N-methyl,N-(6-(methoxy)pyridazin-3-yl)amine derivatives as autotaxin (ATX) modulators for the treatment of inflammatory airway diseases or fibrous diseases

Abstract

To provide a means for treating inflammatory airway diseases or fibrotic diseases. [Solution] The present invention relates to N-methyl,N-(6-(methoxy)pyridazin-3-yl)amine derivatives as autotaxin (ATX) modulators for the treatment of inflammatory airway diseases or fibrotic diseases, such as idiopathic lung disease (IPF) or systemic sclerosis (SSc). This description discloses exemplary compounds (e.g., pages 57-75; Examples 1.1-5) and their related biological data (e.g., pages 15-21, Tables 1-9). An example compound is 1-(6-(4-(((6-((6-((trifluoromethyl)pyridine-3-yl)methoxy)pyridazin-3-yl)amino)methyl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one (Example 1.1).

Description

[Technical Field]

[0001] Field of Invention The present invention relates to novel dapyridines, processes for their preparation, pharmaceutical compositions containing them, and therapies, particularly their use in the treatment and / or prevention of autotaxin-mediated diseases and disorders. [Background technology]

[0002] Background of the Invention Autotaxin (ATX; ENPP2) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) to the bioactive lipid lysophosphatidic acid (LPA) via its lysophospholipase D activity. LPA then exerts its effects through interaction with six GPCRs (LPA receptors 1-6, LPAR1-6) (Houben AJ, 2011). ATX-LPA signaling is thought to be involved in processes such as angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression, and tumor metastasis. For example, LPA acting on LPAR1 induces migration, proliferation, and differentiation of lung fibroblasts; modulates epithelial and endothelial barrier function; and promotes apoptosis of lung epithelial cells (Budd, 2013). ATX inhibition, LPAR1 gene deletion, and selective LPAR1 antagonists have been shown to be effective in preclinical models of pulmonary and cutaneous fibrosis (Tager AM, 2008; Swaney J, 2010, Casetelino FV, 2016).

[0003] In patients with idiopathic pulmonary fibrosis (IPF), LPA levels in bronchoalveolar lavage fluid are elevated (Tager et al., 2008, Nat. Med.), and elevated ATX concentrations are detected in human fibrotic lung tissue (Oikonomou et al., 2012, AJRCMB). LPA levels are elevated in exhaled condensate from IPF subjects (Montesi et al., 2014_BMCPM), and LPC levels double in the serum of stable IPF patients (Rindlisbacher et al., 2018, Resp. Res.). Therefore, elevated ATX levels and / or LPA levels, altered LPA receptor expression, and changes in the response to LPA may affect many pathophysiological conditions involved in ATX-LPA signaling.

[0004] Interstitial lung disease (ILD) is characterized by inflammation and fibrosis of the interstitium, intersacral tissues, and spaces of the lung (du Bois, Nat. Rev. Drug Discov. 2010, 9, 129-140). ILD can occur when lung injury triggers an abnormal healing response. Therefore, ILD includes progressive interstitial lung disease (PFILD) with progressive fibrosis, in which the response to lung injury becomes progressive and self-persistent, independent of the initial clinical relevance or trigger. The most prominent PFILDs are idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD ​​(SSc-ILD). IPF is a chronic, irreversible, and ultimately fatal fibrotic lung disease characterized by progressive fibrosis in the interstitial tissue of the lungs, which reduces lung volume and leads to progressive pulmonary dysfunction. IPF is also characterized by a distinctive histopathological pattern known as typical interstitial pneumonia (UIP) (Raghu et al, Am. J. Respir. Crit. Care Med. 183: 788-824).

[0005] Systemic sclerosis (SSc), also known as scleroderma, is an immune-mediated rheumatic disease with a complex etiology. It is a multi-organ heterogeneous disorder characterized by widespread fibrosis, vascular damage, and autoantibodies against various cellular antigens, and has a high mortality rate. It is a rare and intractable disease with a high level of need that has yet to be addressed. The early clinical signs of SSc can be diverse. Raynaud's phenomenon and gastroesophageal reflux are often present in the early stages of the disease (Rongioletti F, et al., J Eur Acad Dermatol Venereol 2015; 29: 2399-404). Some patients present with inflammatory skin disease, swollen and swollen fingers, musculoskeletal inflammation, or constitutional signs, such as fatigue. Excessive collagen deposition in the patient's skin makes the skin thickened and toughened. Some patients observe organ-based signs of the disease, such as pulmonary fibrosis, pulmonary arterial hypertension, renal failure, or gastrointestinal complications. Furthermore, one of the most common signs of immune involvement is the presence of abnormal levels of autoimmune antibodies (antinuclear antibodies or ANAs) against the nuclei of one's own cells, which is found in almost anyone with SSc (Guiducci S et al., Isr Med Assoc J 2016; 18: 141-43). ILD and pulmonary arterial hypertension (PAH) are the most frequent causes of death in SSc patients (Tyndall AJ et al. Ann Rheum Dis 2010; 69: 1809-15).

[0006] SSc patients are classified into two major disease subsets: diffuse cutaneous systemic sclerosis and localized cutaneous systemic sclerosis (LeRoy EC, et al., J Rheumatol 1988; 15:202-5). Three clinical features, namely excessive fibrosis (scarring), vascular impairment, and autoimmunity, underlie the processes that give rise to the various signs that characterize SSc. SSc is currently considered a sign of dysregulation or dysfunctional repair of connective tissue to injury (Denton CP et al., Lancet 2017; 390: 1685-99). Therefore, it is desirable to provide a powerful ATX inhibitor.

[0007] Various structural classifications of ATX inhibitors are outlined in D. Castagna et al. (J.Med.Chem. 2016, 59, 5604-5621). WO2014 / 139882 discloses a compound that is an ATX inhibitor having the following generalized structural formula. [ka]

[0008] Example 2 is further disclosed by N. Desroy, et al (J.Med.Chem. 2017, 60, 3580-3590, as Example 11) as a first-in-class ATX inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis. C. Kuttruff, et al. (ACS Med. Chem. Lett. 2017, 8, 1252-1257) disclose BI-2545 (Example 19), an ATX inhibitor that significantly reduces LPA levels in vivo. [Overview of the project]

[0009] Detailed description of the invention Surprisingly, this invention is a potent inhibitor of autotaxin (Assay A), and furthermore, - High efficacy in human whole blood (Assay B), and - Significant reduction in plasma LPA concentration levels in the body over several hours (Assay C) This provides a novel pyridazine characterized by [specific feature]. The compounds of the present invention are useful as agents for the treatment or prevention of diseases or conditions involving ATX activity and / or LPA signaling, and are involved in the pathogenesis or pathology of said diseases, or at least associated with at least one symptom of said diseases. ATX-LPA signaling is thought to be involved in, for example, angiogenesis, chronic inflammation, autoimmune diseases, fibrous diseases, cancer progression, and tumor metastasis.

[0010] The compound of the present invention has the following parameters: -Effectiveness as an ATX inhibitor, - Efficacy as an ATX inhibitor in human whole blood, - To reduce the plasma concentration level of LPA in the body over several hours. This combination is superior to those disclosed in prior art. ATX is an active soluble plasma protein in heparinized whole blood. Its substrate, LPC, is present in very large quantities, in the μM range. Therefore, whole blood assays at physiological substrate concentrations are highly relevant for predicting the efficacy of ATX inhibitors in vivo.

[0011] In vivo LPA reduction is determined by measuring the plasma concentration of LPA after oral administration of the compound of the present invention. LPA is a highly physiologically active lipid that efficiently activates downstream pathways in a concentration-dependent manner via LPA receptors 1-6. The clear and sustained blockade of LPA formation via ATX inhibition is assayed by measuring the degree of LPA reduction 8 hours after compound administration. Therefore, a significant reduction in plasma LPA at 8 hours indicates not only the efficacy and duration of action in vivo, but also sustained target engagement of the LPA receptor very well. The compounds of the present invention are structurally different from Examples 2 and 12 of WO2014 / 139882 and Example 19 of ACS Med. Chem. Lett. 2017, 8, 1252-1257, namely, the compounds of the present invention contain a central pyridazine core with substituents at positions 3 and 6. This structural difference unexpectedly results in a superior combination of (i) inhibition of ATX, (ii) inhibition of ATX in human whole blood, and (iii) reduction of plasma concentration levels of LPA in vivo over several hours. As a result, the compounds of the present invention exhibit high in vivo target engagement and can be predicted to have higher efficacy in humans.

[0012] The present invention provides a novel compound of the following formula (I). [ka] (I) Wherein, A is pyridyl substituted with one or two members of the group consisting of fluoro and F -fluoro-C 1-3 -alkyl; E is selected from the group consisting of phenyl and pyridyl optionally substituted with one or two members of the group consisting of fluoro and F 1-7 -fluoro-C 1-3 -alkyl;

[0013] K is the following group

Chemical formula

[0014] Another embodiment of the present invention relates to a compound of formula (I) wherein A is pyridyl substituted with one or two members of the group consisting of F, F 1-3 -fluoro-C1-alkyl; and the substituents E and K are as defined in the preceding embodiment. Another embodiment of the present invention relates to a compound of formula (I) wherein A is pyridyl substituted with one or two members of the group consisting of F, F2HC, and F3C; and the substituents E and K are as defined in the preceding embodiment.

[0015] Another embodiment of the present invention relates to a compound of formula (I) wherein A is selected from the group consisting of the following

Chemical formula

[0016] Another embodiment of the present invention is that E is based on the following [ka] Selected from the group consisting of; The present invention relates to a compound of formula (I) wherein substituents A and K are as defined in any of the prior embodiments.

[0017] According to the present invention, the compound of formula (I) is preferably selected from the group consisting of the following compounds. [ka]

[0018] [ka]

[0019] [ka]

[0020] [ka]

[0021] [ka]

[0022] Further embodiments relate to pharmaceutical compositions comprising at least one compound of Formula I of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Further embodiments relate to compounds of formula (I) of the present invention for use as pharmaceuticals. [Modes for carrying out the invention]

[0023] Terms and definitions used Terms not specifically defined herein shall be given the meanings that a person skilled in the art would give them in light of this disclosure and the context. However, when used herein, unless otherwise specified, the following terms shall have the meanings indicated and the following conventions shall apply. In the groups, radicals, or moieties listed below, the number of carbon atoms is often specified prior to the group; for example, C 1-6 -Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Generally, for groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., the attachment point of the group to the molecule can be determined by those skilled in the art from the free valence of the group itself. For combination groups containing two or more subgroups, the attachment point of the group is the last named subgroup, for example, the substituent "aryl-C 1-3 -alkyl is C 1-3 - This refers to an aryl group bonded to an alkyl group, where the alkyl group is bonded to the core or group to which the substituent is attached. Where the compounds of this invention are described in terms of chemical names and chemical formulas, the formula shall prevail in the event of any inconsistency. Asterisks can be used in sub-formulas to represent bonds attached to the core molecule as defined. The numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached.

[0024] For example, the term "3-carboxypropyl group" refers to the following substituent: [ka] In the formula, the carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" group refer to the following groups. [ka]

[0025] By using an asterisk in the sub-formula, we can represent the bonds that are attached to the core molecule according to the definition. As used herein, the term "substituted" means that one or more hydrogen atoms on a designated atom are replaced by an option from the indicated set, provided that the substitution does not exceed the normal valence of the designated atom and that the substitution results in a stable compound. The term "C" is used alone or in combination with another base. 1-n -alkyl (where n is an integer selected from 2, 3, 4, 5, or 6, preferably 4 or 6) means an acyclic saturated branched or linear hydrocarbon group having 1 to n carbon atoms. For example, term C 1-5 -Alkyl is the group H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C- CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-C Includes H2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. The term "halogen" refers to chlorine, bromine, iodine, and fluorine. The term "halo," when added to an "alkyl," "alkylene," or "cycloalkyl" group (saturated or unsaturated), replaces one or more hydrogen atoms of the alkyl or cycloalkyl group with a halogen atom selected from fluorine, chlorine, or bromine, preferably fluorine and chlorine, and particularly preferably fluorine. Examples include H2FC-, HF2C-, and F3C-.

[0026] The term "phenyl" refers to the group in the following ring. [ka]

[0027] The term pyridinyl refers to the group in the following ring. [ka]

[0028] The term pyridazine refers to the following ring. [ka]

[0029] The term oxetanyl refers to the following ring. [ka]

[0030] Unless otherwise specified, throughout this specification and the appended claims, a given chemical formula or chemical name shall encompass not only tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, but also mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which such isomers and enantiomers exist, as well as salts including pharmaceutically acceptable salts thereof, and solvates including, for example, solvates of free compounds or solvates of salts of compounds. In general, substantially pure stereoisomers can be obtained by means of stereochemically pure starting materials and / or by stereoselective synthesis, for example, by separation of corresponding mixtures, according to synthetic principles known to those skilled in the art. Methods for preparing optically active forms are well known in the art, for example, by racemic separation, or by synthesis starting from optically active starting materials and / or by using chiral reagents.

[0031] The enantiomerically pure compounds or intermediates of the present invention can be prepared by asymmetric synthesis, for example by separation after preparation of suitable diastereomer compounds or intermediates that can be separated by known methods (e.g., chromatographic separation or crystallization), and / or by using chiral reagents such as chiral starting materials, chiral catalysts, or chiral auxiliaries. Furthermore, those skilled in the art know of methods for preparing enantiomerically pure compounds from a corresponding racemic mixture, such as by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by the resolution of the racemic mixture using a suitable resolving agent, for example, by the formation of a diastereomer salt of the racemic compound with an optically active acid or base, followed by the resolution of the salt and the release of the desired compound from the salt; or by the derivatization of the corresponding racemic compound with an optically active chiral auxiliary, followed by diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of the racemate (e.g., enzymatic resolution); by enantioselective crystallization under suitable conditions from an aggregate of enantiomer crystals; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0032] In this specification, the term "pharmaceutically acceptable" refers to any compound, substance, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is balanced by a reasonable benefit-to-risk ratio. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the parent compound forms a salt or complex with an acid or base. Examples of acids that form pharmaceutically acceptable salts with parent compounds containing a basic moiety include mineral acids or organic acids, such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0033] Examples of cations and bases that form pharmaceutically acceptable salts with parent compounds containing acidic moieties include Na + , K + Ca 2+ Mg 2+ NH4 + These include L-arginine, 2,2'-iminobisethanol, L-lysine, N-methyl-D-glucamine, or tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acidic or basic moieties. Generally, these salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of a suitable base or acid in water or in a suitable organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. For example, salts of acids other than the above-mentioned acids (e.g., trifluoroacetate) that are useful for purifying or isolating the compounds of the present invention also constitute part of the present invention.

[0034] Biological assays The biological activity of the compound was determined by the following method. Assay A: Biochemical ATX assay 50 mM Tris buffer (pH 8.0) containing 3 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.14 mM NaCl, and 0.1% bovine serum albumin was supplemented with 5 nM recombinant ATX (Cayman Chemicals). The test compound was dissolved in DMSO and tested in the range of 0.1 nM to 10 μM. The enzymatic reaction (22.5 μL) was initiated by adding 2.5 μL of 10 μM 18:1 LPC (Avanti Lipids, Alabaster, AL, USA). After incubation at room temperature for 2 hours, the reaction was stopped by adding 20 μL of water containing 500 nM 20:4 LPA as an internal standard and 100 μL of 1-butanol for LPA extraction. Subsequently, the plate was centrifuged at 4000 rpm at 4°C for 2 minutes. The resulting upper butanol phase was used directly for injection using the RapidFire system (Agilent).

[0035] A RapidFire autosampler was connected to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). This system contained a 10 μL loop, a 5 μL Waters Atlantis HILIC cartridge (Waters, Elstree, UK), 90% acetonitrile containing 10 mM ammonium acetate as eluent A, and 40% acetonitrile containing 10 mM ammonium acetate as eluent B. See below for details (Bretschneider et al., SLAS Discovery, 2017). One MS was operated in negative mode at a source temperature of 550°C, with curtain gas = 35, gas 1 = 65, and gas 2 = 80. The following transitions and MS parameters (DP: declustering potential and CE: collision energy) were determined for each LPA: (18:1 LPA 435.2 / 152.8, DP=-40, CE=-28 and 20:4 LPA 457.2 / 152.8, DP=-100, CE=-27). The formation of 18:1 LPA was monitored and evaluated as a ratio to 20:4 LPA.

[0036] Table 1: Compound biology data of the present invention obtained by assay A [Table 1]

[0037] Table 2: Biological data of prior art compounds obtained in Assay A (Examples 2 and 12 of WO2014 / 139882) [Table 2]

[0038] Table 3: Biological data of prior art compounds obtained in Assay A (Example 19 from ACS Med. Chem. Lett. 2017, 8, 1252-1257) [Table 3]

[0039] Assay B: Whole blood ATX assay 5 μL of the test compound (concentration range: 0.12 nM to 100 μM) dissolved in phosphate-buffered saline was added to 45 μL of human whole blood. This mixture was incubated at 37°C for 1 hour and stopped by adding 100 μL of 40 mM disodium hydrogen phosphate buffer containing 30 mM citrate (pH 4) and 1 μM 17:0 LPA (internal standard). After extracting the LPA by adding 500 μL of 1-butanol, the mixture was centrifuged at 4000 rpm at 4°C for 10 minutes. From the resulting organic supernatant, 200 μL aliquots were transferred to a 96-deep-well plate and proceeded to MS / MS analysis based on RapidFire. A RapidFire autosampler was connected to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). This system contained a 10 μL loop, a 5 μL Waters Atlantis HILIC cartridge (Waters, Elstree, UK), 90% acetonitrile containing 10 mM ammonium acetate as eluent A, and 40% acetonitrile containing 10 mM ammonium acetate as eluent B. See Bretschneider et al., SLAS Discovery, 2017, 22, 425-432 for further details. This MS was operated in negative mode at a source temperature of 550°C, with curtain gas = 35, gas 1 = 65, and gas 2 = 80. For each LPA, the following transitions and MS parameters (DP: declustering potential and CE: collision energy) were determined: 18:2 LPA 433.2 / 152.8, DP=-150, CE=-27 and 17:0 LPA 423.5 / 152.8, DP=-100. The formation of 18:2 LPA was monitored and evaluated as a ratio to 17:0 LPA.

[0040] Table 4: Compound biology data of the present invention obtained in assay B [Table 4]

[0041] Table 5: Biological data of prior art compounds obtained in Assay B (Examples 2 and 12 of WO2014 / 139882) [Table 5]

[0042] Table 6: Biological data of prior art compounds obtained in Assay B (Example 19 from ACS Med. Chem. Lett. 2017, 8, 1252-1257) [Table 6]

[0043] Assay C: In vivo The test substance was solubilized in 0.5% natrosol supplemented with 0.015% Tween 80 for oral administration to rats at a dose of 5 mg / kg. Blood samples were collected on ice before compound administration and 8 hours after administration using EDTA as a coagulant. Plasma was then prepared by centrifugation and stored at -20°C until analysis. LPA was extracted from plasma samples using the procedure described by Scherer et al. (Clinical Chemistry 2009, 55, 1218-22). 35 μL of heparinized plasma was mixed with 200 μL of 40 mM disodium hydrogen phosphate buffer containing 30 mM citrate (pH 4) and 1 μM 17:0 LPA (internal standard). Subsequently, 500 μL of butanol was added and the mixture was shaken vigorously for 10 minutes. The sample was then centrifuged at 4000 rpm at 4°C for 10 minutes. 500 μL of the organic upper phase was transferred to an unused 96-deep-well plate and heated to 15 psi (1.03 × 10⁻⁶). 5 The mixture was evaporated for 45 minutes with a gentle nitrogen stream at Pa. The resulting residue was dissolved in 100 μL of ethanol before LC-MS analysis.

[0044] LC-MS method for the analysis of in vivo samples A Triple Quad 6500 (ABSciex, Toronto, Canada) was equipped with an Agilent 1290 LC system (Agilent, Santa Clara, CA), a CTC autosampler, and an Atlantis 50×2.1 mm, 3 μm HILIC LC column (Waters, Elstree, UK). Eluting agent A contained 0.2% formic acid and 50 mM ammonium formate in water, while eluting agent B consisted of 0.2% formic acid in acetonitrile. The LC gradient was started with 95% solvent B, reduced to 75% within 1.5 minutes and 50% solvent B within 0.2 minutes, and further reduced from 500 to 700 μL·min. -1The flow rate was increased to [value missing]. After 1.8 minutes, solvent B was returned to 95%, kept constant for 0.7 minutes, and the column was re-equilibrium. The following LPA types were monitored (DP: declustering potential and CE: collision energy): 16:0 LPA 409.2 / 152.8, DP=-150, CE=-28; 18:0 LPA 437.3 / 152.8, DP=-60, CE=-28; 18:1 LPA 435.2 / 152.8, DP=-40, CE=-28; 18:2 LPA 433.2 / 152.8, DP=-150, CE=-28; 20:4 LPA 457.2 / 152.8, DP=-100, CE=-29 and 17:0 LPA 423.5 / 152.8, DP=-100, CE=-36. The percentage reduction in LPA was calculated based on the baseline LPA level before application of the test compound. The total LPA refers to species 16:0;18:0;18:1;18:2 and 20:4.

[0045] Table 7: Biological data of the compound of the present invention obtained in assay C [Table 7]

[0046] Table 8: Biological data of prior art compounds obtained in Assay C (Examples 2 and 12 of WO2014 / 139882) [Table 8]

[0047] Table 9: Biological data of prior art compounds obtained in Assay C (Example 19 from ACS Med. Chem. Lett. 2017, 8, 1252-1257) [Table 9]

[0048] Treatment method The present invention relates to compounds of general formula (I) that are useful for the prevention and / or treatment of diseases and / or conditions associated with or regulated by the physiological activity of ATX and / or LPA, such as, but not limited to, inflammatory conditions, fibrotic diseases, respiratory conditions, renal conditions, hepatic conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus, as well as acute and chronic organ transplant rejection and nervous system conditions.

[0049] Compounds of general formula (I) are used to treat inflammatory conditions, such as, but not limited to, Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases, such as, but not limited to, interstitial lung diseases (ILDs), such as interstitial lung disease with progressive fibrosis (PFILD), such as idiopathic pulmonary fibrosis (IPF) and SSC-ILD; familial interstitial lung diseases; cardiomyopathy and vascular fibrosis; renal fibrosis; hepatic fibrosis; pulmonary fibrosis; dermatofibrosis; collagen vascular diseases, such as systemic sclerosis (SSc) and encapsulating peritonitis. peritonitis, etc.; respiratory conditions, for example, but not limited to, diffuse parenchymal lung diseases of various etiologies, such as iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, etc., systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); renal conditions, for example, but not limited to, end-stage renal disease (ESRD), focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic diseases, and acute and chronic kidney injury and chronic kidney disease (with and without proteinuria), including acute and chronic kidney transplant rejection; liver conditions, for example, but not limited to, cirrhosis, hepatic congestion, cholestatic liver disease, for example, pruritus, primary biliary cholangitis, non-alcoholic fatty liver disease, and acute and chronic liver transplant rejection, etc.; vascular conditions, for example, but not limited to, atherosclerotic Arteriosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative artery disease (e.g., swollen endomycetin cells surrounded by mucinous extracellular matrix and nodular thickening), endothelial dysfunction, etc.; cardiovascular conditions, for example, but not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial pulmonary hypertension, arrhythmias, for example, atrial fibrillation, stroke and other vascular injuries, etc.; cancer and cancer metastasis, for example, but not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer and their progressive and metastatic aggressiveness, etc.; ocular conditions, for example, but not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and moist age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, trauma, glaucoma, etc.; metabolic conditions, for example, but not limited to, obesity, dyslipidemia and diabetes, etc.;It is useful in the prevention and / or treatment of nervous system conditions, including, but not limited to, neuropathic pain, Alzheimer's disease, schizophrenia, neuroinflammation (e.g., astrogliosis), and peripheral and / or autonomic (diabetic) neuropathy.

[0050] Accordingly, the present invention relates to a compound of general formula (I) for use as a pharmaceutical. Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or conditions associated with or regulated by the physiological activity of ATX and / or LPA. Furthermore, the present invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of diseases and / or conditions associated with or regulated by the physiological activity of ATX and / or LPA, such as, but not limited to, inflammatory conditions, fibrotic diseases, respiratory conditions, renal conditions, hepatic conditions, vascular and cardiovascular conditions, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus, as well as acute and chronic organ transplant rejection and nervous system conditions.

[0051] Furthermore, the present invention applies to inflammatory conditions, such as, but not limited to, Sjögren's syndrome, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) and chronic asthma; fibrotic diseases, such as, but not limited to, interstitial lung diseases (ILDs), such as interstitial lung disease with progressive fibrosis (PFILD), such as idiopathic pulmonary fibrosis (IPF) and SSC-ILD, familial interstitial lung diseases, cardiomyopathy and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, dermatofibrosis, collagen vascular diseases, such as systemic sclerosis (SSc) and encapsulating peritonitis. peritonitis, etc.; respiratory conditions, for example, but not limited to, diffuse parenchymal lung diseases of various etiologies, such as iatrogenic drug-induced fibrosis, occupational and / or environmentally induced fibrosis, etc., systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); renal conditions, for example, but not limited to, end-stage renal disease (ESRD), focal segmental glomerulosclerosis, IgA nephropathy, vasculitis / systemic diseases, and acute and chronic kidney injury and chronic kidney disease (with and without proteinuria), including acute and chronic kidney transplant rejection; liver conditions, for example, but not limited to, cirrhosis, hepatic congestion, cholestatic liver disease, for example, pruritus, primary biliary cholangitis, non-alcoholic fatty liver disease, and acute and chronic liver transplant rejection, etc.; vascular conditions, for example, but not limited to, atherosclerotic Arteriosclerosis, thrombotic vascular disease and thrombotic microangiopathy, proliferative artery disease (e.g., swollen endomycetin cells surrounded by mucinous extracellular matrix and nodular thickening), endothelial dysfunction, etc.; cardiovascular conditions, for example, but not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial pulmonary hypertension, arrhythmias, for example, atrial fibrillation, stroke and other vascular injuries, etc.; cancer and cancer metastasis, for example, but not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer and their progressive and metastatic aggressiveness, etc.; ocular conditions, for example, but not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and moist age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, trauma, glaucoma, etc.; metabolic conditions, for example, but not limited to, obesity, dyslipidemia and diabetes, etc.;This invention relates to the use of compounds of general formula (I) for the treatment and / or prevention of nervous system conditions, such as, but not limited to, neuropathic pain, Alzheimer's disease, schizophrenia, neuroinflammation (e.g., astrogliosis), and peripheral and / or autonomic (diabetic) neuropathy.

[0052] In a further embodiment, the present invention relates to a compound of general formula (I) used for the treatment and / or prevention of the above-mentioned diseases and conditions. In a further embodiment, the present invention relates to the use of compounds of general formula (I) for the preparation of pharmaceuticals for the treatment and / or prevention of the above-mentioned diseases and conditions. In a further aspect of the present invention, the present invention relates to a method for treating or preventing the above-mentioned diseases and conditions, comprising administering an effective amount of a compound of general formula (I) to a human.

[0053] Pharmaceutical composition Suitable formulations for administering the compound of formula (I) are obvious to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, liquids, syrups, elixirs, sachets, injections, inhalants, and powders. Suitable tablets can be obtained, for example, by mixing one or more compounds of formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants.

[0054] Combination therapy The compounds of the present invention can be used in combination with other therapeutic options known to be used in the art to treat indications for which the present invention is useful, using effective amounts of at least two active compounds. Combination therapy preferably involves administering the two active compounds to the patient simultaneously, although it is not necessary to administer the compounds to the patient simultaneously, even though effective amounts of each compound will be present in the patient at the same time. The compounds of the present invention may be administered with one or more combination partners described in other parts of this specification. Accordingly, the present invention provides a compound of formula (I) according to any of the above embodiments, characterized in that the compound of formula (I) is administered in addition to treatment with one or more anti-inflammatory molecules from the list consisting of IL6 modulators, anti-IL6R modulators, and IL13 / IL-4 JAKi modulators.

[0055] In another embodiment, the present invention provides a compound of formula (I) according to any of the above embodiments, characterized in that the compound of formula (I) is administered in addition to treatment with one or more antifibrotic molecules from the list consisting of CB2 agonists, TGF modulators, FGFR modulators, VEGFR inhibitors, PDGFR inhibitors, FGF modulators, αvβ6 integrin modulators, anti-CTGF antibodies, ROCK2 inhibitors, rhPTX-2 (pentraxin-2), JNK1 inhibitors, LOXL2 inhibitors, galectin-3 inhibitors, MK2 inhibitors, Wnt pathway inhibitors, TGFR inhibitors, PDE4 modulators, TRPA1 inhibitors, and microRNA modulators. In another embodiment, the present invention provides a compound of formula (I) according to any of the above embodiments, characterized in that the compound of formula (I) is administered in addition to nintedanib. In another embodiment, the present invention provides a compound of formula (I) according to any of the above embodiments, characterized in that the compound of formula (I) is administered in addition to pirfenidone.

[0056] preparation The compounds of the present invention are known to those skilled in the art and can be obtained using synthetic methods described in the literature on organic synthesis. In particular, it is preferable to obtain the compounds in the same manner as the preparation method described below in its entirety, as will be described in the experimental section. The general preparation process of the compounds of the present invention will become apparent to those skilled in the art by studying the following scheme. The starting materials may be prepared by the methods described in the literature or herein, or by similar or equivalent methods. The functional groups of either the starting materials or intermediates may be protected with conventional protecting groups. These protecting groups can be cleaved again at appropriate stages in the reaction sequence using methods familiar to those skilled in the art. [ka]

[0057] Compounds of general formula (I) can be prepared by a palladium-mediated Buchwald reaction or copper-mediated Ullmann reaction of a pyridadinyl halide or triflate (II) with an amine (III), where X is a leaving group representing, for example, Cl, Br, I, or OTf (triflate). [ka] Alternatively, compounds of general formula (I) can be prepared by a palladium-mediated Buchwald reaction or copper-mediated Ullmann reaction of a pyridazinyl halide or triflate (VIII) with an alcohol (VII), where X is a leaving group representing, for example, Cl, Br, I, or OTf (triflate). [Examples]

[0058] Experiment Part The following examples are intended to demonstrate the present invention without limiting it. The terms "ambient temperature" and "room temperature" are used interchangeably, and a temperature of approximately 20°C is specified.

[0059] Abbreviation: [Table 10] JPEG2026082810000029.jpg228168 JPEG2026082810000030.jpg90164

[0060] Preparation of starting compounds Example I Example I.1 3-{[6-(difluoromethyl)pyridine-3-yl]methoxy}-6-iodopyridazine [ka]

[0061] 17.70 g (53.33 mmol) of 3,6-diiodopyridazine (CAS-No. 20698-04-8) and 8.50 g (53.41 mmol) of [6-(difluoromethyl)pyridine-3-yl]methanol (CAS-No. 946578-33-2) in 25 mL of THF are cooled to 0°C, and 2.33 g (53.33 mmol) of sodium hydride (55% purity) is added. The reaction mixture is stirred overnight in RT and concentrated under reduced pressure. The residue is diluted with water (400 mL). The precipitate is filtered, washed with water and tBME, and dried overnight in vacuum at 50°C to obtain 17.50 g of product. C 11 H8F2IN3O (M=363.1g / mol) ESI-MS:364 [M+H] + R t (HPLC): 0.90 min (Method A)

[0062] Prepare the following compounds according to the general procedure described above (I.1 in the example). [ka]

[0063] Example II Example II.1 4-(4-acetylpiperazine-1-yl)-3-fluorobenzonitrile [ka]

[0064] To a solution of 0.40 g (1.95 mmol) of 3-fluoro-4-piperazin-1-yl-benzonitrile (CAS-No. 182181-38-0) and 0.60 ml (4.30 mmol) of triethylamine in 7 mL of DCM, 0.14 mL (1.95 mmol) of acetyl chloride was added, and the mixture was stirred overnight at RT. The reaction mixture was treated with 0.09 mL (1.25 mmol) of triethylamine and stirred at RT for 2 hours. The organic layer was washed with water, dried over PTK, and the solvent was evaporated under reduced pressure to obtain 0.5 g of crude product, which was used in the next step without further purification. C 13 H 14 FN3O (M=247.3g / mol) ESI-MS:248 [M+H] + R t (HPLC): 0.82 B)

[0065] Prepare the following compounds according to the general procedure described above (Example II.1). [ka]

[0066] Example III Example III.1 1-{4-[4-(aminomethyl)-2-fluorophenyl]piperazine-1-yl}ethane-1-one [ka]

[0067] A mixture of 550 mg (2.22 mmol) of 4-(4-acetylpiperazine-1-yl)-3-fluorobenzonitrile (Example II.1), 55.0 mg of Raney nickel, and 15 mL of 7N ammonia in MeOH is heated in a hydrogen atmosphere (50 psi (3.4 × 10⁻¹⁰)). 5 Stirring overnight at -50°C (Pa), filter, and boil in vacuum to obtain 0.51 g of product. C 13 H 18 FN3O (M=251.3g / mol) ESI-MS:252 [M+H] + R t (HPLC): 0.68 min (Method A)

[0068] Prepare the following compounds according to the general procedure described above (Example III.1). [ka] JPEG2026082810000037.jpg236165 JPEG2026082810000038.jpg49161

[0069] Example IV Example IV.1 4-(4-acetylpiperazine-1-yl)-2-fluorobenzonitrile [ka]

[0070] A mixture of 0.50 g (2.50 mmol) of 4-bromo-2-fluorobenzonitrile (CAS No. 105942-08-3), 0.32 g (2.50 mmol) of 1-(piperazin-1-yl)ethane-1-one (CAS No. 13889-98-0), 1.63 g (5.00 mmol) of cesium carbonate, and 0.05 g (0.06 mmol) of XPhos Pd G3 (CAS No. 1445085-55-1) in 2 mL of 1,4-dioxane is stirred overnight at 80°C. The mixture is then diluted with water. The residual solid is filtered, washed with water, and dried under an air atmosphere to obtain 0.57 g of the product. C 13 H 14 FN3O (M=247.3g / mol) ESI-MS:248 [M+H] + R t (HPLC): 0.79 min (Method A)

[0071] Prepare the following compounds according to the general procedure described above (Example IV.1). [ka]

[0072] Example V Example V.1 4-{6-methyl-7-oxo-2,6-diazaspiro[3.4]octan-2-yl}benzonitrile [ka]

[0073] 222 mg (1.81 mmol) of 4-fluorobenzonitrile (CAS No. 1194-02-1) and 320 mg (1.81 mmol) of 6-methyl-2,6-diazaspiro[3.4]octan-7-one hydrochloride (CAS No. 2097951-61-4), diluted with 1.6 mL of DMSO, were treated with 790 mg (5.62 mmol) of K2CO3 and stirred at 120°C for 3 hours and overnight at RT. The reaction mixture was cooled and diluted with water. The precipitate was filtered, washed with water, and dried under vacuum at 50°C to obtain 340 mg of the product. C 14 H 15 N3O (M=241.3g / mol) ESI-MS:242 [M+H] + R t (HPLC): 0.79 min (Method B)

[0074] Prepare the following compounds according to the general procedure described above (Example V.1). [ka] JPEG2026082810000043.jpg220153 JPEG2026082810000044.jpg231154

[0075] [Table 11]

[0076] Example VI Example VI.1 4-{2,7-diazaspiro[3.5]nonan-2-yl}benzonitrile; trifluoroacetic acid [ka]

[0077] Dilute 255 mg (0.78 mmol) of 2-(4-cyanophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl (e.g., V.2) in 5 mL of DCM and add 300 μL (3.89 mmol) of TFA. Stir the reaction mixture under RT for 2 hours and concentrate under reduced pressure to obtain 0.26 g of product. C 14 H 17 N3 * C2HF3O2 (M=341.3g / mol) ESI-MS:228 [M+H] + R t (HPLC): 0.69 min (Method B)

[0078] Prepare the following compounds according to the general procedure described above (Example VI.1). [ka] JPEG2026082810000048.jpg87162

[0079] Example VII Example VII.1 4-{2,6-diazaspiro[3.3]heptan-2-yl}benzonitrile [ka]

[0080] A solution of 0.90 g (3.01 mmol) of 6-(4-cyanophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (e.g., V.3) in 8 mL of ACN is treated with 1.14 g (6.01 mmol) of p-toluenesulfonic acid monohydrate and stirred at RT for 24 hours. The reaction mixture is diluted with DCM and extracted with a saturated NaHCO3 solution. The mixed organic layer is dried over MgSO4 and concentrated under reduced pressure to obtain 0.6 g of the product. C 12 H 13 N3 (M = 199.3 g / mol) ESI-MS:200 [M+H] + R t (HPLC): 0.62 min (Method B)

[0081] Prepare the following compounds according to the general procedure described above (Example VII.1). [ka]

[0082] Example VIII N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridine-3-yl]methoxy}pyridazine-3-amine [ka]

[0083] 1000 mg (2.62 mmol) of 3-iodo-6-{[6-(trifluoromethyl)pyridine-3-yl]methoxy}pyridazine (e.g., I.2), 586 mg (3.15 mmol) of 4-bromobenzylamine, 50 mg (0.26 mmol) of copper iodide, 88 mg (0.52 mmol) of 2-(2-methyl-1-oxopropyl)cyclohexanone, and 2.56 g (7.87 mmol) of cesium carbonate were stirred overnight at 60°C in 10 mL of DMF. The reaction mixture was purified by HPLC to obtain 850 mg of the product. C 18 H 14 BrF3N4O (M=439.2g / mol) ESI-MS:439 / 441 [M+H] + R t (HPLC): 1.08 min (Method A)

[0084] Example IX Example IX.1 5-(4-acetylpiperazine-1-yl)pyridine-2-carbonitrile [ka]

[0085] A mixture of 250 mg (2.05 mmol) of 5-fluoropyridine-2-carbonitride (CAS No. 327056-62-2), 310 mg (2.46 mmol) of 1-acetylpiperazine (CAS No. 13889-98-0), and 700 μL (4.10 mmol) of DIPEA in 3 mL of DMSO was stirred at 80°C for 45 minutes and quenched with semi-concentrated NaCl / solution. The aqueous phase was extracted with siRNA. The mixed organic phase was dried by PTK and concentrated in vacuum to obtain 0.57 g of product. C 12 H 14 N4O (M=230.3g / mol) ESI-MS:231 [M+H] + R t (HPLC): 0.67 min (Method A)

[0086] Prepare the following compounds according to the general procedure described above (Example IX.1). [ka]

[0087] Example X Example X.1 4-(4-acetyl-3,3-dimethylpiperazine-1-yl)benzonitrile [ka]

[0088] Dissolve 800 mg (1.21 mmol) of 4-(3,3-dimethylpiperazin-1-yl)benzonitrile trifluoroacetic acid (e.g., VI.3) in 3 mL of pyridine and add 2.00 mL (21.2 mmol) of acetic anhydride. Evaporate the reaction mixture under reflux and reduced pressure overnight. Take the residue in a saturated NaHCO3 solution and extract with siRNA. Dry the organic layer, concentrate it under vacuum, and purify it by column chromatography (silica gel; gradient: DCM / MeOH = 98:2 → 9:1) to obtain the product. C 15 H 19 N3O (M=257.3g / mol) ESI-MS:258 [M+H] + R t (HPLC): 0.85 min (Method A)

[0089] Prepare the following compounds according to the general procedure described above (Example X.1). [ka] JPEG2026082810000056.jpg116166

[0090] Example XI 6-(difluoromethyl)-5-fluoropyridine-3-carboxylate methyl [ka]

[0091] 800 mg (3.54 mmol) of 5-bromo-2-(difluoromethyl)-3-fluoropyridine [prepared from commercially available 5-bromo-3-fluoropyridine-2-carboxyaldehyde (1 equivalent), CAS-Nr. 669066-93-7, by reacting with deoxofluor (2 equivalents) overnight in DCM] in 40 mL of MeOH is treated with 154.8 mg (0.28 mmol) of 1,1'-bis-(diphenylphosphino)-ferrocene, 63.5 mg (0.28 mmol) of palladium(II) acetate, and 1.5 mL (10.79 mmol) of TEA. The reaction mixture is stirred at 50°C for 15 hours under a carbon monoxide atmosphere (5 bar). The reaction mixture is filtered, and the filtrate is evaporated under vacuum to obtain the product. The residue was purified by column chromatography (silica gel; gradient: Cy / EE = 100:0 → 60:40) to obtain 460 mg of the product. C8H6F3NO2 (M=205.1g / mol) ESI-MS:206 [M+H] + R t (HPLC): 0.88 min (Method B)

[0092] Example XII [6-(difluoromethyl)-5-fluoropyridine-3-yl]methanol [ka]

[0093] Treat the mixture with 460 mg (2.42 mmol) of methyl 6-(difluoromethyl)-5-fluoropyridine-3-carboxylate (e.g., XI), which is prepared by dissolving 98 mg (4.49 mmol) of lithium borohydride in 10 mL of THF under a nitrogen atmosphere. Add 0.2 mL of MeOH and stir the reaction mixture at 50°C for 2 hours. Dilute the reaction mixture with 5 mL of 1 M hydrochloric acid, and after gas generation, evaporate the THF. Make the residue basic with 4 M NaOH, and extract this aqueous solution by DCM. Evaporate the organic phase under vacuum to obtain the product. Purify the residue by column chromatography (silica gel; gradient: Cy / EE = 80:20 → 20:80) to obtain 290 mg of the product. C7H6F3NO (M=177.1g / mol) ESI-MS:178 [M+H] + R t (HPLC): 0.64 min (Method B)

[0094] Example XIII 1-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepine-6-yl]ethane-1-one hydrochloride [ka]

[0095] Dilute 2.64 g (9.3 mmol) of (3aR,8aS)-6-acetyl-decahydropyrrolo[3,4-d]azepine-2-carboxylate tert-butyl (e.g., X.2) in 30 mL of 1,4-dioxane, add 9.3 mL (37.4 mmol) of 4 M hydrogen chloride in the 1,4-dioxane, and stir the reaction mixture at RT for 4 hours. Add 1 equivalent of 4 M hydrogen chloride in the 1,4-dioxane to the reaction mixture and stir at RT overnight. Evaporate the mixture under vacuum, treat the residue with diethyl ether, and filter the precipitate. Dilute the filter cake with MeOH and evaporate to obtain the product. C 10 H 18 N2O * HCl (M = 182.3 g / mol) ESI-MS:183 [M+H] + R t (HPLC): 0.50 min (Method A)

[0096] Example XIV N-(4-((3aR,3bS,6aR,6bS)-Octahydrocyclobuta[1,2-c:3,4-c']dipyrrole-2(1H)-yl)benzyl)-6-((6-(trifluoromethyl)pyridine-3-yl)methoxy)pyridazine-3-amine [ka]

[0097] Dissolve 59.7 mg (0.27 mmol) of (3aR,3bR,6aS,6bS)-decahydrocyclobuta[1,2-c:3,4-c']dipyrrole, 120.0 mg (0.27 mmol) of N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridine-3-yl]methoxy}pyridazine-3-amine (e.g., VIII), 3.07 mg (0.01 mmol) of palladium(II) acetate, 6.5 mg (0.01 mmol) of X-phos, and 89.0 mg (0.27 mmol) of cesium carbonate in 2.00 mL of toluene and 0.50 mL of tert-butanol under an argon atmosphere. Degas the solution several times. Stir the reaction solution overnight at 80°C. Dilute the reaction mixture with water and extract with EE. The organic layer is dried over MgSO4, filtered through charcoal, and evaporated. The residue is purified by HPLC to obtain 15 mg of the product. C 28 H 31 F3N6O2 (M=496.5g / mol) ESI-MS:497 [M+H] + R t (HPLC): 0.98 min (Method A)

[0098] Preparation of the final compound Example 1.1 1-(6-(4-(((6-((6-((trifluoromethyl)pyridine-3-yl)methoxy)pyridazin-3-yl)amino)methyl)phenyl)-2,6-diazaspiro[3,3]heptan-2-yl)ethane-1-one [ka]

[0099] To a solution of 163 mg (0.43 mmol) of 3-iodo-6-((6-(trifluoromethyl)pyridine-3-yl)methoxy)pyridazine (Example I.2) and 150 mg (0.43 mmol) of 1-(6-(4-(aminomethyl)phenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1-one (Example III.6) in 2 mL of dimethylacetamide, 418 mg (1.28 mmol) of cesium carbonate, 8.1 mg (0.04 mmol) of copper(I) iodide, and 14.4 mg (0.09 mmol) of 2-(2-methyl-1-oxopropyl)cyclohexanone are added, and the mixture is stirred overnight at 50°C. The mixture is diluted with acetonitrile, filtered, and the filtrate is purified by HPLC to obtain 43 mg of the desired product. C 25 H 25 F3N6O2 (M=498.5g / mol) ESI-MS:499 [M+H] + R t (HPLC): 0.93 min (Method A) 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.52 Hz, 1H), 8.13 (dd, J=1.39, 8.11 Hz, 1H), 7.92 (d, J=8.11 Hz, 1H), 7.16 (d, J=8.49 Hz, 2H), 6.89-7.03 (m, 2H), 6.84 (t, J=5.64 Hz, 1H), 6.40 (d, J=8.49 Hz, 2H), 5.48 (s, 2H), 4.33 (d, J=5.58 Hz, 2H), 4.27 (s, 2H), 3.99 (s, 2H), 3.89 (s, 4H), 1.74 (s, 3H)

[0100] Prepare the following compounds according to the general procedure described above (Example 1.1). [ka]

[0101] [Table 12]

[0102] [Table 13]

[0103] Example 2.1 N-methyl-N-[1-(4-{[(6-{[6-(trifluoromethyl)pyridine-3-yl]methoxy}pyridazine-3-yl)amino]methyl}phenyl)piperidine-4-yl]acetamide [ka]

[0104] A mixture of 50.0 mg (0.13 mmol) of 3-iodo-6-{[6-(trifluoromethyl)pyridine-3-yl]methoxy}pyridazine (Example I.2), 45.20 mg (0.14 mmol) of 1-{4-[4-(1-aminocyclopropyl)phenyl]-piperazin-1-yl}ethane-1-one (Example III.7), 6.2 mg (32.8 μmol) of copper iodide, 13.2 mg (0.07 mmol) of [(2,6-difluorophenyl)carbamoyl]formic acid (CAS No. 1018295-42-5), and 85.5 mg (0.39 mmol) of potassium phosphate in 2 mL of DMSO is stirred at 80°C for 1.5 hours, then stirred at 100°C for 1 hour. The reaction mixture is purified by HPLC to obtain 54 mg of the product. C 26 H 29 F3N6O2 (M=514.5g / mol) ESI-MS:515 [M+H]+ R t (HPLC): 0.60 min (Method C) 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.14 Hz, 1H), 8.14 (dd, J=1.39, 8.11 Hz, 1H), 7.92 (d, J=8.11 Hz, 1H), 7.19 (d, J=8.24 Hz, 2H), 6.84-7.05 (m, 5H), 5.49 (s, 2H), 4.29-4.46 (m, 3H), 3.64-3.82 (m, 3H), 2.59-2.87 (m, 5H), 1.94-2.11 (m, 3H), 1.45-1.92 (m, 4H)

[0105] Prepare the following compounds according to the general procedure described above (Example 2.1). [ka] JPEG2026082810000067.jpg211160 JPEG2026082810000068.jpg104156

[0106] [Table 14] JPEG2026082810000070.jpg63165

[0107] [Table 15] JPEG2026082810000072.jpg230155 JPEG2026082810000073.jpg161155

[0108] Example 3 1-[4-(4-{[(6-{[6-(Difluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-yl)amino]methyl}-phenyl)piperazin-1-yl]ethan-1-one

Chem.

[0109] A mixture of 80.0 mg (0.22 mmol) of 3-{[6-(difluoromethyl)pyridin-3-yl]methoxy}-6-iodo-pyridazine (Example I.1), 61.7 mg (0.26 mmol) of 1-{4-[4-(aminomethyl)phenyl]piperazin-1-yl}ethan-1-one (Example III.5), 260 μL (0.66 mmol) of sodium tert-pentoxide (2.5 mol / L in methyl-THF), and 2.0 mg (2.20 μmol) of JOSIPHOS SL-J009-1 Pd G3 (MDL No. MFCD27978424) in 0.4 mL of tert-amyl alcohol is stirred at 35 °C overnight. The reaction mixture is diluted with ACN and DMF, filtered, and purified by preparative HPLC to give 12 mg of the product. C 24 H 26 F2N6O2 (M = 468.5 g / mol) ESI-MS: 469 [M+H] + R t (HPLC): 0.88 min (Method A) 1 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.39 Hz, 1H), 8.05 (dd, J = 1.90, 7.98 Hz, 1H), 7.71 (d, J = 7.98 Hz, 1H), 7.22 (d, J = 8.62 Hz, 2H), 6.97 - 7.12 (m, 1H), 6.83 - 6.97 (m, 5H), 5.44 (s, 2H), 4.37 (d, J = 5.58 Hz, 2H), 3.50 - 3.60 (m, 4H), 3.00 - 3.20 (m, 4H), 2.03 (s, 3H)

[0110] Example 4 1-[(3aR,8aS)-2-(4-{[(6-{[6-(Trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-yl)amino]methyl}phenyl)-decahydropyrrolo[3,4-d]azepin-6-yl]ethan-1-one

Chem.

[0111] 59.7 mg (0.27 mmol) of 1-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]ethan-1-one hydrochloride (Example XIII), 100.0 mg (0.23 mmol) of N-[(4-bromophenyl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]methoxy}pyridazin-3-amine (Example VIII), 17.7 mg (0.02 mmol) of the second-generation RuPhos precatalyst (2 nd generation Ruphos precatalyst) and 48.1 mg (0.50 mmol) of sodium tert-butoxide are dissolved in 1.00 mL of methyl-THF under an argon atmosphere. This solution is degassed several times. The reaction solution is stirred at 80 °C for 2 hours. Then another 481 mg (0.50 mmol) of sodium tert-butoxide is added and the reaction solution is stirred at 100 °C overnight. The reaction solution is filtered and purified by HPLC to obtain 14 mg of the product. C 28 H 31 F3N6O2 (M = 540.6 g / mol) ESI-MS: 541 [M+H] + R t (HPLC): 0.81 min (Method F) 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=1.27 Hz, 1H), 8.13 (dd, J=1.46, 8.05 Hz, 1H), 7.92 (d, J=7.98 Hz, 1H), 7.14 (d, J=8.49 Hz, 2H), 6.90-7.05 (m, 2H), 6.79 (t, J=5.64 Hz, 1H), 6.47 (d, J=8.62 Hz, 2H), 5.49 (s, 2H), 4.31 (d, J=5.58 Hz, 2H), 3.57-3.80 (m, 2H), 3.33-3.46 (m, 4H), 3.20-3.30 (m, 2H), 2.93 (td, J=6.23, 9.35 Hz, 2H), 2.00 (s, 3H), 1.53-1.89 (m, 4H)

[0112] Example 5 1-((3aR,3bS,6aR,6bS)-5-(4-(((6-((6-((trifluoromethyl)pyridine-3-yl)methoxy)pyridazin-3-yl)amino)methyl)phenyl)octahydrocyclobuta[1,2-c:3,4-c']dipyrrole-2(1H)-yl)ethane-1-one [ka]

[0113] Dissolve 15 mg (0.03 mmol) of N-(4-((3aR,3bS,6aR,6bS)-octahydrocyclobuta[1,2-c:3,4-c']dipyrrole-2(1H)-yl)benzyl)-6-((6-(trifluoromethyl)pyridine-3-yl)methoxy)pyridazine-3-amine (e.g., XIV) in 0.5 mL of DCM and add 2.86 μL (0.03 mmol) of acetic anhydride. Stir the reaction mixture at RT for 1 hour. Dilute the reaction solution with 0.5 mL of MeOH and purify by HPLC to obtain 7 mg of the product. C 28 H 29 F3N6O2 (M=538.564g / mol) ESI-MS:539 [M+H] + R t (HPLC): 0.99 points (Method A) 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.89 (d, J=1.14 Hz, 1H), 8.19 (dd, J=1.52, 8.11 Hz, 1H), 7.94 (d, J=8.24 Hz, 1H), 7.85 (d, J=9.50 Hz, 1H), 7.41 (d, J=9.38 Hz, 1H), 7.08 (d, J=8.49 Hz, 2H), 6.65 (d, J=8.62 Hz, 2H), 5.63 (s, 2H), 5.06 (s, 2H), 3.79 (d, J=12.17 Hz, 1H), 3.66 (d, J=11.15 Hz, 1H), 3.54 (dd, J=1.90, 9.89 Hz, 2H), 3.35 (br dd, J=6.78, 11.22 Hz, 2H), 3.06 (dd, J=6.84, 12.29 Hz, 1H), 2.82 (br dd, J=6.97, 9.51 Hz, 2H), 2.55-2.64 (m, 1H), 2.44-2.49 (m, 2H), 2.02-2.06 (m, 3H)

[0114] Analytical HPLC Method A JPEG2026082810000077.jpg43161 analysis カラム: XBridge C18 (Waters) 2.5μm; 3.0×30mm; カラム temperature: 60℃ Method B JPEG2026082810000078.jpg42161 analysis カラム:Stable Bond (Agilent) 1.8μm; 3.0×30mm; カラム temperature: 60℃ Method C JPEG2026082810000079.jpg38161 analysis カラム: XBridge (Waters) C18_3.0×30mm_2.5μm; カラム temperature: 60℃ Method D JPEG2026082810000080.jpg37162 Analysis column: XBridge C18_3.0×30mm_2.5μm (Waters); Column temperature: 60℃ Method E JPEG2026082810000081.jpg43161 Analysis column: Sunfire (Waters) 2.5μm; 3.0×30mm; Column temperature: 60℃ Method F JPEG2026082810000082.jpg38161 Analysis column: XBridge C18 (Waters) 2.5μm; 3.0×30mm; Column temperature: 60℃

Claims

1. The following formula (I) 【Chemistry 1】 (I) (In the formula, A is fluoro and F 1-7 -Fluoro-C 1-3 - A pyridyl substituted with one or two members of the alkyl group; E is fluoro and F 1-7 -Fluoro-C 1-3 - Selected from the group consisting of phenyl and pyridyl, which may be optionally substituted with one or two members of the group consisting of alkyl; K is based on the following 【Chemistry 2】 Selected from the group consisting of; R 3 is R 4 (O)C-, oxetanyl, methyl, R 5 (O)C(CH 3 )N- and R 5 selected from the group consisting of (O)CHN-; R 4 It is methyl; R 5 (It is methyl.) A compound of [this].

2. A is F, F 1-3 -Fluoro-C 1 A compound of formula (I) according to claim 1, which is a pyridyl substituted with one or two members of the group consisting of alkyl groups.

3. A is based on the following 【Transformation 3】 A compound of formula (I) according to claim 1, selected from the group consisting of the following.

4. E is F, F 2 HC and F 3 A compound of formula (I) according to any one of claims 1 to 3, selected from the group consisting of phenyl and pyridyl, which may be optionally substituted with one or two members of the group consisting of C.

5. E is based on the following 【Chemistry 4】 A compound of formula (I) according to any one of claims 1 to 3, selected from the group consisting of the following.

6. The following compounds: 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 A compound of formula (I) according to claim 1, selected from the group consisting of the following.

7. A pharmaceutical composition comprising at least one compound of formula (I) as described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

8. A compound of formula (I) according to any one of claims 1 to 7, for use as a pharmaceutical.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of inflammatory airway disease or fibrous disease.

10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of idiopathic lung disease (IPF) or systemic sclerosis (SSc).

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