Pyridazinylamino derivatives as ALK5 inhibitors

Abstract

The present invention relates to compounds of general formula (I) that inhibit transforming growth factor beta (TGF-β) type I receptor (ALK5), methods for producing such compounds, pharmaceutical compositions containing them and their therapeutic uses. The compounds of the present invention may be useful in the treatment of diseases or conditions associated with dysregulation of the ALK5 signaling pathway in mammals.

Description

[Technical field]

[0001] The present invention relates generally to compounds that inhibit the transforming growth factor beta (TGFβ) type 1 receptor (ALK5) (hereinafter ALK5 inhibitors), methods for making such compounds, pharmaceutical compositions containing them and their therapeutic uses; the compounds of the present invention may be useful, for example, in the treatment of a number of diseases, disorders or conditions associated with the ALK5 signaling pathway. [Background technology]

[0002] Transforming growth factor β (TGFβ) is a protein that belongs to the TGFβ superfamily.

[0003] TGFβ is involved in both cellular processes such as proliferation, migration and differentiation, as well as biological processes such as wound healing, immunosuppression, cancer development and extracellular matrix production.

[0004] The TGFβ superfamily also includes other members known, inter alia, as activins (Act) (see, e.g., Hinck AP, FEBS Letters 586 (2012); 1860-1870).

[0005] Binding of the peptide initiates the TGFβ signaling cascade through the formation of a heterotetrameric complex consisting of two distinct serine / threonine kinase receptors: type 1 (TGFβR1 / ALK5) and type 2 (TGFβR2).

[0006] TGFβR1 / ALK5 is recruited and activated by phosphorylation of its intracellular domain by TGFβR2, which in turn phosphorylates the receptor-activated (R)-Smad family, activating the transcription of target genes (e.g., Sheppard D., Proc Am Thorac Soc. (2006);(3):413-417).

[0007] Similar to TGFβ signaling, the type I receptor for activin, ALK4, leads to activation of target gene transcription (e.g., Heldin CH et al., Cold Spring Harb Perspect Biol. (2016) Aug 1;8(8)).

[0008] Several studies have linked excessive and / or dysregulated TGFβ activity to many diseases, including cancer and fibrosis (see, e.g., Syed V, J Cell Biochem. (2016) Jun;117(6):1279-87; Jakowlew SB. Cancer Metastasis Rev. (2006) Sep;25(3):435-57). Among fibrotic disorders, a key role for TGFβ has been shown in organs such as the lung, heart, liver and kidney (see, e.g., Alhamad EH, J Thorac Dis. (2015);7(3):386-93). In particular, TGFβ expression is increased in fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), and in chronic inflammatory conditions such as chronic obstructive pulmonary disease and asthma (see, e.g., Thomas BJ et al., Am J Respir Cell Mol Biol. (2016);(55):759-766).

[0009] In the lung, TGFβ is expressed in several cell types such as epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts.

[0010] These cell populations may produce excess TGFβ in IPF human lung tissue. Moreover, high levels of TGFβ have been detected in lung tissue and BAL of IPF patients (e.g., homas BJ et al., Am J Respir Cell Mol Biol. (2016);(55):759-766).

[0011] Increased TGFβ gene expression and TGFβ protein production have been observed in various animal models of pulmonary fibrosis induced by bleomycin, silica, asbestos, and radiation (see, e.g., Wei F et al., Int Immunopharmacol. (2017) Jul;48:67-75; Choe JY et al., Inflamm Res. (2010) Mar;59(3):177-88; Wang X et al., Respir Res (2009);10, 36), and have reported that TGFβ expression is sufficient to induce progressive fibrosis in rodents (see, e.g., Sime PJ et al., J Clin Invest (1997);100:768-776; Kim KK et al.).

[0012] In contrast, inhibition of TGFβ signaling achieved by using knockout (KO) animals can inhibit the development of fibrosis through TGFβ-related mechanisms (see, e.g., Bonniaud P et al., Am J Respir Crit Care Med (2005);171:889-898; 34).

[0013] Similar results have been achieved using TGFβR1 inhibition in a mouse bleomycin disease model (see, e.g., Wei Y et al., J Clin Invest. (2017);127(10):3675-3688).

[0014] Similar to TGFβ, dysregulated activin signaling is associated with fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) accumulation (see, e.g., Yamashita et al., J. Am. Soc. Nephrol. (2004) 15, 91-101). Additionally, overexpression of activin has been associated with the development of pathology and fibrosis in various organs, such as the liver (see, e.g., Patella et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2006) 290, G137-G144), kidney (see, e.g., Agapova et al., Kidney Int. (2016) 89, 1231-1243), heart (see, e.g., Yndestad et al., Circulation (2004) 109,1379-1385), and lung (see, e.g., de Kretser et al., Crit.Care (2013) 17:R263).

[0015] Taken together, these data suggest the importance of targeting ALK5 for the pharmacological treatment of said diseases associated with a dysregulated TGF signaling pathway.

[0016] TGFβ signaling is heavily involved in cardiovascular homeostasis (e.g., van Meeteren LA et al., Springer (2013)). Several studies in humans and mice have shown a major role for TGFβ in angiogenesis and vascular morphogenesis. In addition, TGFβ plays a key role in cardiac valve development and function. Thus, the importance of selective modulation of the TGFβ pathway to target pathological effects while avoiding the suppression of signaling required for normal homeostasis is clear.

[0017] The answer to this important question may be posed by using the inhaled route to deliver anti-TGFβ drugs.

[0018] The inhalation route may allow treatment of the affected lung compartment while circumventing the problem of cardiac exposure.

[0019] A wide variety of compounds have been described in the literature as ALK5 and / or ALK4 receptor inhibitors.

[0020] Although pyridazinylamino derivatives have been disclosed in the literature, they have not been disclosed as ALK5 inhibitors.

[0021] Among other compounds, WO 2005 / 033105 (Amgen) discloses pyridazinylamino derivatives as vanilloid receptor ligands for the treatment of a number of diseases and disorders not involving fibrosis.

[0022] WO 2002 / 022605 and WO 2002 / 022602 (Vertex) describe pyridazine compounds as protein kinase inhibitors useful, inter alia, for the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia.

[0023] WO 02 / 24681 (Ortho-McNeil Pharmaceutical Inc.) describes pyridazine compounds as antitumor agents and as tyrosine kinase inhibitors useful for treating diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.

[0024] In particular, inhibition of the ALK5 receptor may be useful in the treatment of fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0025] Several efforts have been made in the past few years to develop novel ALK5 receptor inhibitors useful for the treatment of several diseases, and some of these compounds have been shown to be effective in humans.

[0026] However, there remains the possibility of developing receptor ALK5 inhibitors that are characterized by good efficacy and are useful for the treatment of diseases or conditions associated with dysregulation of the ALK5 signaling pathway, in particular fibrosis.

[0027] In particular, there remains the possibility of developing receptor ALK5 inhibitors useful for the treatment of diseases or conditions associated with dysregulation of ALK5 signaling in the respiratory area, in particular idiopathic pulmonary fibrosis (IPF), administered by the inhaled route and characterized by a good inhalation profile corresponding to good pulmonary activity, good lung retention and low metabolic stability to minimize systemic exposure and associated safety issues.

[0028] To this end, we have surprisingly discovered a new series of compounds of general formula (I) that solve the problem of providing potent ALK5 receptor inhibitors for inhaled administration, while at the same time exhibiting a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability, and good kinome-wide selectivity. Summary of the Invention

[0029] In a first aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony, R1 is aryl optionally substituted with one or more halogen atoms; R2 is selected from the group consisting of -NR3C(O)R4 and -NH2; R3 is H or -(C1-C6)alkyl; R4 is selected from the group consisting of -(C1-C6)alkylene-(C4-C6)heterocycloalkyl, where the heterocycloalkyl is substituted with one or more -(C1-C6)alkyl; -(C3-C6)cycloalkyl, optionally substituted with one or more -(C4-C6)heterocycloalkyl, where the -(C4-C6)heterocycloalkyl is substituted with one or more -(C1-C6)alkyl; R5 is -C(O)O-(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -(C4-C6)heterocycloalkyl optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0030] In a second aspect, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in admixture with one or more pharma- ceutically acceptable carriers or excipients.

[0031] In a third aspect, the invention refers to a compound of formula (I) or a pharma- ceutically acceptable salt, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt, for use as a medicament.

[0032] In a further aspect, the invention refers to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of a disease, disorder or condition mediated by the ALK5 receptor in a mammal.

[0033] In a further aspect, the invention refers to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0034] In a further aspect, the invention refers to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0035] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention also include stereoisomers or pharma- ceutically acceptable salts or solvates thereof.

[0036] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If) and formula (Ig).

[0037] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) where the parent compound is suitably modified by converting any free acidic or basic groups, if any, into the corresponding addition salts with any base or acid that are conventionally contemplated as pharmaceutically acceptable.

[0038] Thus, suitable examples of such salts include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acidic residues such as carboxyl groups.

[0039] Inorganic bases which may be suitable for use in preparing salts include alkali metal or alkaline earth metal ions, such as potassium, sodium, calcium or magnesium.

[0040] Those obtained by reacting the main compound, which functions as a base, with an inorganic or organic acid to form salts include hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, camphorsulfonate, acetate, oxalate, maleate, fumarate, succinate and citrate salts.

[0041] The term "solvate" refers to a physical association of one or more organic or inorganic solvent molecules with the compound of the present invention. This physical association includes hydrogen bonds. In certain cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate can contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0042] The term "stereoisomers" refers to isomers of identical structure that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0043] The term "enantiomers" refers to a pair of molecular species that are mirror images of each other and are non-superimposable.

[0044] The term "diastereomers" refers to stereoisomers that are not mirror images.

[0045] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomers, which composition is devoid of optical activity.

[0046] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are intended to be used as described herein and as defined in the literature to indicate atomic configurations relative to a core molecule (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0047] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine and iodine atoms.

[0048] The term "(C x -C y ")Alkyl" refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, for example, when x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

[0049] The term "(C x -C y) alkylene" refers to a C alkylene group having a total of two unsatisfied valences, such as a divalent methylene group. x -C y This refers to an alkyl group.

[0050] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 ring atoms, in which the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0051] The term "(C x -C y "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic (C) heterocycloalkyl in which at least one carbon atom is replaced with at least one heteroatom (e.g., N, S, S(O)2, or O) or may have an -oxo (=O) substituent. x -C y ) cycloalkyl groups. Examples of suitable heterocycloalkyl groups include piperidinyl, azetidinyl, thietanyl, thianyl, oxetanyl and tetrahydropyranyl.

[0052] A dash ("-") that is not between two letters or symbols represents a point of attachment for a substituent.

[0053] Carbonyl groups are preferably represented herein as -C(O)-, instead of other common representations such as -CO-, -(CO)- or -C(=O)-.

[0054] The present invention relates to novel compounds that differ from structures disclosed in the art at least with respect to a common new core structure. Indeed, the present invention relates to compounds that are [pyridazin-4-yl]amino derivatives, which are promising receptor ALK5 inhibitors with therapeutically desirable properties, especially against several fibrotic diseases, including idiopathic pulmonary fibrosis (IPF).

[0055] The compounds of the present invention are active and potent as ALK5 receptor inhibitors and exhibit improved properties such as a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability, and good selectivity across the kinome.

[0056] In this respect, the pyridazinylamino derivatives of general formula (I) according to the invention having inhibitory activity towards the ALK5 receptor, which represent a solution to the abovementioned need, have neither been described nor suggested in the art.

[0057] Among other compounds, pyridazinylamino derivatives are disclosed by Amgen. The compound of formula (I) of the present invention differs from the compound of Amgen at least in the substituents on rings A1, A2 and A3. Amgen discloses compounds as vanilloid receptor ligands for treating a number of diseases and disorders. Amgen does not disclose compounds as ALK5 inhibitors, nor compounds for treating fibrosis.

[0058] Among others, pyridazine derivatives are disclosed by Vertex. The compounds of formula (I) of the present invention differ from the compounds of Vertex at least in the presence of a pyridyl or pyridyl-fused group attached to an amino linker having a pyridazine ring, instead of a triazole group. The compounds of Vertex are described as protein kinase inhibitors useful for the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia. Vertex does not disclose compounds as ALK5 inhibitors, nor for the treatment of fibrosis.

[0059] Pyridazine compounds are described by Ortho-McNeil. The compounds of formula (I) of the present invention differ from Ortho-McNeil's compounds by at least two nitrogen atoms in the pyridazine ring. Ortho-McNeil's compounds are described as tyrosine kinase inhibitors useful as antitumor agents, for treating diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis. Ortho-McNeil does not disclose compounds as ALK5 inhibitors, nor compounds for treating fibrosis.

[0060] More specifically, the present invention refers to a series of compounds represented by general formula (I), which have inhibitory activity against the receptor ALK5, as described in detail herein below.

[0061] Advantageously, inhibitory effects on the ALK5 receptor may be effective in treating those diseases in which the receptor plays a relevant role in diseases such as fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0062] Unlike similar compounds of the prior art, the compounds of formula (I) of the present invention can act as antagonists of the ALK5 receptor, which will be particularly appreciated by those skilled in the art when focusing on suitable and effective compounds useful for the treatment of fibrosis, particularly idiopathic pulmonary fibrosis.

[0063] As shown in the experimental section, particularly in Table 2, the compound of formula (I) of the present invention exhibits remarkable efficacy in inhibitory activity against the receptor ALK5, and has a pKi value of more than 8.5 when tested in a biochemical ALK5 assay, confirming that it can inhibit the ALK5 receptor involved in fibrosis and diseases resulting from fibrosis.

[0064] Advantageously, the compounds of the present invention have extremely high efficacy and can be administered in humans at low dosages relative to prior art compounds, thereby reducing adverse events that typically occur with the administration of high doses of drugs.

[0065] In addition to being remarkably potent in terms of inhibitory activity against the ALK5 receptor, the compounds of the present invention are also characterized by a favorable profile that allows them to act effectively on the pulmonary compartment, while at the same time having low metabolic stability that allows minimizing drawbacks associated with systemic exposure, such as safety and tolerability issues.

[0066] Furthermore, as shown in the experimental section, the comparative examples and in particular in Table 2, it is shown that the presence of a pyridinyl group in the compounds of the present invention, in contrast to compound C1, which is characterized by having a benzothiazolyl instead of a pyridinyl group, unexpectedly and significantly determines the associated increase in inhibitory activity against the ALK5 receptor.

[0067] Thus, the compounds of the present invention will be particularly appreciated by those skilled in the art when looking at suitable and effective compounds useful for the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, and are administered by the inhalation route and are characterized by a good inhibitory profile corresponding to good pulmonary activity, pulmonary retention and low metabolic stability, minimizing systemic exposure and associated safety issues.

[0068] Thus, in one embodiment, the present invention provides a compound of general formula (I): [ka] [During the ceremony, R1 is aryl optionally substituted with one or more halogen atoms; R2 is selected from the group consisting of -NR3C(O)R4 and -NH2; R3 is H or -(C1-C6)alkyl; R4 is selected from the group consisting of -(C1-C6)alkylene-(C4-C6)heterocycloalkyl, where the heterocycloalkyl is substituted with one or more -(C1-C6)alkyl; -(C3-C6)cycloalkyl, optionally substituted with one or more -(C4-C6)heterocycloalkyl, where the -(C4-C6)heterocycloalkyl is substituted with one or more -(C1-C6)alkyl; R5 is -C(O)O-(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -(C4-C6)heterocycloalkyl optionally substituted with one or more groups selected from -C(O)-(C1-C6)alkyl, oxo, and -(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0069] In a more preferred embodiment, the present invention refers to a compound of formula (I) wherein R1 is phenyl substituted with fluorine and chlorine.

[0070] In another preferred embodiment, the present invention refers to a compound of formula (I) wherein R4 is -(4-methylpiperazin-1-yl)ethyl.

[0071] In another preferred embodiment, the present invention relates to a compound in which R5 is tert-butyl (1,2,3,6-tetrahydropyridine-1-carboxylate), tert-butyl piperidine-1-carboxylate, -(1,2,3,6-tetrahydropyridin-4-yl), -(piperidin-4-yl), methyl (1,2,3,6-tetrahydropyridine-1-carboxylate), N-methyl-1,2,3,6-tetrahydropyridin-4-yl, methyl piperidine-1-carboxylate, -(1-methylpiperidin-4-yl), tert-butyl 3-(azetidine-1-carboxylate), -(azetidin-3-yl), -(1-methyl-5-oxopyrrolidin-2-yl), -(oxetan-2-yl), -(oxetan-3-yl), -(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl), -(azetidin-2-yl), tert-butyl 2-(azetidine-1-carboxylate), -(5-oxotetrahydrothiophen-2-yl), tert-butyl -(2,2-dimethyloxazolidine-3-carboxylate), -(tetrahydrofuran-3-yl), -(tetrahydrothiophen-2-yl) and -(1-methyl-5-oxopyrrolidin-3-yl).

[0072] According to a preferred embodiment, the present invention refers to at least one of the compounds of formula (I) and pharma- ceutically acceptable salts thereof listed in Table 1 below. As shown in Table 2, these compounds are particularly active against the ALK5 receptor. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0073] In a further preferred embodiment, the present invention relates to 1 is aryl optionally substituted with one fluorine and one chlorine, and R5 is selected from the group consisting of -(oxetan-2-yl) and -(tetrahydrothiophen-2-yl).

[0074] The compounds of the present invention, including all of the compounds described above, can be prepared from readily available starting materials using the following general synthetic methods and procedures, or by using minor modifications readily available to one of ordinary skill in the art. Although specific embodiments of the present invention may be illustrated or described herein, one of ordinary skill in the art will recognize that all embodiments or aspects of the present invention may be obtained using the methods described herein, or using other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0075] Therefore, the following processes should not be construed as limiting the scope of synthetic methods available for producing the compounds of the present invention.

[0076] In some cases where steps are necessary to mask or protect sensitive or reactive moieties, commonly known protecting groups (PG) can be utilized, following general principles of chemistry (Protective groups in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0077] The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit the receptor ALK5. Advantageously, inhibition of ALK5 can result in the efficient treatment of diseases or conditions in which the ALK5 receptor is involved.

[0078] In this respect, the compounds of formula (I) of the present invention now have pIC 50 (I C 50 is expressed as the negative logarithm of the half-minimal inhibitory final concentration (P<0.01), followed by pK i (Dissociation function K iIt has been found that the inhibitory drug effect, converted to the negative logarithm of pK (negative logarithm of pK), is 8.5 or more against ALK5. Preferably, the compounds of the present invention have a pK of 8.5 to 9.0, more preferably 9.1 to 9.9. i has.

[0079] In one embodiment, the present invention refers to the compound of formula (I) or a pharma- ceutical acceptable salt for use as a medicament.Thus, the present invention preferably refers to the compound of formula (I) in the manufacture of a medicament for use in the prevention and / or treatment of diseases, disorders or conditions associated with the ALK5 signaling pathway.

[0080] In a preferred embodiment, the invention refers to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis and / or treatment of a disease, disorder or condition associated with the ALK5 signaling pathway.

[0081] In certain embodiments, the present invention refers to compounds of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0082] As used herein, the term "fibrosis" or "fibrotic disorder" refers to conditions associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including, but not limited to, fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0083] Preferably, the compounds of formula (I) of the present invention or pharmaceutical compositions comprising the compounds of formula (I) are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0084] More preferably, the compounds of formula (I) of the present invention, or pharmaceutical compositions comprising compounds of formula (I), are useful for the treatment of idiopathic pulmonary fibrosis (IPF).

[0085] As used herein, a "safe and effective amount" of a compound of formula (I) or a pharma- ceutically acceptable salt thereof or other pharma- ceutically active agent means an amount sufficient to treat the patient's condition but low enough to avoid serious side effects, which can be routinely determined by one of ordinary skill in the art.

[0086] The compounds of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at various time intervals over a given period of time. The typical daily dosage may vary depending on the route of administration selected.

[0087] The present invention also refers to pharmaceutical compositions comprising at least a compound of formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients.

[0088] In certain embodiments, the present invention refers to a pharmaceutical composition comprising a compound of Formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients, e.g., those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0089] The administration of the compounds of the present invention and their pharmaceutical compositions can be, for example, administered orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation, depending on the needs of the patient.Preferably, the compounds of the present invention are administered orally or by inhalation.More preferably, the compounds of the present invention are administered by inhalation.

[0090] In a preferred embodiment, the pharmaceutical compositions comprising the compounds of formula (I) are solid oral dosage forms such as tablets, gel capsules, capsules, caplets, granules, lozenges and bulk powders.

[0091] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0092] The compounds of the present invention may be administered alone or in combination with known excipients, including various pharma- ceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.) and suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, colorants, flavoring agents, lubricants, and the like.

[0093] In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as aqueous and non-aqueous solutions, emulsions and suspensions.Such liquid dosage forms may also contain suitable known inert diluents, such as water, and suitable known excipients, such as preservatives, wetting agents, sweeteners, flavoring agents and agents for emulsifying and / or suspending the compound of the present invention.

[0094] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered dose aerosol or a propellant-free inhalable formulation.

[0095] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0096] A diluent or carrier which is inert to the compound of the present invention, such as lactose or other additives suitable for improving the inhalation fraction, may be added to the powdered compound of the present invention.

[0097] Inhalation aerosols containing a propellant gas such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and optionally other excipients.

[0098] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles, which may be delivered by jet or ultrasonic nebulizers or by soft mist nebulizers as known in the prior art.

[0099] The compounds of the invention may be administered as the sole active agent or in combination with other pharma- ceutical active ingredients.

[0100] The dosage of the compounds of the present invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, and the like, among others.

[0101] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention in the form of a single or multiple dose dry powder inhaler or a metered dose inhaler.

[0102] All preferred groups or embodiments described above for the compounds of formula (I) may be applied mutatis mutandis in combination with one another.

[0103] Various aspects of the invention described herein are illustrated by the following examples, which are not meant to limit the invention in any way.

[0104] The compounds of formula (I) and formulas (Ia-f), including all or at least one of the compounds listed above, may generally be prepared using commonly known methods, as detailed in the schemes set out below. [ka]

[0105] Scheme 1 provides a potential synthetic route for the preparation of compounds of formula (I) where R5 is a 6-membered heterocycloalkyl substituted with -C(O)O-(C1-C6)alkyl.

[0106] The commercially available compound (II) can be reacted with a suitable boronic acid or ester under metal catalyzed cross-coupling conditions to give compound (III). A typical cross-coupling reaction can be a Suzuki coupling or a similar reaction described in "Transition Metals for 15 Organic Synthesis", 2nd Ed, 1, 2004. A typical Suzuki reaction condition includes a base such as tripotassium phosphate, sodium carbonate, a palladium catalyst such as Pd(dppf)Cl2, and a suitable solvent mixture such as 1,2-dimethoxyethane and water. Typically, the reaction is carried out under conventional heating at a suitable temperature, such as 100°C. Compound (III) can be converted to compound (IV) by a further cross-coupling reaction, such as a Suzuki cross-coupling reaction, in the presence of a typical Pd catalyst, using a suitable R1-boronic acid / ester derivative as described above. Compound (IV) can then be subjected to a Buchwald-Hartwig cross-coupling reaction to give a compound of formula (I). Typical Buchwald-Hartwig conditions consist of reacting compound (IV) with a suitable halide in the presence of a Pd catalyst such as Pd2(dba)3 or Pd(OAc)2, a suitable base such as cesium carbonate, a suitable ligand such as Xantphos, in a suitable solvent such as 1,2-dimethoxyethane at a suitable temperature, for example 100°C.

[0107] When R5 is selected from the group consisting of -C(O)-(C1-C6)alkyl or 6-membered heterocycloalkyl optionally substituted with -(C1-C6)alkyl, the compounds of formula (I) can be obtained by further chemical modification of the R5 group as shown in Scheme 1A. The nitrogen atom of the heterocycloalkyl in the compounds of formula (Ia)-(If) can be in the meta or para position relative to the pyridazine ring. [ka]

[0108] R under acidic conditions, e.g., a solution of TFA in DCM, at room temperature 5Deprotection of compound (Ia), a compound of formula (I) where R5 is a 6-membered partially saturated heterocycloalkyl substituted with -C(O)O-(C1-C6)alkyl, such as Boc, can give a compound of formula (Ib) where R5 is a 6-membered partially saturated heterocycloalkyl. The secondary amino group can be further functionalized to give a compound of formula (Ic), a compound of formula (I) where R5 is a 6-membered partially saturated heterocycloalkyl substituted with R, where R is -C(O)-(C1-C6)alkyl or -(C1-C6)alkyl. N-functionalization can include acylation with a suitable acylating agent, such as acetic anhydride or a suitable chloroformate, in the presence of an organic base, such as triethylamine, in a suitable solvent, for example DCM. Alternatively, introduction of a substituent consisting of -(C1-C6)alkyl can be achieved by reductive amination. Typical reaction conditions involve the use of an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride in a suitable solvent such as methanol.

[0109] In another embodiment, the compound of formula (Id), which is a compound of formula (I) where R5 is a 6-membered saturated heterocycloalkyl substituted with -C(O)O-(C1-C6)alkyl, such as Boc, can be obtained by carbon-carbon bond reduction with compound (Ia) and a suitable reducing agent, such as H2, in the presence of a Pd catalyst, such as Pd on carbon poisoned with diphenylsulfide, in a suitable solvent, such as EtOH, at a suitable temperature, such as room temperature. The compound of formula (Id) can be subjected to a similar series of chemical transformations as described above to give the compound of formula (Ie) or (If), where R5 is a 6-membered saturated heterocycloalkyl optionally substituted with R, where R is -C(O)-(C1-C6)alkyl or -(C1-C6)alkyl, respectively.

[0110] In another embodiment, the compound of formula (I) represented by formula (Ig), wherein R5 is a 4- or 5-membered heterocycloalkyl optionally substituted with one or more groups selected from -C(O)O-(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, oxo, and -(C1-C6)alkyl, can be prepared as shown in Scheme 2. [ka]

[0111] Compound (VI) can be obtained in two steps starting from commercially available 4-amino-6-chloropyridazine (V). Protection of the amino group with a suitable moiety such as di-tert-butyl dicarbonate in an aprotic non-polar solvent such as DCM using typical conditions including a suitable base such as diisopropylethylamine, triethylamine, followed by Suzuki cross-coupling reaction with a suitable R1-boronic acid / ester derivative under typical conditions as described above can give compound (VI). Acid-catalyzed cleavage of the protecting group can give compound (VII), which can be subjected to Buchwald-Hartwig cross-coupling amination to give compound (VIII). Representative amination conditions are as described above for Schemes 1 and 1A. According to route A of scheme 2, compound (VIII) can serve as a substrate for a Miniskii-like reaction that efficiently leads to compounds of formula (I), where R5 is a 4- or 5-membered heterocycloalkyl, optionally substituted with one or more groups selected from -C(O)O-(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, oxo and -(C1-C6)alkyl. Typical Miniskii-like conditions include redox-active esters (RAEs), which can be obtained by coupling a suitable group, such as N-hydroxyphthalimide, with a carboxylic acid of a commercially available 4- or 5-membered heterocycloalkyl group. These RAE intermediates can react with compound (VIII) in a suitable solvent, such as DMSO, under irradiation conditions with a suitable LED lamp, typically a blue LED lamp, in the presence of a suitable photocatalyst, such as 4CZIPN, to give compounds of formula (I), as described in the literature (Dhar and coworkers, J. Org. Chem. 2018, 83, 3000-3012).

[0112] In another embodiment, the compound of formula (I) can be prepared according to Route B of Scheme 2. Compound (VII) can first be subjected to a Miniski-like reaction under conditions described above to give compound (IX), which can then be subjected to the previously described Buchwald-Hartwig amination to give compound of formula (I).

[0113] Various aspects of the invention described herein are illustrated by the following examples, which are not meant to limit the invention in any way.

[0114] Preparation of intermediates and example compounds Chemical names of compounds were generated using Structure To Name Marvin Sketch Gallium.2 version 20.19.2.

[0115] All reagents whose synthesis is not described in the experimental section are either commercially available or are known compounds or can be formed from known compounds by known methods by those skilled in the art.

[0116] Abbreviation-Meaning Boc = tert-butyloxycarbonyl; (Boc)2O = di-tert-butyl dicarbonate; cHex = cyclohexane; CSA = camphorsulfonic acid; Cs2CO3 = cesium carbonate; Cz4IPN = 2,4,5,6-tetrakis(carbazol-9-yl)-1,3-dicyanobenzene; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; h = hours; hrs = hours; H2 = hydrogen; H2O = water; K2CO3 = potassium carbonate; K3PO4 = tripotassium phosphate; LC-MS = liquid chromatography / mass spectrometry; MeCN = acetonitrile; MeOH = methanol; N = nitrogen; NaSO = sodium sulfate; NaHCO = sodium bicarbonate; NH = ammonia; Pd / C = palladium on carbon; Pd(dppf)Cl = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)ClDCM = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex; Pd(OAc) = palladium(II) acetate; RT = room temperature; SCX = strong cation exchange; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0117] General Experimental Details and Methods Analysis method Instruments, materials and methods used in the analysis 1H-NMR spectra were performed on a Varian MR-400 spectrometer or an Agilent VNMRS-500 or a Bruker Avance 400 operating at 400 MHz (proton frequency) equipped with a self-shielded Z-gradient coil 5 mm 1H / nX broadband probe head for inverse detection, a deuterium digital lock channel unit, a quadrature digital detection unit with frequency shift cancellation transmitter, or on an Agilent Inova 600 operating at 600 MHz equipped with a 5 mm PFG pentaprobe spectrometer. Chemical shifts are reported as 6 values ​​in ppm relative to trimethylsilane (TMS) as the internal standard. Coupling constants (J values) are given in Hertz (Hz) and multiplicities are indicated using the following abbreviations (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, brs=broad singlet, brd=broad doublet, brt=broad triplet, brdd=broad double doublet, nd=undetermined, dd=doublet of doublet, dt=triplet of triplet, ddd=double doublet, quin=quintuplet, td=triplet doublet).

[0118] LC / UV / MS analysis method LC / MS retention times are expected to be affected by an experimental error of +0.5 min. LCMS may be recorded under the following conditions: Diode array DAD chromatographic traces, mass chromatograms and mass spectra may be acquired on a UPLC / PDA / MS Acquity TM system coupled to a Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operating in positive and / or negative electrospray ES ionization mode, and / or a Fractionlynx system used in analytical mode coupled to a ZQTM single quadrupole operating in positive and / or negative electrospray ES ionization mode. Quality control methods may be used and operated under low or high pH conditions.

[0119] Method 1, low pH condition Column: Acquity CSH C18 2.1×50 mm 1.7 um, column temperature was 40° C.; mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B was MeCN + 0.1% HCOOH. Flow rate was 1 mL / min. The gradient table was t=0 min 97% A 3% B, t=1.5 min 0.1% A 99.9% B, t=1.9 min 0.1% A 99.9% B and t=2 min 97% A 3% B. The UV detection range was 210-350 nm and the ES+ / ES- range was 100-1500 AMU.

[0120] Method 2, high pH condition: Column: Acquity Kinetex 1.7 μm EVO C18 100A, 2.1 × 50 mm, column temperature was 40 °C; mobile phase solvent A was 10 mM NH4HCO3 aqueous solution adjusted to pH = 10 with ammonia, and mobile phase solvent B was MeCN. Flow rate was 1 mL / min. Gradient table was t = 0 min 97% A 3% B, t = 1.5 min 0.1% A 99.9% B, t = 1.9 min 0.1% A 99.9% B and t = 2 min 97% A 3% B. UV detection range was 210-350 nm, ES+ / ES- range was 100-1500 AMU.

[0121] Method 3, high pH condition: Column: Acquity Kinetex 1.7 μm EVO C18 100A, 2.1×50 mm, column temperature was 40° C.; solvent A was 10 mM NH4HCO3 aqueous solution adjusted to pH=10 with ammonia, mobile phase solvent B was MeCN. Flow rate was 0.9 mL / min. Gradient table was t=0 min 97% A 3% B, t=1.4 min 0.1% A 99.9% B, t=1.9 min 0.1% A 99.9% B and t=2 min 97% A 3% B. UV detection range was 210-350 nm, ES+ / ES- range was 100-1000 AMU.

[0122] Preparation of intermediates Intermediate 1:N-(4-bromopyridin-2-yl)prop-2-enamide [ka] A mixture of 4-bromo-2-pyridinamine (5.10 g, 29.48 mmol) and TEA (12.1 mL, 88.43 mmol) in dry DCM (130 mL) was stirred under N2 at 0 °C, then acryloyl chloride (3.12 mL, 32.43 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 1 h. H2O was added, the organic solution was separated, washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex ~ 25% EtOAc) to give the title compound (4.8 g, 22.1 mmol, 72% yield). LC-MS (ESI): m / z (M+1): 226.9 (Method 1).

[0123] Intermediate 2: N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propenamide [ka] N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 1, 2.50 g, 11 mmol) was dissolved in THF (12 mL), 1-methylpiperazine (1.83 mL, 16.52 mmol) was added and the reaction solution was stirred at 70° C. for 3 h. The volatiles were removed in vacuo and the residue was purified by flash chromatography on a Biotage silica NH cartridge (cHex~30% EtOAc) to give the title compound (3.5 g, 10.7 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 327.2 (Method 2).

[0124] Intermediate 3: tert-Butyl 4-(4-amino-6-chloropyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] In a round bottom flask, 3,6-dichloropyridazin-4-amine (1.5 g, 9.15 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (3.11 g, 10.06 mmol), Pd(dppf)Cl2·DCM (749 mg, 0.91 mmol) and K3PO4 (4.92 g, 22.87 mmol) were suspended in 1,2-dimethoxyethane (90 mL) / H2O (30 mL). The mixture was degassed (N2 / vacuum) and then stirred at 100 °C for 1.5 h. The mixture was diluted with EtOAc, filtered through a Celite® pad and washed with EtOAc. The organic phase was washed with brine, separated, dried and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~60% EtOAc) to give the title compound (2.41 g, 7.76 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 311.2 (Method 2).

[0125] Intermediate 4: tert-Butyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] In a round bottom flask, a mixture of tert-butyl 4-(4-amino-6-chloropyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (Intermediate 3, 1.27 g, 4.10 mmol), 5-chloro-2-fluorobenzeneboronic acid (1.07 g, 6.15 mmol), K2CO3 (1.7 g, 12.3 mmol) and Pd(dppf)Cl2 (600 mg, 0.82 mmol) in 1,2-dimethoxyethane (14.8 mL) and H2O (1.6 mL) was degassed (vacuum / N2) and then stirred at 100 °C for 90 min. The mixture was diluted with EtOAc, filtered through a Celite® pad and washed with EtOAc. The organic phase was washed with brine, separated, dried and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~60% EtOAc) to give the title compound (990 mg, 2.44 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 405.1 (Method 1).

[0126] Intermediate 5: tert-Butyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (Intermediate 4, 600 mg, 1.48 mmol) in EtOH (24.7 mL) was added diphenyl sulfide, 1% EtOH solution (248 μL, 0.01 mmol) [prepared by diluting 3 μL of diphenyl sulfide with 300 μL of EtOH], and 10% Pd / C (158 mg, 0.15 mmol). The reaction was stirred under H2 atmosphere for 16 hours. Further diphenyl sulfide, 1% EtOH solution (248 μL, 0.01 mmol), 10% Pd / C (158 mg, 0.15 mmol) were added again, and the reaction was stirred under H2 atmosphere for 6 hours. The reaction was diluted with EtOH, filtered through a pad of Celite® and washed with EtOH. The filtrate was evaporated under vacuum and the crude material was purified by preparative HPLC (normal phase) to give the title compound (506 mg, 1.24 mmol, 83% yield). LC-MS (ESI): m / z (M+1): 407.2 (Method 1).

[0127] Intermediate 6 : tert-Butyl N-(6-chloropyridazin-4-yl)carbamate [ka] To a solution of 6-chloropyridazin-4-amine (3 g, 23.16 mmol) in dry DMA (10 mL), (Boc)2O (10.75 mL, 46.3 mmol) was added DMAP (0.283 g, 2.316 mmol) and DIPEA (4.04 mL, 23.16 mmol) and the reaction was stirred at 50 °C for 12 h. The solvent was removed and the residue was diluted in DCM (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The two phases were separated, the organic layer was dried through a phase separation cartridge and the solvent was removed under reduced pressure. The crude was purified by silica gel flash chromatography (heptane to 40% EtOAc) to give the title compound (3.23 g, 14.06 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 230.14 (Method 1).

[0128] Intermediate 7 tert-Butyl N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]carbamate [ka] To a solution of tert-butyl N-(6-chloropyridazin-4-yl)carbamate (Intermediate 6, 2 g, 8.71 mmol) in 1,4-dioxane (10 mL), water (2 mL) was added PdCl2(dppf) (1.274 g, 1.742 mmol), K2CO3 (2.407 g, 17.42 mmol) and (5-chloro-2-fluorophenyl)boronic acid (2.278 g, 13.06 mmol) and the reaction was stirred at 110 °C for 18 h. Afterwards, 1,4-dioxane was removed under reduced pressure and the residue was diluted with DCM and saturated aqueous NaHCO3 (20 mL) was added. The two phases were separated and the aqueous layer was extracted with DCM. The combined organics were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude was purified by silica gel flash chromatography (heptane to 40% EtOAc) to give the title compound (1.5 g, 4.63 mmol, 53% yield). LC-MS (ESI): m / z (M+1): 324.12 (Method 1).

[0129] Intermediate 8 : 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] To a solution of tert-butyl (6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)carbamate (Intermediate 7, 2 g, 6.18 mmol) in MeOH (10 mL) was added 6N HCl in isopropanol (10.30 mL, 61.8 mmol) and the reaction was stirred at 50° C. for 3 h. The solvent was removed and purified by SCX cartridge eluting with 7N NH3MeOH solution to give the title compound (1.1 g, 4.92 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 224.14 (Method 1).

[0130] Intermediate 9 :1-tert-Butyl 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)azetidine-1,3-dicarboxylate [ka] To a solution of Boc-azetidine-3-carboxylic acid (0.5 g, 2.485 mmol) in dry DMSO (10 mL) was added N-hydroxyphthalimide (0.509 mL, 2.73 mmol) and N,N'-diisopropylcarbodiimide (0.345 g, 2.73 mmol), and the solution was stirred for 1 h to give the title compound as a 0.25 M solution in DMSO (861 mg, 2.486 mmol, quantitative yield). The solution was used in the next step without purification. LC-MS (ESI): m / z (M+1): 291.11 (Method 1).

[0131] Intermediate 10 :tert-Butyl 3-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]azetidine-1-carboxylate [ka] To a solution of 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 8, 400 mg, 1.789 mmol) in dry DMSO (3 mL) was added tert-butyl 3-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]azetidine-1-carboxylate 0.25 M DMSO solution (Intermediate 9, 9.30 mL, 2.325 mmol), Cz4IPN (70.6 mg, 0.089 mmol) and CSA (831 mg, 3.58 mmol). The solution was vigorously bubbled with argon, sealed and placed between two 50% intensity blue Kessil brand KSH150B Grow Light LED 34 W lamps (440-456 nm) for 1 h. The mixture was concentrated under reduced pressure and purified by flash chromatography on a Biotage silica NH cartridge (DCM to 50% DCM:DCM / MeOH 9 / 1) to give the title compound (260 mg, 0.686 mmol, 38% yield). LC-MS (ESI): m / z (M+1): 379.23 (Method 1).

[0132] Intermediate 11: tert-Butyl 5-(4-amino-6-chloropyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] Starting from tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.11 g, 10.06 mmol) and 3,6-dichloropyridazin-4-amine (1.5 g, 9.15 mmol), intermediate 11 was prepared according to the method used in the synthesis of intermediate 3 to give the title compound (1.15 g, 3.7 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 310.7 (Method 2).

[0133] Intermediate 12: tert-Butyl 5-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] Starting from intermediate 11 (550 mg, 1.77 mmol) and 5-chloro-2-fluorobenzeneboronic acid (463 mg, 2.65 mmol), intermediate 12 was prepared according to the method used in the synthesis of intermediate 4 to give the title compound (394 mg, 0.97 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 404.7 (Method 2).

[0134] Intermediate 13: tert-Butyl 4-{4-[(1,3-benzothiazol-6-yl)amino]-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] A mixture of intermediate 4 (70 mg, 0.17 mmol), Cs2CO3 (113 mg, 0.35 mmol), Xantphos (34 mg, 0.06 mmol), 6-bromobenzothiazole (41 mg, 0.19 mmol) and Pd(OAc)2 (2 mg, 0.01 mmol) was suspended in dry 1,2-dimethoxyethane (1.4 ml). The vial was sealed, degassed and filled with N2 (3 times) and stirred at 100 °C for 1 h. The mixture was diluted with EtOAc, filtered through a Celite® pad and washed with EtOAc. The organic filtrate was evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage NH silica cartridge (cHex ~ 40% EtOAc) to give the title compound (45 mg, 0.08 mmol, 48% yield). LC-MS (ESI): m / z (M+1): 538.3 (Method 2).

[0135] Intermediate 14 : 1,3-Dioxoisoindolin-2-yl-tetrahydrofuran-3-carboxylate [ka] Starting from tetrahydrofuran-3-carboxylic acid (1.0 g, 8.61 mmol), intermediate 14 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound as a 0.86 M DMSO solution (8.61 mmol, 100% yield), which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 262.12 (Method 1).

[0136] Intermediate 15: 6-(2-chloro-5-fluorophenyl)-3-(tetrahydrofuran-3-yl)pyridazin-4-amine [ka] To a solution of intermediate 8 (200 mg, 0.894 mmol) in dry DMSO (3 mL) was added intermediate 14 (0.86 M in DMSO, 1.56 mL, 1.341 mmol), 4CzIPN (35.3 mg, 0.045 mmol) and CSA (415 mg, 1.789 mmol). The solution was vigorously bubbled with argon, sealed and irradiated with an EVOLUCHEM LED 450DX lamp. The reaction was stirred at room temperature for 1 h. The solvent was removed by SCX cartridge and the crude was purified by flash chromatography on a Biotage silica NH cartridge (elution gradient 0-50% DCM:DCM / MeOH 9 / 1 in DCM) to give the title compound (120 mg, 0.409 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 294.21 (Method 1).

[0137] Intermediate 16: 1,3-Dioxoisoindolin-2-yl tetrahydrothiophene-2-carboxylate [ka] Starting from thiolane-2-carboxylic acid (500 mg, 3.78 mmol), intermediate 16 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (1.05 g, 3.78 mmol, quantitative yield) as a 0.945 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 278.96 (Method 1).

[0138] Intermediate 17: 6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2-yl)pyridazin-4-amine [ka] Starting from intermediate 8 (200 mg, 0.894 mmol), intermediate 17 was prepared using intermediate 16 (0.945 M in DMSO, 1.420 mL, 1.341 mmol) following the method used in the synthesis of intermediate 15. Purification by flash chromatography on a Biotage silica NH cartridge (elution gradient 0-50% DCM:DCM / MeOH 9 / 1 in DCM) afforded the title compound (120 mg, 0.409 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 310.16 (Method 1).

[0139] Intermediate 18: 1,3-Dioxoisoindolin-2-yl 1-methyl-5-oxopyrrolidine-3-carboxylate [ka] Intermediate 18 was prepared according to the method used in the synthesis of intermediate 9 starting from 1-methyl-5-oxopyrrolidine-3-carboxylic acid (0.5 g, 3.49 mmol) to give the title compound (1.0 g, 3.49 mmol, quantitative yield) as a 0.7 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 289.16 (Method 1).

[0140] Intermediate 19:4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)-1-methylpyrrolidin-2-one [ka] Starting from intermediate 8 (250 mg, 1.118 mmol), intermediate 18 (0.7 M in DMSO, 2.4 mL, 1.677 mmol) was used to prepare intermediate 19 following the method used in the synthesis of intermediate 15. The reaction was stirred at room temperature for 6 h. Purification by reversed-phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) afforded the title compound (150 mg, 0.468 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 321.16 (Method 1).

[0141] Intermediate 20: 1-(tert-butyl) 2-(1,3-dioxoisoindolin-2-yl)azetidine-1,2-dicarboxylate [ka] Starting from 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.0 g, 4.97 mmol), intermediate 20 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (quantitative yield) as a 0.5 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1-tBu): 291.33 (Method 1).

[0142] Intermediate 21: tert-Butyl 3-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)azetidine-1-carboxylate [ka] Intermediate 21 was prepared according to the method used in the synthesis of intermediate 15, starting from intermediate 8 (0.15 g, 0.671 mmol) and intermediate 20 (0.5 M in DMSO, 1.12 mL, 1.006 mmol). The reaction was stirred at room temperature for 1 h. Purification by reversed-phase flash chromatography (elution gradient 0-50% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) afforded the title compound (150 mg, 0.396 mmol, 59% yield). LC-MS (ESI): m / z (M+1-tBu): 323.23 (Method 1).

[0143] Intermediate 22: N-(4-((6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a solution of intermediate 8 (1.3 g, 5.81 mmol) in dry dioxane (10 mL) was added Cs2CO3 (3.79 g, 11.63 mmol), PdOAc2 (0.065 g, 0.291 mmol), Xantphos (0.336 g, 0.581 mmol) and intermediate 2 (1.902 g, 5.81 mmol). The suspension was heated at 120 °C for 3 h. The reaction was then diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3. The organic layer was collected, dried through a phase separation cartridge and the solvent removed. Purification by silica gel flash chromatography (elution gradient 0-20% DCM / DCM:NH37N in MeOH (9:1) in DCM) gave the title compound (1.55 g, 3.30 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 470.35 (Method 1).

[0144] Intermediate 23: 1,3-Dioxoisoindolin-2-yl 1-methyl-5-oxopyrrolidine-2-carboxylate [ka] Starting from (2S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid (500 mg, 3.49 mmol), intermediate 23 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (quantitative yield) as a 0.87 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 289.13 (Method 1).

[0145] Intermediate 24: 1,3-Dioxoisoindolin-2-yl 5-oxotetrahydrothiophene-2-carboxylate [ka] Starting from 5-oxothiolane-2-carboxylic acid (0.4 g, 2.74 mmol), intermediate 24 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (quantitative yield) as a 0.5 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 292.04 (Method 1).

[0146] Intermediate 25: 3-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) 2,2-dimethyloxazolidine-3,4-dicarboxylate [ka] Starting from (R)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidine-4-carboxylic acid (0.5 g, 2.039 mmol), intermediate 25 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (quantitative yield) as a 0.4 M DMSO solution, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1-Boc): 291.14 (Method 1).

[0147] Intermediate 26: 3-(tert-butyl) 4-(1,3-dioxoisoindolin-2-yl) 2,2-dimethyloxazolidine-3,4-dicarboxylate [ka] Starting from oxetane-3-carboxylic acid (0.25 g, 2.449 mmol), intermediate 26 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (0.605 g, 2.447 mmol, quantitative yield) as a 0.375 M solution in DMSO, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 248.14 (Method 1).

[0148] Intermediate 27 : 6-(5-chloro-2-fluorophenyl)-3-(oxetan-3-yl)pyridazin-4-amine [ka] Starting from intermediate 8 (0.15 g, 0.671 mmol), intermediate 27 was prepared according to the method used in the synthesis of intermediate 15 using intermediate 26 (0.375 M in DMSO, 5 mL, 1.875 mmol). Purification by reversed-phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) afforded the title compound (120 mg, 0.429 mmol, 34% yield). LC-MS (ESI): m / z (M+1): 280.23 (Method 1).

[0149] Intermediate 28: 1,3-Dioxoisoindolin-2-yl oxetane-2-carboxylate [ka] Starting from oxetane-2-carboxylic acid (500 mg, 4.90 mmol), intermediate 28 was prepared according to the method used in the synthesis of intermediate 9 to give the title compound (1.2 g, 4.90 mmol, quantitative yield) as a 1.23 M solution in DMSO, which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 248.14 (Method 1).

[0150] Preparation of Example Compounds Example 1: tert-Butyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] A mixture of tert-butyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (Intermediate 4, 230 mg, 0.57 mmol), Cs2CO3 (324 mg, 0.99 mmol), Xantphos (34 mg, 0.06 mmol), N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 205 mg, 0.62 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) was suspended in dry 1,2-dimethoxyethane (4 mL). The vial was sealed, degassed, and filled with N2 (3 times) and stirred at 100 °C for 1 h. The mixture was diluted with EtOAc and filtered through a Celite® pad, washing with EtOAc. The organic filtrate was evaporated in vacuo. The crude material was purified by flash chromatography on a Biotage NH silica cartridge (cHex~100% EtOAc) to give the title compound (338 mg, 0.52 mmol, 91% yield). LC-MS(ESI):m / z(M+1):651.4(Method 2) 1H NMR (400MHz, DMSO-d6) δ ppm 10.62(brs, 1H), 8.84-8.99(m, 1H), 8.10(d, J=5.7Hz, 1H), 8.02(dd, J=6.6, 2.6Hz , 1H), 7.96(s, 1H), 7.76(s, 1H), 7.56-7.67(m, 1H), 7.44(dd, J=10.3, 9.0Hz, 1H), 6.89(brd, J=4.6Hz, 1H), 6.11-6.34(m, 1H), 3.94-4.19(m, 2H), 3.55(brs, 2H), 2. 56-2.64(m, 4H), 2.48-2.53(m, 2H), 2.18-2.48(m, 8H), 2.14(s, 3H), 1.44(s, 9H).

[0151] Example 2: tert-Butyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]piperidine-1-carboxylate [ka] Starting from tert-butyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]piperidine-1-carboxylate (Intermediate 5, 200 mg, 0.49 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 177 mg, 0.54 mmol), the compound of Example 2 was prepared according to the method used in the synthesis of Example 1 to give the title compound (290 mg, 0.44 mmol, 91% yield). LC-MS(ESI):m / z(M+1):653.3(Method 2) 1H NMR (500MHz, DMSO-d6) δ ppm 10.62(s, 1H), 8.93(brs, 1H), 8.13(d, J=5.6Hz, 1H), 8.06(s, 1H), 8.00(dd, J=6.4, 2.7H z, 1H), 7.71(s, 1H), 7.53-7.66(m, 1H), 7.42(dd, J=10.4, 9.0Hz, 1H), 6.95(dd, J=5.5, 1 .8Hz, 1H), 4.12(brd, J=10.6Hz, 2H), 3.45-3.63(m, 1H), 2.91(brs, 2H), 2.58-2.62(m, 2 H), 2.50-2.54(m, 2H), 2.16-2.49(m, 8H), 2.14(s, 3H), 1.70-1.94(m, 4H), 1.43(s, 9H).

[0152] Example 3: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a solution of tert-butyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (Example 1, 281 mg, 0.43 mmol) in DCM (4.3 mL) was added TFA (0.33 mL, 4.32 mmol). The reaction was stirred at room temperature for 4 h. Then, further TFA (0.33 mL, 4.32 mmol) was added and the reaction was stirred for 4 h. The volatiles were removed under vacuum. The residue was loaded onto SCX, washed with MeOH and eluted with 1M NH3MeOH solution. The basic fractions were evaporated and purified by flash chromatography on a Biotage NH silica cartridge (DCM to 3% MeOH) to give the title compound (157 mg, 0.28 mmol, 66% yield). LC-MS(ESI):m / z(M+1):551.2(Method 2) 1 H NMR (500MHz, DMSO-d6) δ ppm 10.57(brs, 1H), 8.82(brs, 1H), 8.10(d, J=5.6Hz, 1H), 8.03(dd, J=6.5, 2.7Hz, 1 H), 7.96(s, 1H), 7.74(s, 1H), 7.59-7.65(m, 1H), 7.44(dd, J=10.4, 9.0Hz, 1H), 6 .88(dd, J=5.6, 1.9Hz, 1H), 6.16-6.28(m, 1H), 3.32-3.39(m, 2H), 2.92(t, J=5.5 Hz, 2H), 2.56-2.62(m, 2H), 2.48-2.53(m, 2H), 2.20-2.47(m, 10H), 2.14(s, 3H).

[0153] Example 4: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(piperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Starting from 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]piperidine-1-carboxylate (Example 2, 263 mg, 0.40 mmol), the compound of Example 4 was prepared according to the method used in the synthesis of Example 3 to give the title compound (216 mg, 0.39 mmol, 97% yield). LC-MS(ESI):m / z(M+1):553.3(Method 2) 1H NMR (500MHz, DMSO-d6) δ ppm 10.61(s, 1H), 8.88(brs, 1H), 8.11(d, J=5.6Hz, 1H), 8.05(s, 1H), 8.01(dd, J=6.6, 2.7H z, 1H), 7.70(s, 1H), 7.54-7.64(m, 1H), 7.42(dd, J=10.4, 9.0Hz, 1H), 6.93(dd, J=5.6, 1 .9Hz, 1H), 3.35-3.46(m, 1H), 3.06(brd, J=12.2Hz, 2H), 2.67(td, J=11.9, 3.0Hz, 2H), 2 .56-2.64(m, 2H), 2.50-2.54(m, 2H), 2.21-2.46(m, 8H), 2.14(s, 3H), 1.72-1.89(m, 4H).

[0154] Example 5: Methyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] To an ice-cold solution of N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 3, 60 mg, 0.11 mmol) in DCM (1.09 mL) was added TEA (30 μL, 0.22 mmol) and methyl chloroformate (10 μL, 0.12 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO3. The phases were separated and the organic layer was dried and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage NH silica cartridge (DCM to 3% MeOH) to give the title compound (33 mg, 0.05 mmol, 50% yield). LC-MS(ESI):m / z(M+1):609.3(Method 2) 1H NMR (500MHz, DMSO-d6) δ ppm 10.58(s, 1H), 8.92(s, 1H), 8.10(d, J=5.5Hz, 1H), 8.02(dd, J=6.5, 2.7Hz, 1H), 7 .96(brs, 1H), 7.76(brs, 1H), 7.57-7.66(m, 1H), 7.44(dd, J=10.3, 9.1Hz, 1H), 6. 89(brd, J=4.3Hz, 1H), 6.23(brs, 1H), 4.04(brs, 2H), 3.65(s, 3H), 3.61(brt, J=5 .4Hz, 2H), 2.56-2.62(m, 4H), 2.50-2.54(m, 2H), 2.21-2.46(m, 8H), 2.14(s, 3H).

[0155] Example 6: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a solution of N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 3, 60 mg, 0.110 mmol) in MeOH (0.5 mL) was added acetic acid (15.6 μL, 0.27 mmol) and formaldehyde 37% w / w in water (8 μL, 0.11 mmol). The reaction was stirred at room temperature for 15 min before sodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction was stirred at room temperature for 30 min. The volatiles were removed under vacuum. The residue was loaded onto SCX and washed with MeOH, eluting with 1M NH3MeOH solution. The basic fractions were evaporated and the crude material was purified by flash chromatography on a Biotage NH silica cartridge (DCM to 3% MeOH) to give the title compound (50 mg, 0.09 mmol, 81% yield). LC-MS(ESI):m / z(M+1):565.2(Method 2) 1 H NMR (400MHz, DMSO-d6) δ ppm 10.56(s, 1H), 8.90(s, 1H), 8.09(d, J=5.6Hz, 1H), 8.03(dd, J=6.6, 2.7Hz, 1H), 7.94(s, 1H), 7.75(s, 1H), 7.56-7.67(m, 1H), 7.36-7.50(m, 1H), 6.86 (dd, J=5.6, 1.9Hz, 1H), 6.21(brs, 1H), 3.00(brd, J=2.2Hz, 2H), 2.56-2.6 6(m, 6H), 2.49-2.55(m, 2H), 2.28(s, 3H), 2.22-2.46(m, 8H), 2.14(s, 3H).

[0156] Example 7: Methyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]piperidine-1-carboxylate [ka] The compound of Example 7 was prepared according to the method used in the synthesis of Example 5 starting from N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(piperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 4, 70 mg, 0.13 mmol) to give the title compound (48 mg, 0.08 mmol, 62% yield). LC-MS(ESI):m / z(M+1):611.4(Method 2) 1H NMR (400MHz, DMSO-d6) δ ppm 10.63(brs, 1H), 8.91(brs, 1H), 8.13(d, J=5.7Hz, 1H), 8.06(s, 1H), 8.00(dd, J=6.6, 2.6Hz, 1H), 7.71(s, 1H), 7.60(ddd, J=8.8, 4.1, 3.0Hz, 1H), 7.42(dd, J=10.3, 9.0Hz, 1H), 6.95(dd, J=5.6, 1.9 Hz, 1H), 4.15(brd, J=10.3Hz, 2H), 3.63(s, 3H), 3.48-3.59(m, 1H), 2.84-3.17(m, 2H), 2.57-2.64 (m, 2H), 2.50-2.55(m, 2H), 2.16-2.49(m, 8H), 2.14(s, 3H), 1.86-1.97(m, 2H), 1.73-1.86(m, 2H).

[0157] Example 8: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methylpiperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] The compound of Example 8 was prepared according to the method used in the synthesis of Example 6 starting from N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(piperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 4, 51 mg, 0.09 mmol) to give the title compound (35 mg, 0.06 mmol, 66% yield). LC-MS(ESI):m / z(M+1):567.3(Method 2) 1H NMR (400MHz, DMSO-d6) δ ppm 10.69(s, 1H), 8.81(s, 1H), 8.11(d, J=5.5Hz, 1H), 8.05(s, 1H), 8.01(dd, J=6.6, 2.6Hz, 1H), 7.70(s, 1H), 7.57-7.64(m, 1H), 7.42(dd, J=10.3, 9.0Hz, 1H), 6.93(dd, J=5.5, 1.8Hz, 1H), 3 .22-3.31(m, 1H), 2.91(brd, J=10.7Hz, 2H), 2.57-2.64(m, 2H), 2.50-2.55(m, 2H), 2.20-2.4 9(m, 8H), 2.22(s, 3H), 2.14(s, 3H), 1.99-2.10(m, 2H), 1.90-2.00(m, 2H), 1.79-1.88(m, 2H).

[0158] Example 9: tert-Butyl 3-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-1-carboxylate [ka] Starting from tert-butyl 3-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]azetidine-1-carboxylate (Intermediate 10, 150 mg, 0.396 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 130 mg, 0.396 mmol), the compound of Example 9 was prepared according to the method used in the synthesis of Example 1. Purification by reverse phase flash chromatography (HO+0.1% HCOOH to 50% MeCN+0.1% HCOOH) afforded the title compound (64 mg, 0.102 mmol, 26% yield). LC-MS(ESI):m / z(M+1):625.37(Method 1) 1H NMR (400MHz, DMSO-d6) δ ppm 10.60(s, 1H), 8.79(s, 1H), 8.10(d, J=5.48Hz, 1H), 7.94-8.04(m, 2H), 7.71(s, 1H), 7.52-7.66(m, 1H), 7.32-7.50(m, 1H), 6.90(brdd, J=5. 48, 1.53Hz, 1H), 4.28-4.40(m, 1H), 4.16-4.28(m, 4H), 2.54-2.61(m, 2H), 2.48-2.50(m, 2H), 2.14-2.45(m, 8H), 2.10(s, 3H), 1.36(s, 9H).

[0159] Example 10: N-(4-{[3-(azetidin-3-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a solution of tert-butyl 3-(6-(2-chloro-5-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)azetidine-1-carboxylate (Example 9, 50 mg, 0.080 mmol) in dry DCM (5 mL), TFA (2 mL, 26.0 mmol) was added and the solution was stirred for 3 h. The solvent was then removed and the crude was purified by reverse phase flash chromatography (HO+0.1% HCOOH to 30% MeCN+0.1% HCOOH) to give the title compound as a bis-TFA salt (35 mg, 0.067 mmol, 83% yield). LC-MS(ESI):m / z(M+1):525.26(Method 1) 1H NMR (400MHz, DMSO-d6) δ ppm 10.53(brs, 1H), 9.58(brs, 1H), 9.12(brs, 1H), 8.96(s, 1H), 8.84(brs, 1H), 8.16(d, J=5.48H z, 1H), 7.97-8.05(m, 2H), 7.78(s, 1H), 7.59-7.70(m, 1H), 7.46(t, J=9.52Hz, 1H), 6.93(dd, J= 5.48, 1.53Hz, 1H), 4.62(q, J=7.97Hz, 1H), 4.35-4.46(m, 4H), 3.38-3.46(m, 2H), 2.96-3.00(m , 2H), 2.98(brs, 2H), 2.77(brs, 3H), 2.63-2.73(m, 2H), 2.53-2.63(m, 2H), 2.24-2.37(m, 2H).

[0160] Example 11: tert-Butyl 5-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate [ka] Starting from intermediate 12 (200 mg, 0.49 mmol) and intermediate 2 (177 mg, 0.54 mmol), the compound of example 11 was prepared according to the method used in the synthesis of example 1 to obtain the title compound (289 mg, 0.44 mmol, 90% yield). LC-MS (ESI): m / z (M+1): 651.3 (method 2). 1H NMR (400 MHz, chloroform-d) δ ppm 11.20 (brs, 1H), 8.24 (d, J = 5.7 Hz, 1H), 8.20 (dd, J = 6.6, 2.6 Hz, 1H), 7.97-8.14 (m, 1H), 7.87 (s, 1H), 7.35-7.43 (m, 1H), 7.10-7.19 (m, 1H), 6.96 (brd, J = 4.2 Hz, 1H), 7.27 (b rs, 1H), 6.22-6.54(m, 1H), 4.26-4.59(m, 2H), 3.71(t, J=5.8Hz, 2H), 2.73-2.80(m, 2H) ), 2.53-2.58(m, 2H), 2.51-2.88(m, 8H), 2.42-2.51(m, 2H), 2.37(s, 3H), 1.51(s, 9H).

[0161] Example 12: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,5,6-tetrahydropyridin-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide CHD-071569 [ka] Starting from the compound of Example 11 (289 mg, 0.44 mmol), the compound of Example 12 was prepared according to the method used in the synthesis of Example 3 to give the title compound (178 mg, 0.32 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 551.3 (Method 3). 1H NMR (400MHz, chloroform-d) δ ppm 11.21(s, 1H), 8.23(d, J=5.7Hz, 1H), 8.20(dd, J=6.7, 2.7Hz, 1H), 8.02(d, J=2.0Hz, 1H), 7.84(d, J=1.3Hz, 1H), 7.39(ddd, J=8.8, 4.1, 2.9Hz, 1H), 7.13(dd, J=10.5, 8.8Hz, 1H), 6.99(s, 1H), 6.94( dd, J=5.6, 2.1Hz, 1H), 6.36(brs, 1H), 3.87(brd, J=1.8Hz, 2H), 3.16(t, J=5.7Hz, 2H), 2.73-2.79 (m, 2H), 2.52-2.58(m, 2H), 2.45-2.86(m, 8H), 2.38-2.44(m, 2H), 2.37(s, 3H), 1.57-1.70(m, 1H).

[0162] Example 13: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Starting from the compound of Example 12 (50 mg, 0.09 mmol), the compound of Example 13 was prepared according to the method used in the synthesis of Example 6 to give the title compound (25 mg, 0.05 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 565.3 (Method 3). 1H NMR (400MHz, chloroform-d) δ ppm 11.17(brs, 1H), 8.22(d, J=5.8Hz, 1H), 8.20(dd, J=6.7, 2.6Hz, 1H), 8.05(d, J=1. 4Hz, 1H), 7.86(s, 1H), 7.39(ddd, J=8.7, 4.1, 2.9Hz, 1H), 7.13(dd, J=10.4, 8.9Hz, 1H), 7.09(brs, 1H), 6.93(dd, J=5.6, 1.8Hz, 1H), 6.34(brs, 1H), 3.50(brs, 2H), 2 .73-2.79(m, 4H), 2.54-2.58(m, 4H), 2.52(s, 3H), 2.46-2.84(m, 8H), 2.37(s, 3H).

[0163] Example 14: N-(4-{[3-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a mixture of the compound of Example 12 (36 mg, 0.07 mmol) and TEA (18 μL, 0.13 mmol) in DCM (0.19 mL) was added acetic anhydride (7 μL, 0.07 mmol). The reaction was stirred at room temperature for 15 min. The mixture was diluted with DCM and washed with saturated aqueous NaCl. The phases were separated and the organic phase was dried and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage NH silica cartridge (DCM to 3% MeOH) to give the title compound (25 mg, 0.04 mmol, 65% yield). LC-MS (ESI): m / z (M+1): 593.3 (Method 3). 1H NMR (400MHz, DMSO-d6) δ ppm 10.59(brs, 1H), 8.92(brs, 1H), 8.12(dd, J=5.5, 2.5Hz, 1H), 8.03(dd, J=6.4, 2.5 Hz, 1H), 7.97(brs, 1H), 7.77(s, 1H), 7.66-7.58(m, 1H), 7.44(t, J=9.7Hz, 1H), 6.9 5-6.87(m, 1H), 6.47-6.31(m, 1H), 4.50-4.38(m, 2H), 3.68-3.56(m, 2H), 2.64-2. 56(m, 2H), 2.54-2.47(m, 2H), 2.47-2.16(m, 10H), 2.13(s, 3H), 2.10-2.03(m, 3H).

[0164] Example 15: tert-Butyl 2-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-1-carboxylate [ka] Starting from intermediate 21 (45 mg, 0.12 mmol), intermediate 2 (43 mg, 0.13 mmol) was used to prepare the compound of example 15 according to the method used in the synthesis of example 1 to obtain the title compound (30 mg, 0.50 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 652.3 (method 3). 1 H NMR (400MHz, chloroform-d) δ ppm 10.93(brs, 1H), 10.26(brs, 1H), 8.22(dd, J=6.6, 2.6Hz, 1H), 8.17(d, J=5. 5Hz, 1H), 8.14(d, J=1.5Hz, 1H), 7.96(s, 1H), 7.35-7.42(m, 1H), 7.10-7.17( m, 1H), 6.84(dd, J=5.6, 1.9Hz, 1H), 5.56(dd, J=9.0, 5.5Hz, 1H), 4.01-4.18 (m, 2H), 3.81-3.97(m, 1H), 2.48-2.95(m, 13H), 2.39(brs, 3H), 1.52(s, 9H).

[0165] Example 16: N-(4-{[3-(azetidin-2-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide CHD-071596 [ka] Starting from Example 15 (43 mg, 0.07 mmol), the compound of Example 16 was prepared according to the method used in the synthesis of Example 3 to give the title compound (12 mg, 0.02 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 525.2 (Method 3). 1 H NMR (400 MHz, chloroform-d) δ ppm 12.02 (brs, 1H), 10.98 (brs, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 6.6, 2.6 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.85 (s, 1H), 7.38 (dt, J = 8.7, 3.5 Hz, 1H), 7.13 (dd, J = 10.3, 9.0 Hz, 1H), 6.94 (dd, J=5.6, 1.9Hz, 1H), 5.72(t, J=8.8Hz, 1H), 3.86-4.06(m, 1H), 3.42-3.65(m, 1H), 2.87(d t, J=19.7, 9.6Hz, 1H), 2.75-2.81(m, 2H), 2.53-2.59(m, 2H), 2.48-2.88(m, 9H), 2.39(s, 3H).

[0166] Example 17 N-(4-((6-(5-chloro-2-fluorophenyl)-3-(1-methyl-5-oxopyrrolidin-2-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] To a solution of intermediate 22 (100 mg, 0.213 mmol) in dry DMSO (5 mL) was added intermediate 23 (0.87 M in DMSO, 0.37 mL, 0.319 mmol), 4CzIPN (8.39 mg, 10.64 μMol) and CSA (99 mg, 0.426 mmol). The solution was vigorously bubbled with argon, sealed and illuminated with an EVOLUCHEM LED 450DX lamp. The reaction was stirred at room temperature for 18 h. Purification by reverse phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) afforded the title compound (31 mg, 0.055 mmol, 26% yield). LC-MS (ESI): m / z (M+1): 567.60 (Method 1). 1 H-NMR (400MHz, DMSO-d6) δ ppm 10.65(s, 1H), 9.02(s, 1H), 8.15(d, d, J=5.70Hz, 1H), 8.08(s, 1H), 8.04(dd, J=6. 58, 2.85Hz, 1H), 7.81(s, 1H), 7.53-7.71(m, 1H), 7.44(dd, J=10.63, 8.88Hz, 1H), 6 .99(dd, J=5.59, 1.86Hz, 1H), 5.40(dd, J=8.44, 2.52Hz, 1H), 2.67(s, 3H), 2.58-2. 63(m, 2H), 2.52-2.54(m, 2H), 2.24-2.48(m, 11H), 2.14(s, 3H), 1.92-2.02(m, 1H).

[0167] Example 18: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxetan-2-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Starting from intermediate 28 (100 mg, 0.358 mmol), intermediate 22 (117 mg, 0.358 mmol) was used to prepare the compound of example 18 according to the method used in the synthesis of example 17. Purification by reversed-phase flash chromatography (elution gradient 0-50% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) gave the title compound (10 mg, 0.019 mmol, 5% yield). LC-MS (ESI): m / z (M+1): 527.31 (Method 1). 1 H NMR (400MHz, DMSO-d6) δ ppm 10.75(s, 1H), 9.41(s, 1H), 8.24(d, J=5.70Hz, 1H), 8.13-8.20(m, 1H), 7.90(dd, J= 6.47, 2.74Hz, 1H), 7.60-7.66(m, 1H), 7.55(s, 1H), 7.42-7.49(m, 1H), 7.12(dd, J= 5.81, 2.08Hz, 1H), 4.25-4.38(m, 2H), 4.12(dd, J=9.87, 5.26Hz, 1H), 3.74-3.95(m , 3H), 2.58-2.64(m, 2H), 2.55(brd, J=6.14Hz, 2H), 2.29-2.44(m, 8H), 2.14(s, 3H).

[0168] Example 19: N-(4-((6-(5-chloro-2-fluorophenyl)-3-(5-oxotetrahydrothiophen-2-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Starting from intermediate 22 (130 mg, 0.277 mmol), intermediate 24 (0.5 M in DMSO, 0.754 ml, 0.415 mmol) was used to prepare the compound of example 19 according to the method used in the synthesis of example 17. The crude material was purified by reversed-phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH). Appropriate fractions were collected and evaporated under vacuum, and the remaining material was further purified by semi-preparative HPLC under basic conditions to give the title compound (16 mg, 0.013 mmol, 5% yield). LC-MS (ESI): m / z (M+1): 570.20 (Method 1). 1 H NMR (500MHz, chloroform-d) δ ppm 10.35-11.33(m, 1H), 8.32(s, 1H), 8.17-8.25(m, 2H), 8.02(s, 1H), 7.88( s, 1H), 7.42(ddd, J=8.7, 4.2, 2.8Hz, 1H), 7.14(dd, J=10.5, 8.9Hz, 1H), 6 .86(dd, J=5.6, 2.1Hz, 1H), 6.29-6.74(m, 1H), 5.35(t, J=5.7Hz, 1H), 3.1 9-3.37(m, 2H), 2.67-3.00(m, 12H), 2.59(brt, J=5.8Hz, 2H), 2.53(s, 3H).

[0169] Example 20: tert-Butyl 4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)-2,2-dimethyloxazolidine-3-carboxylate [ka] Starting from intermediate 22 (120 mg, 0.255 mmol), intermediate 25 (0.4 M in DMSO, 0.376 mL, 0.384 mmol) was used to prepare the compound of example 19 according to the method used in the synthesis of example 17. Purification by reversed-phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) gave the title compound (7.0 mg, 10.46 μMol, 4% yield). LC-MS (ESI): m / z (M+1): 570.20 (Method 1). 1 H NMR (600MHz, DMSO-d6) δ ppm 10.64(s, 1H), 9.00(s, 1H), 8.14(d, J=5.51Hz, 1H), 8.08(brs, 1H), 7.99-8.05(m, 1H), 7.78(s, 1H), 7.59-7.66(m, 1H), 7.44(dd, J=10.26, 9.10Hz, 1H), 6.90-7.01(m, 1H), 5.4 9-5.67(m, 1H), 4.40(brs, 1H), 3.92-4.00(m, 1H), 2.59-2.62(m, 2H), 2.51-2.53(m, 2H) ), 2.18-2.48(m, 8H), 2.14(s, 3H), 1.76(s, 3H), 1.58(s, 3H), 1.42(s, 3H), 1.09(s, 6H).

[0170] Example 21: N-(4-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrofuran-3-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide. [ka] Starting from intermediate 15 (50 mg, 0.170 mmol), intermediate 2 (55.7 mg, 0.170 mmol) was used to prepare the compound of example 21 according to the method used in the synthesis of example 1. Purification by silica gel flash chromatography (elution gradient 0-50% DCM / DCM:NH37N MeOH (9:1) in DCM) afforded the title compound (40 mg, 0.074 mmol, 44% yield). LC-MS (ESI): m / z (M+1): 540.29 (Method 1). 1 H NMR (DMSO-d6, 400MHz)δ 10.60(s, 1H), 8.91(s, 1H), 8.10(d, J=5.5Hz, 1H), 8.1-8.0(m, 1H), 7.97(dd, J=2.8, 6.5Hz, 1H), 7.71(s, 1H), 7.6-7.5(m, 1H) , 7.39(dd, J=8.9, 10.5Hz, 1H), 6.93(dd, J=2.0, 5.5Hz, 1H), 4.2-4.1(m, 1H), 4.1-3.8(m, 4H), 2.6-2.2(m, 14H), 2.10(s, 3H).

[0171] Example 22: N-(4-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide. [ka] Starting from intermediate 17 (693 mg, 2.237 mmol), intermediate 2 (471 mg, 1.790 mmol) was used to prepare the compound of example 22 according to the method used in the synthesis of example 1. Purification by silica gel flash chromatography (elution gradient 0-50% DCM:NH37N MeOH (9:1) in DCM) gave the title compound (150 mg, 0.270 mmol, 12% yield). LC-MS (ESI): m / z (M+1): 556.25 (Method 1). 1H NMR (400MHz, DMSO-d6) δ ppm 10.51(s, 1H), 8.93(s, 1H), 8.16-8.10(m, 1H), 8.06(brs, 1H), 8.02(dd, J=6.58, 2.63Hz, 1H), 7.74(brs, 1H), 7.64-7.58(m, 1H), 7.44(dd, J=10. 52, 8.99Hz, 1H), 6.93(dd, J=5.70, 2.19Hz, 1H), 5.18(t, J=5.92Hz, 1H), 2.99-2.89(m, 4H), 2.76-2.56(m, 10H), 2.54(s, 3H), 2.26-2.08(m, 4H).

[0172] Example 23: N-(4-((6-(5-chloro-2-fluorophenyl)-3-(1-methyl-5-oxopyrrolidin-3-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide. [ka] Starting from intermediate 19 (150 mg, 0.468 mmol), intermediate 2 (153 mg, 0.468 mmol) was used to prepare the compound of example 23 according to the method used in the synthesis of example 1. Purification by reversed-phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) gave the title compound (20 mg, 0.035 mmol, 8% yield). LC-MS (ESI): m / z (M+1): 567.35 (Method 1).

[0173] Example 24 N-(4-((6-(5-chloro-2-fluorophenyl)-3-(oxetan-3-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Starting from intermediate 2 (100 mg, 0.213 mmol), intermediate 27 (0.375 M in DMSO, 0.850 mL, 0.319 mmol) was used to prepare the compound of example 24 according to the method used in the synthesis of example 1. The reaction was stirred at room temperature for 18 hours. Purification by reverse phase flash chromatography (elution gradient 0-30% MeCN / H2O 95:5 + 0.1% HCOOH H2O / MeCN 95:5 solution + 0.1% HCOOH) afforded the title compound (21 mg, 0.040 mmol, 19% yield). LC-MS (ESI): m / z (M+1): 526.31 (Method 1). 1 H NMR (400MHz, DMSO-d6) δ ppm 10.60(s, 1H), 8.78(brs, 1H), 8.11(d, J=5.70Hz, 1H), 7.98-8.01(m, 1H), 7.75(s, 1 H), 7.54-7.66(m, 1H), 7.35-7.47(m, 1H), 6.94(dd, J=5.48, 1.75Hz, 1H), 6.31(t, J =7.45Hz, 1H), 4.75(td, J=7.73, 5.81Hz, 1H), 4.62(dt, J=9.15, 5.84Hz, 1H), 3.29- 3.44(m, 2H), 2.96-3.05(m, 1H), 2.49-2.64(m, 4H), 2.16-2.45(m, 8H), 2.10(s, 3H).

[0174] Newly synthesized comparative compounds with benzothiazolyl instead of pyridinyl groups Example C1 N-[6-(5-chloro-2-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]-1,3-benzothiazol-6-amine [ka] Starting from intermediate 13 (45 mg, 0.08 mmol), the compound of Example C1 was synthesized according to the method used in the synthesis of Example 3 to give the title compound (22 mg, 0.05 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 438.3 (Method 3). 1H NMR (400MHz, chloroform-d) δ ppm 9.00(s, 1H), 8.12-8.21(m, 2H), 7.85(d, J=1.5Hz, 1H), 7.48(d, J=1.0Hz, 1H), 7.42(dd, J=8.7, 1.9Hz, 1H), 7.35(dt, J=7.9, 3.9H z, 1H), 7.03-7.11(m, 1H), 6.96(s, 1H), 6.36(brs, 1H), 3.67(brd, J=2.9Hz, 2H), 3.26(t, J=5.6Hz, 2H), 2.76(brd, J=1.5Hz, 2H).

[0175] Pharmacological activity of the compounds of the invention In vitro assays The enzymatic activity of the compounds of the present invention was monitored by measuring ADP formation using ADP-GLO kinase assay. After the purified enzyme, substrate and ATP were incubated, the generated ADP was converted to ATP, which was then converted to light by Ultra-Glo luciferase. The luminescence signal was positively correlated with the amount of ADP and the kinase activity. Briefly, the kinase reaction was carried out by incubating 2.6 nM of purified commercially available human ALK5 (recombinant TGFβ1 N-terminal GST tagged, 80-end), a final concentration of 94.5 μM of TGFβ1 peptide (Promega, T36-58) and ultra-pure ATP (Promega V915B). The final concentration of ATP was set to the Km value (the final concentration of the substrate at which the enzyme achieves half of the maximum velocity (Vmax)) of ALK5 (0.5 μM). The compounds and ALK5 kinase were mixed and incubated for 15 minutes. The reaction was started by adding ATP to the assay solution at a final concentration of 0.83 μM. After 120 min of incubation, the reaction was stopped and ADP generation was detected using the ADP-Glo ​​kit according to the manufacturer's instructions. To overcome the assay wall limit for highly potent compounds, the assay protocol was modified by using a high final concentration (30x Km) of ATP. Compounds and ALK5 kinase were mixed for 15 min and the reaction was started by adding TGFβ1 peptide and a final concentration of ATP to the assay solution of 15 μM. After 60 min of incubation, the kinase reaction was stopped and ADP generation was detected using the ADP-Glo ​​kit according to the manufacturer's instructions.

[0176] All reactions and incubation steps were carried out at 25° C. and the assay was performed in a 384-well format and validated using a selection of standard compounds tested in 11-point final concentration-response curves.

[0177] The results for the individual compounds are provided in Table 2, and the compounds are categorized according to their inhibitory activity against the ALK5 receptor. 50 (I C 50 (negative logarithm of pK i(Dissociation function K i The negative logarithm of pK i The higher the value, the greater the inhibition of ALK5 activity.

[0178] As can be seen, all compounds in Table 2 exhibit pKi values ​​greater than 8.5 when tested in the biochemical ALK5 assay. [Table 2]

[0179] Comparative Example The compound of Example C1 was tested in an in vitro assay similar to that described above. [Table 3]

[0180] As shown in Table 2, the compounds of the present invention have a pKi greater than 8.5, while the compound of Comparative Example C1 has a pKi less than 7.22. These data demonstrate that the presence of a pyridinyl group in the compounds of the present invention, in contrast to compound C1, which is characterized by having a benzothiazolyl instead of a pyridinyl group, unexpectedly and significantly determines the associated increase in inhibitory activity against the ALK5 receptor.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, R １ is aryl optionally substituted with one or more halogen atoms; R ２ is -NR ３ C(O)R ４ and -NH ２ Selected from: R ３ is H or -(C １ -C ６ ) alkyl; R ４ is a heterocycloalkyl group having one or more -(C １ -C ６ ) alkyl-substituted -(C １ -C ６ ) alkylene-(C ４ -C ６ )heterocycloalkyl; -(C ４ -C ６ ) Heterocycloalkyl is one or more -(C １ -C ６ ) alkyl substituted with one or more -(C ４ -C ６ ) optionally substituted with heterocycloalkyl -(C ３ -C ６ ) cycloalkyl; R ５ is -C(O)O-(C １ -C ６ ) alkyl, —C(O)—(C １ -C ６ ) alkyl, oxo and -(C １ -C ６ ) alkyl, ４ -C ６ ) heterocycloalkyl. or a pharma- ceutically acceptable salt thereof.

2. R １ 2. A compound of formula (I) according to claim 1, wherein is phenyl substituted with fluorine and chlorine.

3. R ４ A compound of formula (I) according to claim 1 or 2, wherein is -(4-methylpiperazin-1-yl)ethyl.

4. At least one of the following compounds: tert-butyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate; tert-butyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]piperidine-1-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(piperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Methyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; methyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]piperidine-1-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methylpiperidin-4-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; tert-butyl 3-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-1-carboxylate; N-(4-{[3-(azetidin-3-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; tert-butyl 5-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1,2,5,6-tetrahydropyridin-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[3-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; tert-butyl 2-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-1-carboxylate; N-(4-{[3-(azetidin-2-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-5-oxopyrrolidin-2-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxetan-2-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-((6-(5-chloro-2-fluorophenyl)-3-(5-oxotetrahydrothiophen-2-yl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; tert-butyl 4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)-2,2-dimethyloxazolidine-3-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(thiolan-2-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(1-methyl-5-oxopyrrolidin-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxetan-3-yl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide A compound of formula (I) according to any one of claims 1 to 3, selected from:

5. R １ is an aryl optionally substituted with one fluorine and one chlorine; R ５ The compound of formula (I) according to claim 1 or 2, wherein is selected from the group consisting of -(oxetan-2-yl) and -(tetrahydrothiophen-2-yl).

6. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 5 in admixture with a pharma- ceutically acceptable carrier or excipient.

7. 7. The pharmaceutical composition of claim 6, for administration by inhalation.

8. A compound of formula (I) as defined in any one of claims 1 to 5 or a pharmaceutical composition as defined in claims 6 and 7 for use as a medicament.

9. 9. A compound of formula (I) or a pharmaceutical composition for use according to claim 8 in the prevention and / or treatment of a disease, disorder or condition mediated by the ALK5 signaling pathway in a mammal.

10. A compound of formula (I) or a pharmaceutical composition for use according to claims 8 and 9 in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions in which fibrosis is involved.

11. 11. A compound of formula (I) or a pharmaceutical composition according to claim 10 for use in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

12. A compound of formula (I) or a pharmaceutical composition for use according to claim 10 in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

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