg), which was used in the subsequent synthetic step without further purification.

[0720] LCMS (Method 1): Rt = 1.19 min, ES + m / z 374.9 / 376.9 [M+H] + .

[0721] Step 3

[0722]

[0723] 5-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenol (Intermediate 35-3)

[0724] To a degassed mixture of Intermediate 35-2 (500 mg, 1.33 mmol) and K 2 CO 3 (553 mg, 4.00 mmol) in MeOH (15 mL) was added Pd(PPh 3 ) 4 (50.0 mg, 0.04 mmol). The RM was stirred at 60 °C for 30 min. After cooling to RT, the RM was concentrated and suspended in water, acidified to pH 3 and extracted with DCM. The combined organic layers were dried over Na 2 SO4 Dry over and evaporate to dryness. Grind the residue in DCM / MeOH to afford the desired product (200 mg), which is used in the subsequent synthetic step without further purification.

[0725] LCMS (Method 1): Rt = 1.09 min, ES + m / z 335.1 / 337.1 [M+H] + 。

[0726] Step 4

[0727]

[0728] 2-Amino-5-(6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxyphenol (Intermediate 35-4)

[0729] To a warm refluxing solution of Intermediate 35-3 (500 mg, 1.49 mmol) in MeOH (30 mL) was added a solution of NH 4 Cl (320 mg, 5.98 mmol) in water (5 mL) and iron (834 mg, 14.9 mmol). The RM was heated at reflux temperature for 2 days. After cooling to RT, the RM was filtered through a Celite pad. The filtrate was evaporated in vacuo, and the residue was dispersed in DCM and washed with water. The aqueous phase was back-extracted with DCM (3 x 50 mL), and the combined organic layers were washed with saturated aqueous NaCl solution and passed through a phase separator. The organic phase was evaporated in vacuo to afford the desired product (126.9 mg), which was used in the subsequent step without further purification.

[0730] LCMS (Method 1): Rt = 0.72 min, ES + m / z 305.0 / 306.9 [M+H] + 。

[0731] Step 5

[0732]

[0733] 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)

[0734] Intermediate 35-4 (125 mg, 0.34 mmol), DABAL-Me 3(131 mg, 0.51 mmol) and methyl 2-bromo-2,2-difluoroacetate (71 mg, 0.37 mmol) in THF (3 mL) were stirred for 15 minutes at 130 °C under nitrogen and microwave irradiation. After cooling to RT, the reaction was carefully quenched with 4 M HCl / 1,4-dioxane (2 mL). The resulting mixture was poured into saturated NaHCO 3 aqueous solution and extracted with DCM. The organic phase was evaporated in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 90% DCM / MeOH (20:1) in DCM, providing the title product (25 mg).

[0735] LCMS (Method 1): Rt = 1.09 min, ES + m / z 461.0 / 463.1 / 465.0 [M+H] + .

[0736] Step 6

[0737]

[0738] 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)

[0739] 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 in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH (20:1) in DCM, providing the title product (12.4 mg).

[0740] LCMS (Method 1): Rt = 1.09 min, ES + m / z 381.1 / 383.1 [M+H] + .

[0741] Intermediate 36

[0742] Step 1

[0743]

[0744] 3-(5-Chloro-4-methoxy-2-nitrophenoxy)propan-1-ol (Intermediate 36-1)

[0745] 5-Chloro-4-methoxy-2-nitrophenol (1.00 g, 4.91 mmol), 3-iodopropan-1-ol (685 μL, 7.37 mmol) and K 2 CO 3 (2.04 mg, 14.7 mmol) were suspended in DMF (15 mL), and the mixture was stirred at 70 °C for 5 h. After cooling to RT, the mixture was diluted with water (30 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with water (40 mL) and saturated aqueous NaCl solution (40 mL), and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 40% DCM / MeOH (99:1) in DCM, to afford the title product (1.08 g).

[0746] LCMS (Method 1): Rt = 0.93 min, ES + m / z 262.1 [M+H] + .

[0747] Step 2

[0748]

[0749] 3-(5-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenoxy)propan-1-ol (Intermediate 36-2)

[0750] 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 K 2 CO 3 (1.51 g, 10.9 mmol) in DMSO (10.0 mL) was stirred at 120 °C for 5 h. After cooling to RT, the mixture was diluted with water. The precipitate formed was collected by filtration, washed with water, and dried, to afford the title product (700 mg), which was used in the subsequent synthetic step without further purification.

[0751] LCMS (Method 1): Rt = 1.00 min, ES + m / z 393.2 / 395.2 [M+H] + .

[0752] Step 3

[0753]

[0754] 3-(5-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methoxy-2-nitrophenoxy)propyl methanesulfonate (Intermediate 36-3)

[0755] To a solution of Intermediate 36-2 (200 mg, 0.51 mmol) in DMF (5 mL) cooled to 0 °C was added methanesulfonyl chloride (59 μL, 0.76 mmol) 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 afford the title product (225 mg), which was used in the subsequent synthetic step without further purification.

[0756] LCMS (Method 1): Rt = 1.11 min, ES + m / z 471.1 / 473.1 [M+H] + 。

[0757] Step 4

[0758]

[0759] 8-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-7-methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]oxazine (Intermediate 36)

[0760] To a stirred solution of Intermediate 36-3 (210 mg, 0.42 mmol) in ethanol (10 mL) at 80 °C was added a solution of NH 4 Cl (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 in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-50% DCM / MeOH (95:5) in DCM to afford the title product (65 mg).

[0761] LCMS (Method 1): Rt = 0.99 min, ES + m / z 345.2 [M+H] + 。

[0762] Intermediate 37a

[0763]

[0764] 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)

[0765] 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 NaHCO 3 (4 x 4 mL) and saturated aqueous NaCl (10 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 85% DCM / MeOH / NH 4 OH (95:9:1.5) in DCM to afford the title product (63.6 mg).

[0766] LCMS (Method 1): Rt = 0.92 min, ES + m / z 545.4 / 547.3 [M+H] + .

[0767] Intermediates 37b to 37k

[0768] The following intermediates were prepared in a similar manner to Intermediate 37a, starting from the indicated starting materials.

[0769]

[0770]

[0771]

[0772] Intermediate 37m

[0773] Step 1

[0774]

[0775] 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]pyridin-3-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 37m-1)

[0776] To a solution of intermediate 37l (1.0 g, 1.48 mmol) in THF (10 mL) was added 1 M aqueous LiOH (10.6 mL, 11.8 mmol), and the mixture was stirred at RT for 16 h. The mixture was evaporated in vacuo and the residue was treated with water. The pH was adjusted to 6.5 with 1 M aqueous HCl. The aqueous phase was extracted with DCM (3 x 10 mL), and the combined organic layers were evaporated to dryness in vacuo to afford the title product (756 mg).

[0777] LCMS (Method 1): Rt = 0.99 min, ES + m / z 615.1 / 617.1 [M+H] +

[0778] Step 2

[0779]

[0780] 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)

[0781] A mixture 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 mixture 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 in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 70% DCM / MeOH / NH 4 OH (90:5:0.5) to afford the title product (26 mg).

[0782] LCMS (Method 2): Rt = 0.95 min, ES + m / z 642.4 / 644.4 [M+H] +

[0783] Intermediate 37n

[0784] Step 1

[0785]

[0786] 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)

[0787] 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 in vacuo. The residue was dissolved in MeOH and passed through an SCX column, washed with methanol and eluted with ammonia in methanol solution (7M) to afford the title product (63 mg).

[0788] LCMS (Method 2): Rt = 0.68 min, ES + m / z 415.2 / 4.17.2 [M+H] +

[0789] Step 2

[0790]

[0791] 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)

[0792] A mixture of Intermediate 37n-1 (50 mg, 0.12 mmol), 4-(bromomethyl)tetrahydropyran (33.3 mg, 0.13 mmol) and K 2 CO 3 (33.3 mg, 0.24 mmol) in DMF (1.5 mmol) was stirred at 80 °C for 7 h. A second equivalent 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 x 15 mL). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL) and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 15% DCM / MeOH / NH 4 OH (90:9:0.5) in DCM to afford the title product (48 mg).

[0793] LCMS (Method 2): Rt = 0.72, ES + m / z 557.2 / 559.2.

[0794] Intermediate 37o

[0795]

[0796] (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)

[0797] Under an argon atmosphere, under μW irradiation, Intermediate 21-5 (30 mg, 77 μmol), DABAL-Me 3 (30 mg, 0.12 mmol), THF (1 mL), and [(2R)-4-methylmorpholin-2-yl]methylamine (15 mg, 0.12 mmol) were heated at 130 °C for 45 minutes. After cooling to RT, the RM was quenched with 4 M HCl / dioxane (2 mL) and poured into saturated NaHCO 3 aqueous solution. The mixture was extracted with DCM and the combined organic layers were evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH (9:1) in DCM, to afford the title product (26 mg).

[0798] LCMS (Method 1): Rt = 0.81 min, ES + m / z 489.2 / 491.2 [M+H] +

[0799] Intermediate 37p

[0800]

[0801] 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)

[0802] The title compound was prepared in a similar manner to Intermediate 37o, starting from Intermediate 27b and N’,N’-dimethylpropane-1,3-diamine.

[0803] LCMS (Method 1): Rt = 0.77 min, ES + m / z 443.0 / 445.0 [M+H] + .

[0804] Intermediate 37q

[0805] Step 1

[0806]

[0807] tert-Butyl 7-(3-((2-bromoethyl)carbamoyl)-6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 37q-1)

[0808] Intermediate 37q-1 was prepared in a similar manner to Intermediate 37a, starting from Intermediate 24 and 2-bromoethylamine hydrochloride.

[0809] LCMS (Method 2): Rt = 1.38 min, ES + m / z 566.6 / 568.1 / 570.1 [M+H] +

[0810] Step 2

[0811]

[0812] tert-Butyl 7-(6-chloro-3-((2-(4-methoxypiperidin-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 37q)

[0813] 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 anhydrous DMF (1.3 mL) was stirred overnight at RT under argon. Saturated NH 4 Cl aqueous solution was added to quench the RM, and then extracted with EtOAc (x2). The combined organic layers were washed with water and saturated NaCl aqueous solution, dried over Na 2 SO 4 and evaporated to dryness. The residue was purified by flash chromatography on a Si column, eluting with a DCM / MeOH mixture (20:1 to 10:1) to afford the title product (50.0 mg).

[0814] LCMS (Method 1): Rt = 0.95 min, ES + m / z 601.0 / 603.2 [M+H] +

[0815] Intermediates 37q to 37w

[0816] The following intermediates were prepared in a similar manner to Intermediate 37q, starting from the indicated starting materials.

[0817]

[0818]

[0819] Intermediate 37x

[0820] Step 1

[0821]

[0822] 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)

[0823] 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 hours. The RM was neutralized with saturated NaHCO 3 aqueous solution (20 mL) and the layers were separated. The organic phase was washed with saturated NaHCO 3 aqueous solution, passed through a phase separator and evaporated in vacuo to give the desired product (223.6 mg), which was used in the subsequent synthetic step without further purification.

[0824] LCMS (Method 1): Rt = 1.07 min, ES + m / z 466.1 / 468.1 / 470.0 [M+H] +

[0825] Step 2

[0826]

[0827] 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]dec-8-yl)ethyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Intermediate 37x)

[0828] To a mixture of Intermediate 37x-1 (40.0 mg, 81 μmol) in acetone (0.5 mL) was added 1-oxa-8-azaspiro[4.5]decan-2-one hydrochloride (49 mg, 240 μmol) in acetone (1.0 mL), Na 2 CO 3(8.6 mg, 81 μmol) and NaI (1.3 mg, 8.1 μmol), and RM was stirred at 40 °C for 24 h. RM was evaporated in vacuo and the residue was partitioned between water (10 mL) and DCM (10 mL). After the aqueous phase was additionally extracted with DCM (3 x 10 mL), the combined organic layers were passed through a phase separator and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:5:0.5) to afford the title product (22 mg).

[0829] LCMS (Method 1): Rt = 0.71 min, ES + m / z 541.1 / 543.1 [M+H] +

[0830] Intermediate 38a

[0831]

[0832] 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)

[0833] To a solution of Intermediate 28 (60 mg, 0.14 mmol) in DCM (0.9 mL) cooled to 0 °C was added pyridine (15 μL, 0.18 mmol), 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 NaHCO 3 aqueous solution and extracted with DCM (4 x 15 mL). The combined organic layers were washed with saturated NaHCO 3 aqueous solution and saturated NaCl aqueous solution, dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:9:1.5) to afford the title product (30.6 mg).

[0834] LCMS (Method 1): Rt = 1.27 min, ES + m / z 490.1 / 492.0 [M+H] +

[0835] Intermediate 38b

[0836]

[0837] 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)

[0838] 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, then a solution of 2-(dimethylamino)ethanol (293 μL, 2.89 mmol) and TEA (161 μL, 1.16 mmol) in DCM (7.5 mL) was added. The RM was stirred at -78 °C for an additional 1 h, then allowed to warm to RT and quenched with saturated NaHCO 3 aqueous solution. The aqueous phase was further extracted with DCM (3 × 25 mL), and the combined organic layers were dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:9:1) in DCM to afford the title product (310 mg).

[0839] LCMS (Method 2): Rt = 1.23 min, ES + m / z 547.3 / 549.2 [M+H] +

[0840] Intermediates 38c to 38k

[0841] The following intermediates were prepared in a manner similar to Intermediate 38b, starting from the indicated starting materials. If the base, solvent, or temperature was varied, it is stated otherwise.

[0842]

[0843]

[0844]

[0845] Intermediate 38l

[0846]

[0847] (6-Chloro-1-(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamic acid 2-(dimethylamino)ethyl ester (Intermediate 38l)

[0848] Under argon, 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. 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 Na 2 SO 4 and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0-100% DCM / MeOH / NH 4 OH (90:9:0.5) in DCM to afford the title product (19.5 mg).

[0849] LCMS (Method 2): Rt = 0.94 min, ES + m / z 459.1 / 461.1 [M+H] +

[0850] Intermediate 38m

[0851]

[0852] (6-Chloro-1-(6-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamic acid 2-(dimethylamino)ethyl ester (Intermediate 38m)

[0853] A mixture of Intermediate 21 (200 mg, 0.53 mmol), (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-Me THF (20 mL) was refluxed for 1 h. A solution of 2-(dimethylamino)ethanol (95 mg, 1.1 mmol) in 2-Me THF (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 solution (3x10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried over Na2 SO 4 Drying and vacuum concentration were performed. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH(90:9:1.5) in DCM to afford the title product (116 mg).

[0854] LCMS (Method 1): Rt = 0.75 min, ES + m / z 463.2 / 465.2 [M + H] +

[0855] Intermediates 38n to 38x

[0856] The following intermediates were prepared in a similar manner to Intermediate 38m, starting from the indicated starting materials.

[0857]

[0858]

[0859]

[0860] Intermediate 38y

[0861] Step 1

[0862]

[0863] 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)

[0864] To a solution of Intermediate 28 (100 mg, 0.23 mmol) in DCM (5 mL) cooled to -78 °C was added TEA (97 μL, 0.70 mmol) and bis(trichloromethyl) carbonate (68.7 mg, 0.23 mmol), and the reaction mixture 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 reaction mixture was stirred overnight at RT. The reaction mixture was quenched with saturated NaHCO 3 aqueous solution (10 mL) and extracted with DCM (15 mL). The combined organic layers were washed with saturated NaCl aqueous solution and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 10% EtOAc / DCM to afford the title product (182 mg).

[0865] LCMS (Method 2): Rt = 1.32 min, ES + m / z 649.3 / 661.3 [M+H] +

[0866] Step 2

[0867]

[0868] 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)

[0869] 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 NaCl aqueous solution (10 mL) and the solvent was removed in vacuo to afford the desired product (81.7 mg), which was used in the subsequent synthetic step without further purification.

[0870] LCMS (Method 2): Rt = 0.92 min, ES + m / z 519.2 / 521.2 [M+H] +

[0871] Step 3

[0872]

[0873] 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)

[0874] 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 x 10 mL) and saturated NaCl aqueous solution (15 mL). The solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, using 0 - 5% DCM / MeOH / NH in DCM 4Eluted with OH(90:5:0.5) to give the title product (30 mg)

[0875] LCMS (Method 2): Rt = 0.95 min, ES + m / z 603.3 / 605.3 [M+H] +

[0876] Intermediate 39a

[0877]

[0878] 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)

[0879] Intermediate 21 (40.0 mg, 0.11 mmol) was taken (50.0% DMF solution, (124 μL, 0.21 mmol), azido(trimethyl)silane (28.2 μL, 0.21 mmol) and TEA (44.4 μL, 0.32 mmol) in 2-Me THF (0.5 ml) was refluxed overnight. After cooling to RT, the RM was diluted with EtOAc (25 mL) and washed with saturated NaHCO 3 aqueous solution (3x15 mL) and saturated NaCl aqueous solution (15 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 30% DCM / MeOH (90:1) in DCM to give the title product (10 mg).

[0880] LCMS (Method 1): Rt = 1.01 min, ES + m / z 419.1 / 421.1 [M+H] +

[0881] Intermediate 39b

[0882]

[0883] 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)

[0884] To a solution of Intermediate 28 (50.0 mg, 0.12 mmol) cooled to -78 °C in DCM (3 mL) was added DIPEA (48.4 μL, 0.35 mmol) and bis(trichloromethyl) carbonate (34.4 mg, 0.12 mmol), and the reaction mixture (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 allowed to warm to RT and diluted with saturated NaHCO 3 aqueous solution. The aqueous layer was further extracted with DCM (3 × 15 mL), and the combined organic layers were dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:9:0.5) in DCM, to afford the title product (19.4 mg).

[0885] LCMS (Method 2): Rt = 1.24 min, ES + m / z 602.3 / 604.3 [M+H] +

[0886] Intermediate 40

[0887] Step 1

[0888]

[0889] tert-Butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 40-1)

[0890] To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.64 mmol) in DCM (10 mL) at 0 °C was added NaHCO 3 (1.68 g) and m-CPBA (1.43 g, 7.89 mmol), and the RM was stirred at RT for 3 h. The RM was diluted with DCM (10 mL) and saturated NaHCO 3 aqueous solution (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 in vacuo. The residue was triturated in a DCM / MeOH mixture, the insoluble solid was filtered off and the filtrate was evaporated in vacuo to afford the title product (1.11 g).

[0891] 1 H-NMR (500 MHz, DMSO-d 6) δ: 4.39 (s, 2H), 3.87 (bs, 4H), 2.83 (s, 2H), 1.37 (s, 9H).

[0892] Step 2

[0893]

[0894] 6 - Oxo - 2 - azaspiro[3.4]octane - 7 - one trifluoroacetate (Intermediate 40 - 2)

[0895] 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 h. The volatiles were evaporated in vacuo and the residue was triturated in diethyl ether to afford the title product (198.9 mg).

[0896] 1 1H - NMR (500 MHz, DMSO - d 6 ) δ: 8.80 (bs, 2H), 4.40 (s, 2H), 4.04 (bs, 4H), 2.90 (s, 2H).

[0897] Step 3

[0898]

[0899] (2 - (7 - Oxo - 6 - oxo - 2 - azaspiro[3.4]octane - 2 - yl)ethyl)carbamic acid tert - butyl ester (Intermediate 40 - 3)

[0900] A mixture 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 sieve 200 mg) in methanol (4.0 mL) was stirred at RT for 1 h. Na(CN)BH 3 (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 by a phase separator. The organic layer was evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH (10:1) in DCM to afford the title product.

[0901] LCMS (Method 2): Rt = 0.75 min, ES + m / z 271.2 [M + H] +

[0902] Step 3

[0903]

[0904] 2-(2-Aminoethyl)-6-oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate (Intermediate 40)

[0905] 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 in diethyl ether to afford the desired product (93 mg), which was used in the subsequent synthetic step without further purification.

[0906] LCMS (Method 2): Rt = 0.34 min, ES + m / z 171.2 [M+H] +

[0907] Intermediate 41

[0908] Step 1

[0909]

[0910] (R)-1-(2-((tert-Butoxycarbonyl)amino)ethyl)pyrrolidine-3-carboxylate methyl ester (Intermediate 41-1)

[0911] A mixture of (R)-Pyrrolidine-3-carboxylic acid hydrochloride (406 mg, 2.5 mmol), K 2 CO 3 (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 was dissolved in EtOAc and washed with water. The aqueous solution was extracted with EtOAc (2x15 mL), and the combined organic layers were further washed with water (3x15 mL), saturated aqueous NH 4 Cl (15 mL) and saturated aqueous NaCl (15 mL). The organic layer was passed through a phase separator and the solvent was evaporated to afford the title product (422 mg), which was used in the subsequent synthetic step without further purification.

[0912] 1 1H-NMR (300 MHz, CDCl 3)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).

[0913] Step 2

[0914]

[0915] (R)-1-(2-Aminoethyl)pyrrolidine-3-carboxylic acid methyl ester (Intermediate 41)

[0916] To a solution of Intermediate 41-1 (420 mg, 1.54 mmol) in anhydrous DCM (3 ml) at 0 °C was added dropwise TFA (1.77 mL, 23.1 mmol). 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 2N ammonia in MeOH solution (50 mL). The MeOH fraction was evaporated to give the desired product (263 mg).

[0917] 1 H-NMR (300 MHz, CDCl 3 )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).

[0918] Intermediate 42a-b

[0919] The following intermediates were prepared in a similar manner to Intermediate 37a, starting from the indicated starting materials.

[0920]

[0921] Intermediate 43

[0922]

[0923] 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)

[0924] 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 equivalent 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 NaHCO 3 aqueous solution and saturated NH 4 Cl aqueous solution (10 mL each). The organic layer was separated through a phase separator and the solvent was removed in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 40% DCM / MeOH / NH 4 OH (90:9:1.5) in DCM to afford the desired product (44 mg).

[0925] LCMS (method 2): Rt = 1.21 min, ES + m / z 557.3 / 559.3 [M+H] +

[0926] Intermediate 44

[0927] Step 1

[0928]

[0929] 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)

[0930] A solution of intermediate 27a (500 mg, 1.1 mmol), (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-Me THF (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 NaHCO 3 aqueous solution. The aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated NaCl aqueous solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 35% DCM / MeOH / NH 4 OH (90:9:1.5) in DCM to afford the title product (279 mg).

[0931] LCMS (Method 1): Rt = 1.20 min, ES + m / z 430.2 / 432.2 [M+H] +

[0932] Step 2

[0933]

[0934] 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)

[0935] Cool a solution of Intermediate 44-1 (100 mg, 0.23 mmol) and TEA (97.3 μL, 0.70 mmol) in DCM (5 mL) to -78 °C and add bis(trichloromethyl) carbonate (69.0 mg, 0.23 mmol) in one portion. Stir the RM for 1 h under the same conditions. Add a solution of Intermediate 13 (151 mg, 0.93 mmol) and TEA (64.8 μL, 0.47 mmol) in DCM (2.5 mL) to the RM at -78 °C and stir under cooling for 2 h and overnight at RT. Quench the reaction with saturated NaHCO 3 aqueous solution and add DCM and water. Separate the layers and extract the aqueous layer with DCM (3 × 20 mL). Wash the combined organic layers with saturated NaCl aqueous solution, dry over Na 2 SO 4 and remove the solvent in vacuo. Purify the residue by flash chromatography on a Si column, eluting with 0-35% DCM / EtOH / NH 4 OH (90:4:1) in DCM to afford the title product (177 mg).

[0936] LCMS (Method 2): Rt = 1.28 min, ES + m / z 618.2 / 620.2 [M+H] +

[0937] Intermediates 45a to 45d

[0938] The following intermediates are prepared in a manner similar to Step 2 of Intermediate 37q, starting from the indicated starting materials.

[0939]

[0940]

[0941] Intermediate 45e

[0942]

[0943] tert-Butyl 7-(6-chloro-3-((2-(2-methyl-6-oxomorpholin-4-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 45e)

[0944] A mixture of Intermediate 45a (42.0 mg, 0.07 mmol), K 2 CO 3 (11.4 mg, 0.08 mmol) and ethyl 2-bromoacetate (9.1 μL, 0.08 mmol) in anhydrous MeCN (9 mL) was stirred overnight at RT and then heated at 110 °C for 9 h in a pressure vial. After cooling to RT, the solvent was removed in vacuo and the residue was treated with DCM (20 mL) and washed with saturated aqueous NaHCO 3 solution (3 x 10 mL) and saturated aqueous NaCl (10 mL). The organic layer was evaporated to afford the title product (45 mg), which was used in the subsequent step without further purification.

[0945] LCMS (Method 2): Rt = 1.25 min, ES + m / z 601.3 / 603.3 [M+H] +

[0946] Intermediate 45f

[0947] Step 1

[0948]

[0949] 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)

[0950] A solution of Intermediate 45d (80 mg, 0.14 mmol) and TFA (517 μL, 7.0 mmol) in DCM (9.5 mL) was stirred overnight at RT. The solvent was removed in vacuo and the residue was purified on an SCX column, eluting with methanol and ammoniacal methanol solution to afford the title compound (55.1 mg), which was used in the subsequent step without further purification.

[0951] LCMS (Method 1): Rt = 0.70 min, ES +m / z 475.2 / 477.1 [M+H] +

[0952] Step 2

[0953]

[0954] 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)

[0955] A solution of Intermediate 45f-1 (55 mg, 0.12 mmol) in toluene / acetonitrile was added to a mixture of glyoxal (40%, 15 μL, 0.12 mmol) in toluene (0.3 mL) pre-cooled to 10 °C. The RM was stirred at 10 °C for 3 h 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 in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:5:0.5) to afford the title product (32 mg).

[0956] LCMS (Method 2): Rt = 0.99 min, ES + m / z 515.2 / 517.1 [M+H] +

[0957] Preparation of Examples

[0958] Example 1

[0959]

[0960] 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)

[0961] To degassed 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 K 3 PO 4A solution of (38.2 mg, 0.18 mmol) in THF (0.5 mL) and water (0.2 mL) was added to XPhos Pd G3 (7.62 mg, 9.0 μmol), and RM was stirred at 75 °C for 2 h. After cooling to RT, RM was diluted with water and extracted with DCM (3 x 5 mL). The combined organic layers were passed through a phase separator and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 50% DCM / MeOH / NH 4 OH (90:9:0.5), and purified by passing through an SCX column to afford the title compound (17 mg).

[0962] LCMS (Method 4): Rt = 4.42 min, ES + m / z 450.1 [M+H] +

[0963] 1 H-NMR (500 MHz, DMSO-d 6 ) 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).

[0964] Examples 2 to 39

[0965] The following examples were prepared in a similar manner to Example 1, starting from the indicated intermediates.

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982] Example 40

[0983] Step 1

[0984]

[0985] 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)

[0986] Under nitrogen at 55 °C, degassed 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), K 3 PO 4 (169 mg, 0.80 mmol) and XPhos PdG3 (17 mg, 20 μmol) in a mixture of water (1 mL) / THF (2 mL) were stirred for 1.5 h. After cooling to RT, the RM was diluted with water (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with water and saturated NaCl aqueous solution (10 mL each), dried over Na 2 SO 4 and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 80% DCM / MeOH / NH 4 OH (90:9:0.5) in DCM, to afford the title product (158.4 mg).

[0987] LCMS (Method 2), Rt = 1.22, ES + m / z 514.3.

[0988] Step 2

[0989]

[0990] 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)

[0991] TFA (0.7 mL, 9.23 mmol) was added to a solution of the intermediate from Step 1 of Example 1 (158 mg, 0.31 mmol) in DCM (5.0 mL) and stirred overnight at RT. The solvent was removed in vacuo and the residue was loaded onto an SCX column, washed with methanol and eluted with ammonia in methanol solution (7 M) to afford the title product (78.7 mg).

[0992] LCMS (Method 3), Rt = 2.67 min, ES + m / z 414.1 [M+H] +

[0993] 1 1H-NMR (600 MHz, DMSO-d 6 ) 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, 4.1 Hz, 1H); 6.73 (s, 1H); 6.46 (s, 1H); 6.26 (brs, 1H); 4.13 (t, J = 3.3 Hz, 2H); 3.62 (s, 3H); 3.36 (m, 2H); 2.60 (s, 3H).

[0994] Examples 41 to 70

[0995] The following examples were prepared by a two-step method similar to Example 40, starting from the indicated intermediates.

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013] Example 71

[1014] Step 1

[1015]

[1016] 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'-indoline]-2'-one (Example 71 - Step 1)

[1017] The title compound was prepared similarly 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.

[1018] LCMS (Method 1), Rt = 1.32, ES + m / z 568.3

[1019] Step 2

[1020]

[1021] 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)

[1022] A solution of the ice-bath cooled intermediate of Example 71 - Step 1 (32.0 mg, 0.05 mmol) in anhydrous DCM (1 mL) was treated with TFA (371 μL, 4.85 mmol) and stirred overnight at RT. The RM was evaporated in vacuo, and the residue was partitioned between DCM (2 x 10 mL) / NaHCO3 (15 mL). The combined organic layers were evaporated in vacuo and the residue was dispersed in DCM (1 mL), treated with 7N ammonia in methanol solution (200 μL), and then stirred at RT for 4 hours. The RM was diluted with DCM (8 mL) and washed with saturated NaHCO 3 aqueous solution (10 mL) and saturated NaCl aqueous solution (10 mL). The organic layer was evaporated in vacuo, and the residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:5:0.5) in DCM to afford the title product (12.5 mg).

[1023] LCMS (Method 4): Rt = 3.89 minutes, ES + m / z 438.2 [M+H] +

[1024] 1 1H-NMR (600 MHz, DMSO-d 6 ) 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).

[1025] Example 72

[1026] Step 1

[1027]

[1028] 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)-1,3-benzoxazol-2(3H)-one (Example 72 - Step 1)

[1029] The title compound was prepared similarly to the Example 72 - Step 1 intermediate, starting from Intermediate 19 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine.

[1030] LCMS (Method 1), Rt = 0.79, ES + m / z 658.5

[1031] Step 2

[1032]

[1033] 5-Methoxy-6-(3-((2-morpholinoethyl)amino)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,3-benzoxazol-2(3H)-one (Example 72)

[1034] The title compound was prepared similarly to Example 72 (Step 2), starting from the Example 72 - Step 1 intermediate.

[1035] LCMS (Method 4): Rt = 3.52 minutes, ES + m / z 528.2 [M+H] +

[1036] 1 H-NMR (500 MHz, DMSO-d 6 ) 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, overlapping with DMSO); 2.35 - 2.38 (m, 2H).

[1037] Example 73

[1038] Step 1

[1039]

[1040] 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)

[1041] 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 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 made to pH 9 with 2N aqueous NaOH and extracted with EtOAc (15 mL). The combined organic layers were evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 90% DCM / MeOH / NH 4 OH (90:9:1.5) to afford the title product (38 mg).

[1042] LCMS (Method 1), Rt = 0.86, ES + m / z 628.4

[1043] Step 2

[1044]

[1045] 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)

[1046] The title compound was prepared similarly to Example 40 (Step 2).

[1047] LCMS (Method 4), Rt = 3.94 minutes, ES + m / z 528.2 [M+H] +

[1048] 1 1H-NMR (600 MHz, DMSO-d 6)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).

[1049] Example 74

[1050] Step 1

[1051]

[1052] 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)

[1053] A mixture of degassed 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 PdG3 (3.5 mg, 4.1 μmol) in dioxane (600 μL) was stirred overnight at 100 °C. After cooling to RT, the RM was chromatographed on a Si column, eluting with 0 - 30% DCM / MeOH / NH 4 OH (90:15:1.5) to afford the title product (11 mg).

[1054] LCMS (Method 2): Rt = 1.59 min, ES + m / z 692.4 [M+H] +

[1055] Step 2

[1056]

[1057] 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)

[1058] A solution of the intermediate of 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 column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:15:1.5) in DCM to afford the title product (2 mg).

[1059] 1 1H-NMR (600 MHz, DMSO-d 6 ) 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).

[1060] LCMS (Method 4): Rt = 4.34, ES + m / z 478.1 [M+H] +

[1061] Examples 75 to 76

[1062] The following examples were prepared by a two-step method similar to Example 74, starting from the indicated intermediates.

[1063]

[1064] Example 77

[1065]

[1066] 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)

[1067] The title compound was prepared in a manner similar to Example 1, starting from Intermediate 45f and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine.

[1068] LCMS (Method 3), Rt = 4.51 min, ES + m / z 598.3 [M+H] +

[1069] 1 H-NMR (500 MHz, DMSO-d 6 ) 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).

[1070] Example 78

[1071] Step 1

[1072]

[1073] 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)

[1074] The title compound was prepared similarly to Intermediate 24 (Method 1), starting from 6-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid and Intermediate 1.

[1075] LCMS (Method 1), Rt = 1.22 min, ES + m / z 497.1 / 499.0 [M+H] +

[1076] Step 2

[1077]

[1078] 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)

[1079] To degassed 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 K 3 PO 4 (0.5 M, in water, 1.61 mL, 0.81 mmol) in a mixture of THF / water (5.61 mL) was added XPhos Pd G3 (19 mg, 22 μmol), and the RM was heated at 80 °C for 1 hour. The warm reaction mixture was filtered, and the THF was evaporated in vacuo. Water was added to the RM until the solid dissolved, filtered, and saturated NH 4 Cl aqueous solution was added to form a precipitate, which was collected by filtration to afford the title product (77 mg), which was used in the subsequent step without further purification.

[1080] LCMS (Method 1), Rt = 1.01 min, ES + m / z 580.2 [M + H] +

[1081] Step 3

[1082]

[1083] 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)

[1084] The title compound was prepared similarly to Intermediate 37a, starting from Example 78 - Step 2 and N',N' - dimethylpropane - 1,3 - diamine.

[1085] LCMS (Method 1), Rt = 0.86 min, ES + m / z 664.3 [M + H] +

[1086] Step 4

[1087]

[1088] 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)

[1089] The title compound was prepared similarly to Step 2 of Example 40, starting from Example 78 - Step 3.

[1090] LCMS (Method 4): Rt = 3.92, ES + m / z 564.2 [M+H] +

[1091] 1 1H-NMR (500 MHz, DMSO-d 6 ) 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 (quintet, J = 7.1 Hz, 2H).

[1092] Example 79

[1093] Step 1

[1094]

[1095] 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)

[1096] The degassed 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), K 3 PO 4(233 mg, 1.1 mmol) and XPhosPdG3 (46 mg, 0.055 mmol) in a mixture of THF / water (2:1, 9 mL) were 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 mixture of DCM / isopropanol (4 x 20 mL). The combined organic layers were passed through a phase separator and evaporated in vacuo. The residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH:HCO 2 H (90:9:2) to afford the title product (320 mg).

[1097] LCMS (Method 1): Rt = 0.74 min, ES + m / z 698.4 [M+H] +

[1098] Step 2

[1099]

[1100] 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)

[1101] 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 NH 4 Cl (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 in vacuo and the residue was purified by flash chromatography on a Si column, eluting with 0 - 100% DCM / MeOH / NH 4 OH (90:9:0.5) to afford the title product (32 mg).

[1102] LCMS (Method 1): Rt = 0.74 min, ES + m / z 697.4 [M+H] +

[1103] Step 3

[1104]

[1105] 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)

[1106] The title compound was prepared similarly to Step 2 of Example 40, starting from Example 79 - Step 2.

[1107] LCMS (Method 4): Rt = 3.61, ES + m / z 597.2 [M+H] +

[1108] 1 1H-NMR (500 MHz, DMSO-d 6 ) 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).

[1109] Example 80

[1110] Step 1

[1111]

[1112] (R)-tert-Butyl 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)

[1113] The title compound was prepared similarly to Example 1, starting from Intermediate 42b and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine.

[1114] LCMS (Method 2): Rt = 1.17 min, ES + m / z 698.3 [M+H] +

[1115] Step 2

[1116]

[1117] (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)

[1118] 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 overnight at RT. 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 x 15 mL). The combined organic layers were dried over Na 2 SO 4 and evaporated to dryness to afford the title compound (553 mg), which was used in the subsequent step without further purification.

[1119] LCMS (Method 1): Rt = 0.82 min, ES + m / z 684.4 [M+H] +

[1120] Step 3

[1121]

[1122] (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-carboxylic acid tert-butyl ester (Example 80 - Step 2)

[1123] The title compound was prepared similarly to Example 79 Step 2, starting from Example 80 - Step 1.

[1124] LCMS (Method 2): Rt = 1.00 min, ES + m / z 683.4 [M+H] +

[1125] Step 4

[1126]

[1127] (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)

[1128] The title compound was prepared similarly to Step 2 of Example 40, starting from Example 80 - Step 3.

[1129] LCMS (Method 4): Rt = 3.56, ES + m / z 583.1 [M+H] +

[1130] 1 H-NMR (500 MHz, DMSO-d 6 ) 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 (quintet, 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).

[1131] Examples 81 to 86

[1132] The following examples were prepared in a two-step method similar to Example 40, starting from the indicated intermediates. If the base, catalyst, solvent or temperature was varied, it is stated otherwise.

[1133]

[1134]

[1135]

[1136] Pharmacological activity of the compounds (1-86) of the present invention

[1137] Biochemical potencies against JAK1, JAK2, JAK3 and Tyk2

[1138] Principle of the assay

[1139] The aim of this study was to evaluate the ability of the compounds to inhibit the activity of all 4 JAK isoforms in a cell-free environment. Assays for JAK1, JAK2, JAK3 and TYK2 were performed by time-resolved fluorescence resonance energy transfer (TR-FRET) technology. This technology consists of the measurement of the interaction of two labeled binding partners detected by the energy transfer from an excited donor to an acceptor dye and the light emission of the acceptor dye. The LANCE Ultra kinase assay was used. In the presence of JAK1, JAK2, JAK3 and TYK2 kinases and ATP (equivalent to Km), the ULight peptide substrate (LANCE Ulight-JAK-1(Tyr1023) peptide, Perkin Elmer, TRF0121) was phosphorylated. It was then captured by the Eu-anti-phospho-substrate antibody (LANCE Eu-W1024 anti-phosphotyrosine (PT66), Perkin Elmer, AD0069), which brought the Eu-chelate donor and the ULight acceptor dye into close proximity. Upon excitation at 320 nm, the Eu-chelate transferred its energy to the ULight dye, resulting in fluorescence emission at 665 nm.

[1140] Compound testing

[1141] Serial dilutions of the compounds in pure DMSO were prepared from a 10 mM DMSO stock solution. Starting from the highest concentration of 20 μM (20 μM - 2 pM), 11 consecutive 5-fold dilutions of the compounds were tested in 384-well plates. 200 nL of the compounds were transferred from the master plate to the test plate using a Mosquito (TTP labtech). Assays were performed in 384-well Perkin Elmer test plates with a 20 μL assay volume (kinase reaction) and a 40 μL total volume (stop reagent and antibody detection reagent). In 10 μL of the substrate solution (peptide + ATP), 30 / 50 / 20 / 10 nM peptide and 20 / 0.7 / 0.2 / 12 μM ATP were added for JAK 1, JAK 2, JAK 3, and TYK2, respectively. 10 μL of the enzyme solution was added to the kinase reaction at the following concentrations: 0.15 / 0.083 / 0.025 / 0.144 ng / μL of JAK 1, JAK 2, JAK 3, and TYK2, respectively. After shaking and incubating at room temperature for 1.5 h, 20 μL of the stop (10 μL EDTA) and detection mixture (10 μL europium - anti-phosphorylated antibody, final: 0.5 nM) were added. Readings were taken on an EnVision 2104 reader (Perkin Elmer) after incubating for 1 h.

[1142] Calculations of IC50 data, curves, and QC analysis were performed using Excel tools and GraphPad Prism software v9. Briefly, individual concentration - effect curves were generated by plotting the logarithm (X) of the test concentration of the test compound against the corresponding percent inhibition value (Y) using least squares (ordinary) fitting. The best - fit IC50 values were calculated using the Log(Inhibitor) vs. Normalized Response - Variable Slope equation, where Y = 100 / (1 + 10^((LogIC50 - X)*Hill slope)). QC standard parameters (Z’, S:B, R2, Hill slope) of each IC50 curve were examined. Calculations of IC50 data, curves, and QC analysis were performed using Excel tools and GraphPad Prism software. QC standard parameters: Z'≥0.5, Hill slope range 0.5 - 5, S:B>2.

[1143] Regarding their inhibitory activity against all JAK isoforms, the compounds of the present invention show pIC50 values higher than 6, corresponding to an inhibitory concentration of ≤1 μM. At least regarding their inhibitory activity against JAK1, most compounds preferably show values higher than 7.3, even more preferably higher than 8.3; corresponding to an inhibitory concentration of ≤50 nM, even more preferably ≤5 nM.

[1144] Data for compounds 1 - 76 are reported in the table below.

[1145]

[1146]

[1147]

[1148] According to the following classification criteria, the compounds were classified in the above table according to the potency of their inhibitory activity against JAK1, JAK2, JAK3, and TYK2 isoforms:

[1149] +++:pIC 50 ≥8.3

[1150] ++:8.3 > pIC 50 ≥7.3

[1151] +:pIC 50 <7.3

[1152] Inhibition of IL-13-induced pSTAT6 in BEAS

[1153] BEAS-2B human cell line was seeded (100,000 cells / well) and incubated at 37 °C, 5% CO2, 95% humidity for 48 h. Compounds were added and incubated for 30 minutes, followed by addition of IL-13 as a trigger. After 30 minutes of incubation, cells were lysed and pSTAT6 was determined by Fastscan phospho-stat6 (Tyr641) sandwich ELISA kit (Cell Signaling). Inhibitors were tested in duplicate at 11 consecutive 5-fold dilutions starting from 10 μM (10 μM - 40 pM). Calculations of IC50 data, curves, and QC analysis were performed using Excel tools and GraphPad Prism software. QC standard parameters: Z' ≥ 0.35, Hill slope range 0.5 - 5, S:B > 2.

[1154]

[1155] According to the following classification criteria, the compounds were classified in the above table according to the potency of their functional activity in BEAS:

[1156] §§§§:pIC 50 ≥8.3

[1157] §§§:8.3 > pIC 50 ≥7.3

[1158] §§:7.3 > pIC 50 ≥6.3

[1159] §:pIC 50 <6.3

[1160] If numerical limits or ranges are stated in this application, the endpoints are included. In addition, all values and sub-ranges within the numerical limits or ranges are specifically included when not explicitly written out. As used in this application, words such as "a" and "an" have the meaning of "one or more".

[1161] Obviously, many variations and changes of the present invention are possible in light of the above teachings. Accordingly, it is to be understood that within the scope of the appended claims, the invention may be practiced in other ways than as specifically described in this application.

Claims

1. Compounds of formula I wherein R 1 is a heteroaryl selected from: 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 group of the following formula: which are substituents attached to the molecular backbone, wherein V is absent (meaning it is a bond) or is a divalent group selected from 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 ); Q is selected from 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 the (C 3 -C 8 )cycloalkyl and (C 3 -C 10 )heterocycloalkyl are further optionally substituted by one or more substituents selected from -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 hydroxy-(C 3 -C 6 ) Heterocycloalkyl; R 3 is the bicyclic moiety which are substituents attached to the backbone as shown in the following diagram: where the dashed line --- indicates a single or double bond X is selected from N, S, C; Y is selected from C, N; Z is selected from C, N, O; K is absent (meaning a bond) or selected from O, C, S; G is absent (meaning a bond) or selected from C, O; is the point of attachment of the substituent to the rest of the molecule n and m are each independently 0 or an integer selected from 1, 2, 3, and 4; R 4 and R 5 are the same or different and are selected from: -H， (C 1 -C 6 ) alkyl (C 1 -C 6 ) haloalkyl, and (C 3 -C 6 )heterocycloalkyl; R 6 Each occurrence is independently selected from H, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) hydroxyalkyl; R 7 is one or more groups (preferably 1 or 2), which are each independently selected from -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 Selected from: (C 1 -C 6 )alkoxy group, (C 1 -C 6 )haloalkoxy group; its individual enantiomers, diastereoisomers and mixtures thereof in any ratio or pharmaceutically acceptable salts or solvates.

2. The compound of formula I according to claim 1 wherein the bicyclic moiety R 3 selected from 3. The compound of formula I according to claim 2 Among them, the bicyclic moiety R 3 is selected from J 1 -J 13 4. The compound of formula I according to claim 3 wherein R 3 is J1 and R 8 is methoxy; so that the compound is represented by formula Ia wherein R 1 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(R 6 ), N(R 6 )C(O)O; Q is selected from (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 the (C 3 -C 8 ) cycloalkyl and (C 3 -C 12 ) heterocycloalkyl are further optionally substituted by one or more substituents selected from 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 are each independently 0 or an integer selected from 1, 2, 3, and 4; R 4 and R 5 are the same or different and are each independently selected from: -H， (C 1 -C 6 ) alkyl (C 1 -C 6 )haloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of formula Ia according to claim 4, wherein V is N(R 6 )C(O)O; Q is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, -(CH 2 ) m NR 4 R 5 ), and (C 3 -C 6 ) heterocycloalkyl, which is the group wherein X 1 is selected from CH 2 , O, S, NH, NCH 3 , (C=O) and S(=O) 2 ; individual enantiomers, diastereoisomers and mixtures thereof in any ratio or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of formula Ia according to claim 4, wherein V is C(O)N(R 6 ) Q is selected from -(CH 2 ) m NR 4 R 5 , and (C 3 -C 6 ), a heterocyclic alkyl group, which is a group where X 1 is selected from CHR 9 , O, S, NH, NCH 3 , CF 2 , (C 1 -C 6 ), an alkoxy group or (C 1 -C 6 ), an alkoxy(C 1 -C 6 )alkyl group, where R 9 is H or -(CO)NR 4 R 5 its individual enantiomers, diastereoisomers and mixtures thereof in any ratio or a pharmaceutically acceptable salt or solvate.

7. The compound of formula Ia according to claim 4, wherein Q is (C 3 -C 6 ) heterocycloalkyl, -S-(C 3 -C 6 ) heterocycloalkyl or -N(R 6 )-(C 3 -C 6 ) heterocycloalkyl, selected from:

8. The compound according to claim 1, selected from: 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]oxazine 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]dec-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, (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)carbamic acid 3-(2-oxomorpholino)propyl ester, (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)carbamic acid 2-(methyl(2-oxotetrahydrofuran-3-yl)amino)ethyl ester, (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, (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)carbamic acid 2-(dimethylamino)ethyl ester, (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)carbamic acid 2-(dimethylamino)ethyl ester, (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)carbamic acid 2-morpholinoethyl ester, (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)carbamic acid 3-(4-methylpiperazin-1-yl)propyl ester, (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)carbamic acid 2-(piperidin-1-yl)ethyl ester, (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)carbamic acid (R)-1-methylpyrrolidin-3-yl ester, (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)carbamic acid (S)-1-methylpyrrolidin-3-yl ester, (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)carbamic acid (4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl ester, (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)carbamic acid (R)-2-(3-methoxypyrrolidin-1-yl)ethyl ester, 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]dec-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]dec-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]pyridine-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, (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)methyl carbamate, (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)carbamic acid 2-(dimethylamino)ethyl ester, (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)carbamic acid 2-morpholinoethyl ester, (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)carbamic acid 3-(4-methylpiperazin-1-yl)propyl ester, (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)carbamic acid 3-(dimethylamino)propyl ester, (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)carbamic acid 3-morpholinopropyl ester, (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)carbamic acid 2-(1,1-dioxosulfomorpholino)ethyl ester, (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)carbamic acid 2-(4-methylpiperazin-1-yl)ethyl ester, (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)carbamic acid 2-thiomorpholinoethyl ester, (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)carbamic acid (S)-(4-methylmorpholin-2-yl)methyl ester, (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)carbamic acid 2-(piperidin-1-yl)ethyl ester, (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)carbamic acid 2-((2-oxotetrahydrofuran-3-yl)thio)ethyl ester, (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)carbamic acid 2-((2-oxotetrahydrofuran-3-yl)amino)ethyl ester, (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)carbamic acid 2-(dimethylamino)ethyl ester, 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-oxomorpholin-4-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-(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-oxomorpholin-4-yl)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]pyridine-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 its individual enantiomers, diastereoisomers and mixtures thereof in any ratio or a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients admixed therewith.

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

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

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

13. A compound or pharmaceutical composition for use according to claim 12 for the prevention and / or treatment of lung diseases selected from asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury and acute respiratory distress syndrome (ARDS).

14. A combination of a compound as defined in any one 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 the person skilled in the art, such as β2-agonists, antimuscarinics, corticosteroids, mitogen-activated protein kinase (p38 MAP kinase) inhibitors, PI3K inhibitors (phosphoinositide 3-kinases), nuclear factor κ-B kinase subunit β inhibitors (IKK2), Rho kinase inhibitors (ROCKi), human neutrophil elastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modifiers, non-steroidal anti-inflammatory drugs (NSAIDs) and mucolytics.

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