Pyridazinyl amino derivatives as ALK5 inhibitors

Abstract

The present invention generally relates to compounds of formula (I) inhibiting the transforming growth factor β (TGF (3) type I receptor (ALK5) (hereinafter ALK5 inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic uses thereof, the compounds of the invention may be useful for instance in the treatment of many disease, disorder, or condition associated with ALK5 signaling pathway.

Description

[0001] PYRIDAZINYL AMINO DERIVATIVES AS ALK5 INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] The present invention generally relates to compounds inhibiting the transforming growth factor P (TGF P) type I receptor (ALK5) (hereinafter ALK5 inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic uses thereof; the compounds of the invention may be useful for instance in the treatment of many diseases, disorder, or condition associated with ALK5 signaling pathway.

[0004] BACKGROUND OF THE INVENTION

[0005] The Transforming Growth Factor P (TGFP) is a protein belonging to the TGFP superfamily. It is involved in several processes, both cellular, such as proliferation, migration and differentiation, and biological, including wound healing, immune suppression, cancer ogene sis and extracellular matrix production.

[0006] The TGFP superfamily also includes, among others, other members known as activins (Acts) (see e.g. Hinck AP, FEBS Letters 586 (2012); 1860-1870). The binding of the peptide initiates the TGFP signalling cascade through the formation of a heterotetrameric complex composed of two different serine / threonine kinases receptors: type 1 (TGFPR1 / ALK5) and type 2 (TGFPR2). TGFPR1 / ALK5 is recruited and activated through the phosphorylation of its intracellular domain by TGFPR2, leading in turn to the phosphorylation of the receptor-activated (R)-Smad family, resulting in the activation of target gene transcription (see e.g. Sheppard D., Proc Am Thorac Soc. (2006);(3):413-417).

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

[0008] Several studies have linked an excessive and / or dysregulated TGFP activity with 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 crucial role of TGFP has been shown in organs such as lung, heart, liver, and kidney (see e.g. Alhamad EH, J Thorac Dis. (2015);7(3):386-93). In particular, TGFP 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 JRespir Cell Mol Biol. (2016);(55):759-766). In lung, TGFP is expressed in several cell types, like epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts. These cell populations may produce excess of TGFP in IPF human lung tissue. Moreover, high levels of TGFp have been detected in lung tissue and BAL of IPF patients (see e.g. Bergeron A et al., Eur Respir J (2003);22:69-76).

[0009] TGFp gene expression and TGFp protein production have been observed to increase in a variety of animal models of pulmonary fibrosis caused 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 it has also been reported how the TGFp 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.). Contrarily, TGFP signalling inhibition obtained by employing knockout (KO) animals can inhibit fibrosis development through TGFP-linked mechanisms (see e.g. Bonniaud P et al., Am J Respir Crit Care Med (2005); 171 ^SOSOS; 34). Similar results have been achieved with inhibition of TGFpRl in mouse bleomycin disease model (see e.g. Wei Y et al., J Clin Invest. (2017);127(10):3675-3688).

[0010] Activin signalling dysregulation, similarly to TGFP, is associated to fibroblasts proliferation, myofibroblasts differentiation and accumulation of extracellular matrix (ECM) (see e.g. Yamashita et al., J. Am. Soc. Nephrol. (2004) 15, 91-101). Moreover, overexpression of activin has been linked to pathological conditions and fibrosis development in different organs, such as 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).

[0011] Taken together these data suggest the importance of targeting ALK5 to treat pharmacologically the aforementioned diseases, linked to the dysregulated TGF signaling pathway. The TGFP signaling is strongly involved in the cardiovascular homeostasis (see e.g. van Meeteren LA et al., Springer (2013)). Several studies in humans and mice have shown the main role of TGFP in angiogenesis and vascular morphogenesis. Moreover, TGFP plays a key role in the development and functionality of cardiac valves.

[0012] It is therefore clear the importance of a selective regulation of TGFp pathway to target the pathological effects avoiding the suppression of the signaling needed for a correct homeostasis. The answer to this crucial point could be addressed by using the inhalation route to deliver an anti- TGFP drug. The inhalatory route would allow the treatment of the affected lung compartment bypassing the issue of the heart exposure.

[0013] Various compounds have been described in the literature as ALK5 and / or ALK4 receptor inhibitors. Pyridazinyl amino derivatives have been disclosed in international applications No. WO 2022 / 013307, WO 2023 / 046698 and in WO 2023 / 135107, in the name of the Applicant, as potent ALK5 inhibitors.

[0014] Of note, inhibition of ALK5 receptor may be useful for the treatment of fibrosis and disease, disorder and conditions that result from fibrosis.

[0015] Several efforts have been done in the past years to develop novel ALK5 receptor inhibitors useful for the treatment of several diseases and some of those compounds have shown efficacy also in humans.

[0016] However, there remains a potential for developing inhibitors of receptors ALK5 characterized by good potency, useful for the treatment of diseases or conditions associated with a dysregulation of ALK5 signaling pathway, in particular fibrosis. In particular, there remains a potential for developing inhibitors of receptors ALK5 useful for the treatment of diseases or conditions associated with a dysregulation of ALK5 signaling in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), to be administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity on the lung and a good lung retention, and endowed with low microsomal stability, low plasma stability, in order to minimize the systemic exposure and correlated safety issues.

[0017] In this direction, we have surprisingly found a new series of compounds of general formula (I) that solves the problem of providing potent inhibitors of ALK5 receptor for administration by inhalation, that shows, at the same time, a good inhalatory profile, low microsomal stability, low systemic exposure, improved safety and tolerability, and good selectivity across the kinome.

[0018] SUMMARY OF THE INVENTION

[0019] In a first aspect, the present invention relates to compounds of formula (I) wherein Ri is selected from the group consisting of -(Ci-Ce)alkylene-(C3- C7)heterocycloalkyl, wherein said -(C3-C7)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkyl, wherein said -(C3- C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-C6)heterocycloalkyl, -(Ci-Ce)hydroxyalkyl, -(Ci- Ce)alkylene-O-(Ci-C6)hydroxy alkyl; and pharmaceutically acceptable salts thereof.

[0020] In a second aspect, the invention refers to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof in admixture with one or more pharmaceutically acceptable carrier or excipient. In a third aspect, the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use as a medicament.

[0021] In a further aspect, the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in preventing and / or treating a disease, disorder or condition mediated by ALK5 receptor in a mammal.

[0022] In a further aspect, the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis.

[0023] In a further aspect, the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and / or treatment idiopathic pulmonary fibrosis (IPF).

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] Definitions

[0026] Unless otherwise specified, the compound of formula (I) of the present invention is intended to include also stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0027] The term “pharmaceutically acceptable salts”, as used herein, refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.

[0028] Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0029] Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0030] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0031] The term "diastereomer" refers to stereoisomers that are not mirror images.

[0032] The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.

[0033] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s). The isomeric descriptors "R" and "S" are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0034] The term "(Cx-Cy)alkyl", wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n- hexyl.

[0035] The term "(Cx-Cy)alkylene", wherein x and y are integers, refers to a (Cx-Cy)alkyl radical having in total two unsatisfied valencies, such as a divalent methylene radical.

[0036] The term “(Cx-Cy)cycloalkyl” wherein x and y are integers, refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0037] The term “(Cx-Cy)heterocycloalkyl” wherein x and y are integers, refers to saturated or partially unsaturated monocyclic or polycyclic groups containing the indicated number of ring carbon atoms in which at least one ring carbon atom is replaced by at least one heteroatom or hetero-group (e.g. N, NH, S or O) or may bear an oxo (=0) substituent group. The said heterocycloalkyl (i.e. heterocyclic radical or group) might be further optionally substituted on the available positions in the ring, namely on a carbon atom, or on a heteroatom or hetero-group available for substitution. Substitution on a carbon atom includes spiro di -substitution as well as substitution on two adjacent carbon atoms, in both cases thus forming an additional condensed 5- to 6-membered heterocyclic ring.

[0038] Throughout the specification the use of an asterisk in the definition of a structural formula, indicates the point of attachment for the radical group to the rest of the molecule.

[0039] A dash (“-”) that is not between two letters or symbols is meant to represent the point of attachment for a substituent.

[0040] The carbonyl group is herein preferably represented as -C(0)- as an alternative to the other common representations such as -CO-, -(CO)- or -C(=0)-.

[0041] In general, the bracketed group is a lateral group, not included into the chain, and brackets are used, when deemed useful, to help disambiguating linear chemical formulas; e.g. the sulfonyl group -SO2- might be also represented as -S(O)2- to disambiguate e.g. with respect to the sulfinic group -S(O)O-

[0042] The present invention relates to novel compounds differing from the structures disclosed in the prior art at least for a common new core scaffold. In fact, the invention relates to compounds that are (pyridazin-4-yl)amino pyrimidin-4-yl derivatives, which are active as inhibitors of receptor ALK5, having therefore therapeutically desirable characteristics, particularly promising for some fibrosis, including idiopathic pulmonary fibrosis (IPF).

[0043] In this respect, the state of the art does not describe or suggest (pyridazin-4-yl)amino pyrimidin-4-yl derivatives of general formula (I), advantageously characterized by good potency and low microsomial stability, which represents a solution to the aforementioned need.

[0044] In more details, the present invention refers to a series of compounds represented by the general formula (I), which are endowed with inhibitory activity on ALK5 receptor and low microsomal stability in human, and furthermore characterized by low systemic exposure; improved safety and tolerability; and good selectivity across the kinome. Advantageously, the inhibitory action on ALK5 receptor can be effective in the treatment of those diseases where this receptor plays a relevant role in the pathogenesis, such as fibrosis and / or diseases, disorders or conditions that involve fibrosis.

[0045] Differently from similar compounds of the prior art, the compounds of formula (I) of the present invention are able to act as antagonists of ALK5 receptor, particularly appreciated by the skilled person when looking at a suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis.

[0046] As indicated in the experimental part, in particular in Table 6, the compounds of formula (I) of the present invention show a microsomal half-life (ti / 2) < 11 minutes in human; due to this microsomial half-life, the compounds allow to minimize the systemic exposure and correlated safety issues.

[0047] Referring to the results outlined in Table 5, the compounds of the present invention are endowed by a very high potency, corresponding to a pKi > 9.3; due to their potency, the compounds according to the invention could be administered in human at a lower dosage compared to the compounds of the prior art, thus reducing the adverse events that typically occur administering higher dosages of drug.

[0048] In addition to being notably potent with respect to their inhibitory activity on receptor ALK5, the compounds of the present invention are also characterized by a good inhalatory profile, that permits to act effectively on the lung compartment, and have, at the same time, a low metabolic stability, that allows to minimize the drawbacks associated with the systemic exposure, such as safety and tolerability issues. Therefore, the compounds of the present invention are particularly appreciated by the skilled person when looking at a suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity on the lung, a good lung retention and to a low metabolic stability, that minimizes the systemic exposure and correlated safety issues.

[0049] In one aspect, the present invention relates to a compound of general formula (I) wherein Ri is selected from the group consisting of -(Ci-Ce)alkylene-(C3- C7)heterocycloalkyl, wherein said -(C3-C7)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkyl, wherein said - (C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-C6)heterocycloalkyl, -(Ci-Ce)hydroxyalkyl, -(Ci-C6)alkylene-O-(Ci-C6)hydroxyalkyl; and pharmaceutically acceptable salts thereof. According to a preferred embodiment, the invention refers to at least one of the compounds of Formula (I) listed in Table 1 below and pharmaceutically acceptable salts thereof.

[0050] Table 1: List of preferred compounds of Formula (I)

[0051] According to a preferred embodiment, the present invention refers to a compound of Formula (I), wherein Ri is selected from the group consisting of -(Ci-Ce)alkylene-(C3- C7)heterocycloalkyl, said -(C3-C7)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkyl, said -(C3- C6)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-C6)heterocycloalkyl and -(Ci-Ce)alkylene- O-(Ci-Ce)hydroxyalkyl.

[0052] Even more preferably, according to the first preferred embodiment of the compound of Formula (I), Ri is selected from the group consisting of (N-4-methylpiperazin-l-yl)ethyl; (N-4-methylpiperazin-l-yl)cyclobutan-l-yl; 3-morpholinopropyl; 2-morpholinoethyl; (3,5- dimethylpiperazin-l-yl)propyl; R2 is selected from the group consisting of methyl, tetrahydrothiophen-2-yl, and (2-hydroxyethoxy)methyl.

[0053] Preferably, the invention refers to at least one of the compounds of Formula (I) according to the first preferred embodiment (as listed in the Table la) and pharmaceutically acceptable salts thereof. These compounds are active on receptor ALK5, as shown in Table 5, and have good microsomal stability (ti / 2), as shown in Table 6. Table la: List of preferred compounds of Formula (I) According to another preferred embodiment, the present invention refers to a compound of Formula (I), wherein Ri is selected from the group consisting of -(Ci- C6)alkylene-(C3-C7)heterocycloalkyl, said -(C3-C7)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkyl, said -(C3-C6)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3- C6)heterocycloalkyl, -(Ci-C6)hydroxyalkyl.

[0054] In a more preferred embodiment the present invention refers to a compound of formula (I), wherein Ri is selected from the group consisting of 3 -morpholinopropyl, 2-morpholinoethyl, (3,5-dimethylpiperazin-l-yl)cyclobut-l-yl and (4-methyl-l,4-diazepan-l-yl)methyl; R2 is selected from the group consisting of methyl, tetrahydrothiophen-2-yl, and hydroxymethyl.

[0055] According to a preferred embodiment, the invention refers to at least one of the compounds of Formula (I) according to the second preferred embodiment (as listed in the Table lb) and pharmaceutically acceptable salts thereof. These compounds are active on receptor ALK5, as shown in Table 5, and have the best microsomal stability (ti / 2) amongst the compounds of Formula (I), as shown in Table 6.

[0056] Table lb: List of preferred compounds of Formula (I)

[0057] The compounds of the invention, including all the compounds here above listed, can be prepared from readily available starting materials using the following general methods and procedures outlined in detail below, or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by using other known methods, reagents and starting materials.

[0058] When typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. While the optimum reaction conditions may vary depending on the specific reactants or solvent used, such conditions can be readily determined by those skilled in the art by routine optimization procedures. Thus, processes described below should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention.

[0059] In some cases, a step is needed to mask or protect sensitive or reactive moieties, generally known protective groups (PG) could be employed, in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts).

[0060] The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit the receptor ALK5. Advantageously, the inhibition of ALK5 may result in efficacious treatment of the diseases or condition wherein the ALK5 receptor is involved.

[0061] In this respect, it has now been found that the compounds of formula (I) of the present invention have an inhibitory drug potency, measured as pICso (negative logarithm of ICso, half maximal inhibitory concentration) and subsequently converted to pKi (negative logarithm of dissociate function Ki), equal or higher than 9.3 on ALK5, as shown in the experimental part, Table 5.

[0062] It has now been found that the compounds of formula (I) of the present invention have a microsomal stability in human, expressed as half-life (ti / 2) < 11 minutes as shown in the experimental part (Table 6). Preferably, the compounds of the present invention have a microsomal half-life in human comprised between 3 and 10, more preferably comprised between 3 and 6.

[0063] In one aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament. Thus, the invention refers to a compound of formula (I) in the preparation of a medicament, preferably for use in the prevention and / or treatment of a disease, disorder or condition associated with ALK5 signaling pathway.

[0064] In a preferred embodiment, the invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease, disorder or condition associated with ALK5 signaling pathway.

[0065] In one embodiment, the present invention refers to a compound of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis.

[0066] The terms "fibrosis" or "fibrosing disorder" as used herein, refers to conditions that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are 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 digestive tract.

[0067] Preferably, the compounds of formula (I) of the present invention, or a pharmaceutical composition comprising a compound of formula (I) are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0068] More preferably, the compounds of formula (I) of the present invention, or a pharmaceutical composition comprising a compound of formula (I), are useful for the treatment of idiopathic pulmonary fibrosis (IPF).

[0069] As used herein, "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan. The compounds of formula (I) may be administered once or according to a dosing regimen, wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen.

[0070] The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) in admixture with at least one or more pharmaceutically acceptable carrier or excipient.

[0071] In one embodiment, the invention refers to a pharmaceutical composition including at least one of the compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

[0072] Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation. 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.

[0073] In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0074] In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is a tablet.

[0075] The compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.

[0076] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions and suspensions. Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and / or suspending the compounds of the invention.

[0077] In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.

[0078] For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir. A diluent or carrier chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.

[0079] Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

[0080] The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by j et or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.

[0081] The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.

[0082] The dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.

[0083] The invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in form of a single- or multidose dry powder inhaler or a metered dose inhaler.

[0084] All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and applied as well, mutatis mutandis.

[0085] The compounds of formula (I) including all the compounds or at least one of the here above listed compounds can be generally prepared according to the procedure outlined in detail in the Schemes shown below, using generally known methods.

[0086] Scheme 1

[0087] Scheme 1 provides a possible synthetic route for the preparation of a compound of formula (I).

[0088] A compound of formula (I) might be obtained by reacting a compound of formula (II) and a suitable halide (III) under standard Buchwald-Hartwig amination conditions. Typical Buchwald-Hartwig conditions involve the presence of an appropriate base, such as tripotassium phosphate, a suitable ligand reagent, such as Xantphos, and a suitable catalyst such as Pd2(dba)3, in an appropriate solvent such as 1,2-dimethoxy ethane and at an appropriate temperature, such as, for example, 100 °C.

[0089] In another embodiment, compounds of formula (I) can be prepared as described in

[0090] Scheme 2.

[0091] Scheme 2

[0092] Scheme 2 provides a possible synthetic route for the preparation of a compound of formula (I).

[0093] Compounds of formula (V) may be achieved using, for example, metal-catalyzed cross coupling reaction such as Buchwald-Hartwig amination of compound (IV) with the suitable halide (III), as described above. Deprotection of compound (V) under standard literature conditions such as by reaction with IN HC1, in a suitable solvent such as THF at an appropriate temperature, such as room temperature, afforded compound (I).

[0094] In another embodiment, compounds of formula (I) can be prepared as described in Scheme 3.

[0095] Scheme 3

[0096] Scheme 3 provides the possible synthetic routes for the preparation of a compound of formula (I). Compounds of Formula II may be obtained introducing R2 radical on compound VI by Minisci-like reaction involving redox active esters (RAEs, such as N-Hydroxy Phtalimide Esters NHPI), a suitable photocatalyst, such as 4CZIPN, in a suitable solvent, such as DMSO, under irradiation of an appropriate LED lamp, typically blue, as described in literature (Dhar and coworkers, J. Org. Chem. 2018, 83, 3000-3012). Then, the compound (I) is obtained from compound (II) by Buchwald-Hartwig cross coupling under similar reaction conditions reported for the synthesis of compound (I) in Scheme 2.

[0097] When R2 is -CH2OCH2CH2OH compound of formula (II) might be obtained as described in Scheme 4.

[0098] Scheme 4

[0099] Compound of formula (VIII) may be obtained with a one-step procedure from compound (VI) by transformation in a suitable leaving group, such as by reaction with methanesulfonic anhydride, in a presence of a suitable base, such as DIPEA, in a suitable solvent such as DCM, at an opportune temperature, such as from 0°C to room temperature, followed by nucleophilic substitution with ethylene glycol. N-deprotection of compound (VIII) under acidic conditions, such as, for example, TFA solution in DCM at room temperature, allowed to obtain compounds of formula (II).

[0100] Compound of formula (III) might be obtained as described in Scheme 5.

[0101] Scheme 5

[0102] Compounds of formula (III) may be achieved using, for example, metal-catalyzed cross coupling reaction such as Buchwald-Hartwig amination between the opportune amide (IX) and the commercially available 4,6-dichloropyrimidine (X). Typical Buchwald-Hartwig conditions involve the presence of an appropriate base, such as CS2CO3, a suitable ligand reagent, such as Xantphos, and a suitable catalyst such as Pd(OAc)2, in an appropriate solvent such as 1,2-dimethoxy ethane and at an appropriate temperature, such as, for example, 75 °C. PREPARATIONS OF INTERMEDIATES AND EXAMPLES

[0103] Chemical Names of the compounds were generated with Structure To Name function of ChemDraw 22.0. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

[0104] Abbreviation - meaning cHex= Cyclohexane; DCM= Dichloromethane; DME= 1,2-Dimeth oxy ethane; EtOAc= Ethyl acetate; EtOH= Ethanol; FCC= flash column chromatography; H2O= water; h= hour; hrs= hours; K3PO4= Potassium phosphate tribasic; MeCN= Acetonitrile; MeOH= MethanolN2= nitrogen; Na2SO4= Sodium sulfate; NaHCO3= Sodium bicarbonate; Pd2(dba)3= Tris(dibenzylideneacetone)dipalladium (0); Pd(OAc)2= Palladium(II) acetate; RT= room temperature; SCX= Strong cation exchange cartridge; SFC= Supercritical fluid chromatography; TFA= Trifluoroacetic acid; THF= Tetrahydrofuran; ty? = Retention time; UPLC = Ultra high-performance liquid chromatography; LCMS = liquid chromatographymass spectrometry; Xanthphos= 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

[0105] General Experimental Details and methods

[0106] Analytical methods

[0107] Instruments, materials, and methods employed for analyses.

[0108] 'H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHZ (proton frequency), equipped with: a self-shielded Z-gradient coil 5 mm IH / nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift, or on Agilent VNMRS-500, or on a Bruker Avance 400. Chemical shifts are reported as 5 values in ppm relative to trimethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation (s= singlet, d= doublet, t= triplet, q= quartet, m=multiplet, br. s.= broad singlet, br. d.= broad doublet, dd= double-doublet, dt= doublet of triplets, ddd= double-double- doublet, quin= quintuplet).

[0109] In some cases, signals NH from amide bond or amine bond (Exchangeable protons) are not visible. In a few cases, some signals could be hidden under the signal of water or under the signal of DMSO or other residual solvents.

[0110] LC / UV / MS Analytical Methods

[0111] LC / MS retention times were estimated 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 taken on UPLC / PDA / MS AcquityTM system coupled with Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operated in positive and / or negative electron spray ES ionization mode and / or Fractionlynx system used in analytical mode coupled with ZQTM single quadrupole operated in positive and / or negative ES ionisation mode. Quality Control methods used operated under low pH conditions or under high pH conditions:

[0112] Method 1, low pH conditions column: Acquity CSH C18 2.1x50mm 1.7pm, the column temperature was 40 °C; mobile phase solvent A was milliQ water+0.1% HCOOH, mobile phase solvent B MeCN+0.1% HCOOH. The flow rate was 0.9 mL / min.

[0113] The 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. The UV detection range was 210-350 nm and ES+ZES- range was 100 to 1000 AMU.

[0114] Method 2, high pH conditions: column: Acquity Kinetex 1.7 um EVO C18 100A, 2.1x50mm, the column temperature was 40 °C; mobile phase solvent A was 10 mM aqueous solution of NH4HCO3 adjusted to pH=10 with ammonia, mobile phase solvent B MeCN. The flow rate was 0.9 mL / min. The 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. The UV detection range was 210-350 nm and ES+ZES- range was 100 to 1000 AMU.

[0115] Method 3, Acquity CSH C18 column 50mm x 2.1mm 1.7pm, maintained at 40°C; Mobile Phase: Eluent B (ACN) in Eluent A (water +0.1% HCOOH) from 1% to 99.9% within 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0116] Purification methods

[0117] Preparative chiral HPLC. The purification was performed using Chiralpak AD-H or AS.H column in the conditions detailed in the Experimental Part.

[0118] FCC. The purification was performed on Biotage silica or NH or reversed phase Cl 8 cartridges in the conditions detailed in the Experimental Part.

[0119] 1.2 General Synthetic procedures

[0120] Intermediate 1 : 3-morpholinopropanamide

[0121] 2-propenamide (500 mg, 7.03 mmol) and morpholine (0.61 mL, 7.03 mmol) were mixed in water (9.8 mL) / MeCN (1.6 mL) and stirred at 60 °C for 8 hrs. The day after volatiles were removed under vacuum to afford the title compound (1.15 g, 7.27 mmol, recovery assumed quantitative).

[0122] 'H NMR (400 MHz, CDCls) 5 7.92 (br. s., 1 H) 5.51 (br. s., 1 H) 3.73 (t, J= 4.62 Hz, 4 H) 2.34 - 2.70 (m, 8 H). Intermediate 2: N-(6-chloropyrimidin-4-yl)-4-morpholinobutanamide

[0123] A mixture of 4-morpholinobutanamide (synthesised as reported in WO2015177367, Intermediate 17, 500 mg, 2.9 mmol), CS2CO3 (1.9 g, 5.81 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), 4,6-dichloropyrimidine (433 mg, 2.9 mmol) and xanthphos (202 mg, 0.35 mmol) in DME (12 mL) was degassed (^ lvacuum), then heated at 75 °C for 45 min. The mixture was cooled to RT and diluted with EtOAc, filtered washing with EtOAc. The filtrate was evaporated under vacuum. The residual material was purified by FCC on Biotage NH silica cartridge (from cHex to 20% EtOAc / EtOH 3 / 1) to give the title compound (445 mg, 1.56 mmol, 54% yield).

[0124] LCMS method 2: ty? 0.61 min, MS (ESI) m / z = 285.0 [M+H]+

[0125] 'H NMR (400 MHz, DMSOde) 5 11.19 (s, 1H), 8.74 (s, 1H), 8.14 (d, J= 0.8 Hz, 1H), 3.47-3.53 (m, 4H), 2.47 (s, 2H), 2.25-2.36 (m, 6H), 1.70-1.79 (m, 2H).

[0126] Intermediate 3 : 2-((6-(5-chloro-2-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridazin- 3 -yl)methoxy)ethan- 1 -ol

[0127] Methanesulfonic anhydride (1.52 g, 8.74 mmol) was added to an ice cooled solution of (6-(5-chloro-2-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)pyridazin-3-yl)methanol (synthesised as reported in W02022013307 Intermediate 270, 2.52 g, 6.24 mmol) and DIPEA (2.83 mL, 16.22 mmol) in DCM (78 mL). The reaction mixture was stirred at the same temperature for 40 min, then ethylene glycol (8.72 mL, 156 mmol) was added. The mixture was stirred at 0 °C for 15 minutes, then warmed to RT and stirred overnight. The reaction was diluted with DCM and washed with sat. aq. NaHCCh. The organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by FCC on Biotage silica cartridge (from cHex to 30% EtOAc / EtOH) to give the title compound (1.36 g, 3.04 mmol, 49% yield).

[0128] LCMS method 2: tz? 0.94 min, MS (ESI) m / z = 448.2 [M+H]+

[0129] 'H NMR (400 MHz, CDCls) 5 8.08 (dd, J= 6.6, 2.7 Hz, 1H), 7.35 (ddd, J= 8.8, 4.2, 2.7 Hz, 1H), 7.17 (d, J= 8.2 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.51 - 6.43 (m, 2H), 6.17 (t, J = 5.5 Hz, 1H), 4.96 (s, 2H), 4.34 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.74 (dt, J =

[0130] 4.8, 2.5 Hz, 3H), 3.65 - 3.61 (m, 2H).

[0131] Intermediate 4: 2-((4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)methoxy)ethan-l-ol

[0132] A solution of Intermediate 3 (2.6 g, 5.8 mmol) and TFA (13.34 mL, 174.15 mmol) in dry DCM (11.6 mL) was stirred at RT for 24 hrs. Toluene was added and the solvents were evaporated. The resulting crude material was purified by SCX cartridge (70 g, eluting with NH3 IN in MeOH) and then by FCC on Biotage NH cartridge (from cHex to 50% EtOAc / EtOH 3 / 1) to give the title compound (1.66 g, 5.58 mmol, 96 % yield).

[0133] LCMS method 2: tz? 0.60 min, MS (ESI) m / z = 298.1 [M+H]+.

[0134] Intermediate 5a: L3-dioxoisoindolin-2-yl tetrahydrothiophene-2-carboxylate

[0135] To a solution of thiolane-2-carboxylic acid (500 mg, 3.78 mmol) in dry dry-DMSO (4 mL), N-hydroxy phthalimide (617 mg, 3.78 mmol) and N,N'-diisopropylcarbodiimide (0.586 mL, 3.78 mmol) were added and the solution was stirred for 1 hr affording title compound 0.945 M in DMSO (1049 mg, 3.78 mmol, 100 % yield) and it was used in the next step without any purification.

[0136] LCMS method 3: tz? 1.02 min, MS (ESI) m / z = 278.5 [M+H]+.

[0137] Intermediate 5b: 6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2-yl)pyridazin-4- amine

[0138] To a solution of 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (synthesized as reported in W02022013307 Int.3, 200 mg, 0.894 mmol) in dry DMSO (3 ml), 1,3- dioxoisoindolin-2-yl tetrahydrofuran-3-carboxylate 0.945 M in DMSO (1.420 mL, 1.341 mmol), 4CZIPN (35.3 mg, 0.045 mmol), CSA (415 mg, 1.789 mmol) were added. The solution bubbled vigorously with Argon, sealed, and irradiated with EVOLUCHEM LED 450DX lamp. The reaction was stirred at rt for Ih. the solvent was removed by SCX cartridge and the crude was purified by NH-Silica column (eluent: DCM: DCM / MeOH 9 / 1 from 100:0 to 50:50) to give title compound 6-(5-chloro-2-fluorophenyl)-3-(tetrahydrofuran-3- yl)pyridazin-4-amine (120 mg, 0.409 mmol, 45.7 % yield).

[0139] LCMS method 3: tR0.57 min, MS (ESI) m / z = 310.07 [M+H]+.

[0140] Intermediate 6; tert-butyl (2S,6R)-4-(3-((6-((6-(5-chloro-2-fluorophenyl)-3- methylpyridazin-4-yl)amino)pyrimidin-4-yl)amino)-3-oxopropyl)-2,6-dimethylpiperazine-l- carboxylate

[0141] In a vial, a mixture of tert-butyl (2S,6R)-4-(3-((6-chloropyrimidin-4-yl)amino)-3- oxopropyl)-2,6-dimethylpiperazine-l -carboxylate (synthesised as reported in WO2023046698 Intermediate 308, 195 mg, 0.49 mmol), 6-(5-chloro-2-fluorophenyl)-3- methylpyridazin-4-amine (synthesised as reported in W02022013307 Intermediate 308, 120 mg, 0.49 mmol), K3PO4 (208 mg, 0.98 mmol), Pd2(dba)3 (45 mg, 0.05 mmol) and xanthphos (42 mg, 0.07 mmol) was suspended in DME (3.5 mL). The mixture was degassed ( i / vacuum) then heated at 100 °C for 2 hrs. The mixture was diluted with EtOAc, filtered washing with EtOAc and the solvent removed under reduced pressure. The crude product was purified by FCC on Biotage NH cartridge (from cHex to 55% of EtOAc) to give the title compound (160 mg, 0.27 mmol, 55% yield).

[0142] LCMS method 2: tz? 1.19 min, MS (ESI) m / z = 599.2 [M+H]+.

[0143] The Intermediates listed in Table 2 were prepared from the suitable reagents in analogy to the procedures followed for Intermediate 6 using the appropriate amine and the opportune aryl chloride intermediates.

[0144] Intermediate 7, 8: Table 2

[0145] Intermediate 9: N-(6-((6-(5-chloro-2-fluorophenyl)-3-(hvdroxymethyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-2-( 1 ,4-diazepan- 1 -yDacetamide A mixture of Intermediate 7 (150 mg, 0.210 mmol) in THF (4 mL) was treated with IN

[0146] HC1 (2.14 mL, 2.14 mmol) and stirred for 5 hrs at RT. Only silyl group was removed. The mixture was concentrated under reduced pressure and the residue was purified by SCX (washing with MeOH and eluting with IN NH3 in MeOH). On SCX cartridge also the BOC group was cleaved. Basic fractions were collected and concentrated under reduced pressure to give the title compound (70 mg, 0.14 mmol, 67% yield).

[0147] LCMS method 2: ty? 0.78 min, MS (ESI) m / z = 487.1 [M+H]+

[0148] Example 1 : N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin- 4-yl)-3-(4-methylpiperazin-l-yl)propanamide

[0149] In a vial, a mixture of N-(6-chloropyrimidin-4-yl)-3-(4-methylpiperazin-l- yl)propanamide (synthesised as reported in WO2023046698 Intermediate 272, 131 mg, 0.46 mmol), 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (synthesised as reported in W02022013307 Intermediate 90, 100 mg, 0.42 mmol), K3PO4 (181 mg, 0.84 mmol), Pd2(dba)3 (39 mg, 0.04 mmol) and xanthphos (37 mg, 0.06 mmol) was suspended in DME (4.2 mL). The mixture was degassed ( i / vacuun ) then heated at 100 °C for 3 hrs. The mixture was diluted with EtOAc, filtered washing with EtOAc and the solvent removed under reduced pressure. The crude product was purified by FCC on Biotage NH cartridge (from cHex to 100% EtOAc), then it was further purified by FCC on Biotage silica cartridge (from DCM to 30% MeOH) to give the title compound (111 mg, 0.23 mmol, 54% yield).

[0150] LCMS method 2: tz? 0.82 min, MS (ESI) m / z = 485.2 [M+H]+

[0151] ’H NMR (500 MHz, MeOD-d4) 5 9.03 (d, J=1.5 Hz, 1 H), 8.52 (d, J=l.l Hz, 1 H), 7.99 (d, .7=1.0 Hz, 1 H), 7.92 (dd, J=6.4, 2.7 Hz, 1 H), 7.50 - 7.57 (m, 1 H), 7.31 (dd, J=10.3, 8.9 Hz, 1 H), 2.78 (s, 3 H), 2.76 - 2.81 (m, 2 H), 2.62 - 2.66 (m, 2 H), 2.31 (s, 3 H), 2.57 (br. s., 8 H).

[0152] The Examples listed in Table 3 were prepared from the suitable reagents in analogy to the procedures followed for Example 1. In some cases, where modification involved equivalents, such change was reported in the table. Purification conditions were adjusted for each compounds making changes easily identifiable by the skilled person. Examples 2-4: Table 3

[0153] Example 5 (Enantiomer 1) and Example 6 (Enantiomer 2): (ls,3s)-N-(6-((6-(5-chloro-2- fluorophenyl)-3-(tetrahydrothiophen-2-yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3-(4- methylpiperazin-l-yl)cyclobutane-l -carboxamide (single enantiomers) Racemic (ls,3s)-N-(6-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2- yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3 -(4-methylpiperazin- 1 -yl)cyclobutane- 1 - carboxamide (206 mg, 0.35 mmol, y= 30%) was prepared in analogy to the procedure followed for Example 1 starting Intermediate 5b (360 mg, 1.16 mmol) and (ls,3s)-N-(6- chloropyrimidin-4-yl)-3-(4-methylpiperazin-l-yl)cyclobutane-l -carboxamide (synthesised as reported in WO2023046698 Intermediate 190, 404 mg, 1.28 mmol). It was separated into the single enantiomers by preparative chiral HPLC on a Chiralpak AS-H (25 x 2.0 cm), 5p column with 400 pl Loop using n-Hexane / (Ethanol / Methanol 1 / 1 + 0.1 % isopropylamine) 50 / 50 % v / v as eluent at Flow rate = 17 ml / min, with DAD at 220 nm.

[0154] Example 5 was obtained as first eluted enantiomer (75 mg) Rt = 4.0 min, ee 100%

[0155] LCMS method 2: tz? 0.97 min, MS (ESI) m / z = 583.1 [M+H]+

[0156] 'H NMR (500 MHz, CDCls) 5 9.81 (s, 1 H), 8.96 (s, 1 H), 8.55 (s, 1 H), 8.50 (s, 1 H), 8.18 (dd, J= 6.6, 2.7 Hz, 1 H), 7.74 (s, 1 H), 7.41 (ddd, J= 8.7, 4.0, 3.0 Hz, 1 H), 7.16 (dd, J= 10.3, 8.9 Hz, 1 H), 5.08 (t, J= 7.8 Hz, 1 H), 3.21 - 3.28 (m, 2 H), 3.00 (quin, J= 7.8 Hz, 1 H), 2.88 - 2.95 (m, 1 H), 2.45 - 2.59 (m, 8 H), 2.41 - 3.10 (m, 8 H), 2.20 - 2.29 (m, 2 H), 2.08 - 2.18 (m, 1 H).

[0157] Example 6 was obtained as the second eluted enantiomer (68 mg)

[0158] Rt = 5.5 min, ee 96.8%

[0159] LCMS method 2: tz? 0.97 min, MS (ESI) m / z = 583.1 [M+H]+

[0160] 'H NMR (500 MHz, CDCls) 5 9.81 (s, 1 H), 8.96 (s, 1 H), 8.55 (s, 1 H), 8.50 (s, 1 H), 8.18 (dd, J= 6.6, 2.7 Hz, 1 H), 7.74 (s, 1 H), 7.41 (ddd, J= 8.7, 4.0, 3.0 Hz, 1 H), 7.16 (dd, J = 10.3, 8.9 Hz, 1 H), 5.08 (t, J= 7.8 Hz, 1 H), 3.21 - 3.28 (m, 2 H), 3.00 (quin, J= 7.8 Hz, 1 H), 2.88 - 2.95 (m, 1 H), 2.45 - 2.59 (m, 8 H), 2.41 - 3.10 (m, 8 H), 2.20 - 2.29 (m, 2 H), 2.08 - 2.18 (m, 1 H).

[0161] Example 7 : N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin- 4-yl)-3-morpholinopropanamide

[0162] A mixture of CS2CO3 (310 mg, 0.90 mmol), xanthphos (33 mg, 0.06 mmol), 4,6- dichloropyrimidine (70 mg, 0.47 mmol), Intermediate 1 (74 mg, 0.47 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) in DME (2 m ) was degassed ( 2 / vacuum)., then heated at 80 °C for 1 h. The reaction was cooled down to RT, 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4- amine (synthesised as reported in W02022013307 Intermediate 90, 100 mg, 0.41 mmol), CS2CO3 (310 mg, 0.94 mmol), xanthphos (33 mg, 0.06 mmol), Pd(OAc)2 (5 mg, 0.02 mmol) were added, degassed (Ni / vacuui ), then heated at 100 °C for 1.5 h. The mixture was diluted with EtOAc, filtered through a celite® pad, washing with EtOAc. The filtrate was evaporated under vacuum. The crude material was purified by FCC on Biotage NH cartridge (from cHex to 100% EtOAc) affording the title compound (93 mg, 0.20 mmol, 48% yield).

[0163] LCMS method 2: tz? 0.86 min, MS (ESI) m / z = 472.4 [M+H]+

[0164] 'H NMR (500 MHz, CDCh . 5 11.66 (s, 1 H), 8.99 (d, J= 0.8 Hz, 1 H), 8.59 (s, 1 H), 8.14 (dd, J= 6.6, 2.7 Hz, 1 H), 7.77 (d, J = 0.8 Hz, 1 H), 7.35 - 7.45 (m, 1 H), 7.16 (dd, J = 10.3, 8.9 Hz, 1 H), 6.68 (s, 1 H), 3.89 (t, J= 4.5 Hz, 4 H), 2.80 (s, 3 H), 2.74 - 2.79 (m, 2 H), 2.65 (br. s., 4 H), 2.55 - 2.61 (m, 2 H).

[0165] The Example listed in Table 4 was prepared from the suitable reagents in analogy to the procedures followed for Example 7. Modification of equivalents was reported in the table. Purification conditions were adjusted for each compounds making changes easily identifiable by the skilled person.

[0166] Example 8: N-(6-((6-(5-chloro-2-fluorophenyl)-3-((2-hydroxyethoxy)methyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-3-morpholinopropanamide

[0167] Table 4

[0168] Example 9: N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin-

[0169] 4-yl)-34(3SAR)-3A-dimethylpiperazin-l-yl)propanamide

[0170] TFA (0.2 mL, 2.67 mmol) was added to a solution of Intermediate 6 (160 mg, 0.27 mmol) in DCM (4 mL). The mixture was stirred at RT for 4 hrs, volatiles were removed under vacuum, the residue was purified by SCX cartridge, washing with MeOH and eluting with IN NH3 in MeOH. Basic fraction was evaporated to afford a yellow oil, addiction of MeCN afforded a white precipitate which was filtered rinsing with more MeCN, then dried to give the title compound (98 mg, 0.20 mmol, 74% yield). LCMS method 2: tz? 0.83 min, MS (ESI) m / z = 499.1 [M+H]+

[0171] 'H NMR (500 MHz, DMSO-de) 5 11.10 (s, 1 H), 9.30 (br. s., 1 H), 8.86 (s, 1 H), 8.51 (s, 1 H), 8.02 (s, 1 H), 7.96 (dd, J= 6.6, 2.7 Hz, 1 H), 7.63 (ddd, J= 8.7, 4.1, 3.0 Hz, 1 H), 1A1 (dd, J = 10.4, 9.0 Hz, 1 H), 2.73 (s, 3 H), 2.72 - 2.79 (m, 4 H), 2.52 - 2.63 (m, 4 H), 1.94 (br. s., 1 H), 1.44 - 1.56 (m, 2 H), 0.92 (d, J= 6.2 Hz, 6 H).

[0172] Example 10 (Enantiomer 1) and Example 11 (Enantiomer 2): (ls,3s)-N-(6-((6-(5-chloro-2- fluorophenyl)-3-(tetrahydrothiophen-2-yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3-((3S,5R)-3,5- dimethylpiperazin-l-yl)cyclobutane-l -carboxamide (single enantiomers)

[0173] Racemic (ls,3s)-N-(6-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2- yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3-((3S,5R)-3,5-dimethylpiperazin-l- yl)cyclobutane-l -carboxamide (19 mg, 0.03 mmol, y= 49%) was prepared in analogy to the procedure followed for Example 9 starting from Intermediate 8 (45 mg, 0.06 mmol). It was separated into the single enantiomers by preparative chiral HPLC on a Chiralpak AD-H (25 x 2.0 cm), 5 p column with 1000 pl Loop using n-Hexane / (Ethanol / Methanol 1 / 1 + 0.1 % isopropylamine) 40 / 60 % v / v as eluent at Flow rate = 17 mL / min, with DAD at 220 nm.

[0174] Example 10 was obtained as first eluted enantiomer (7 mg)

[0175] Rt = 5.0 min, ee 100%

[0176] LCMS method 2: tz? 1.02 min, MS (ESI) m / z = 597.3 [M+H]+

[0177] >H NMR (500 MHz, CDCls) 5 9.90 (s, 1H), 8.94 (d, J= 1.4 Hz, 1H), 8.56 (d, J= 0.8 Hz, 1H), 8.47 (br. s., 1H), 8.18 (dd, J= 6.7, 2.7 Hz, 1H), 7.75 (d, J= 0.8 Hz, 1H), 7.41 (ddd, J = 8.7, 4.2, 2.7 Hz, 1H), 7.16 (dd, J = 10.4, 8.9 Hz, 1H), 5.08 (t, J = 7.8 Hz, 1H), 3.24 (dd, J = 8.2, 4.1 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.99 (quin, J = 7.8 Hz, 1H), 2.90 (br. d., J= 9.5 Hz, 2H), 2.79 (quin, J = 6.4 Hz, 1H), 2.57 - 2.44 (m, 5H), 2.29 - 2.20 (m, 2H), 2.18 - 2.05 (m, 1H), 1.47 (t, J = 10.6 Hz, 2H), 1.39 - 1.15 (m, 1H), 1.09 (d, J = 6.3 Hz, 6H).

[0178] Example 11 was obtained as the second eluted enantiomer (7.4 mg)

[0179] Rt = 12.6 min, ee 100%

[0180] LCMS method 2: tz? 1.02 min, MS (ESI) m / z = 597.3 [M+H]+

[0181] >H NMR (500 MHz, CDCls) 5 9.90 (s, 1H), 8.94 (d, J= 1.4 Hz, 1H), 8.56 (d, J= 0.8 Hz, 1H), 8.47 (br. s., 1H), 8.18 (dd, J= 6.7, 2.7 Hz, 1H), 7.75 (d, J= 0.8 Hz, 1H), 7.41 (ddd, J = 8.7, 4.2, 2.7 Hz, 1H), 7.16 (dd, J = 10.4, 8.9 Hz, 1H), 5.08 (t, J = 7.8 Hz, 1H), 3.24 (dd, J = 8.2, 4.1 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.99 (quin, J = 7.8 Hz, 1H), 2.90 (br. d., J= 9.5 Hz, 2H), 2.79 (quin, J = 6.4 Hz, 1H), 2.57 - 2.44 (m, 5H), 2.29 - 2.20 (m, 2H), 2.18 - 2.05 (m, 1H), 1.47 (t, J = 10.6 Hz, 2H), 1.39 - 1.15 (m, 1H), 1.09 (d, J = 6.3 Hz, 6H)

[0182] Example 12: N-(6-((6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-2-(4-methyl- 1 ,4-diazepan- 1 -yDacetamide

[0183] To a stirred solution of Intermediate 9 (70 mg, 0.14 mmol) in MeOH (3 mL), at RT, formaldehyde 37 wt. % in H2O (17 pL, 0.22 mmol) and acetic acid (12 pL, 0.22 mmol) were subsequently added. After 15 min sodium cyanoborohydride (12 mg, 0.20 mmol) was added portion-wise and the resulting reaction mixture was stirred at RT overnight. Volatiles were removed under vacuum, the crude material was purified by SCX (washing with MeOH and eluting with IN NH3 in MeOH). Basic fractions were collected an evaporated, the solid obtained was suspended in DCM and filtered to afford the title compound (41 mg, 0.08 mmol, 57% yield).

[0184] LCMS method 2: tz? 0.89 min, MS (ESI) m / z = 501.4 [M+H]+

[0185] ’H NMR (400 MHz, DMSO d6) 5 10.16 (br. s., 1 H), 9.39 (br. s., 1 H), 9.03 (s, 1 H), 8.58 (s, 1 H), 7.97 (dd, J= 6.6, 2.6 Hz, 1 H), 7.92 (s, 1 H), 7.58 - 7.73 (m, 1 H), 7.40 - 7.55 (m, 1 H), 5.36 - 6.38 (m, 1 H), 5.02 (s, 2 H), 3.38 (s, 2 H), 2.75 - 2.87 (m, 4 H), 2.53 - 2.60 (m, 4 H), 2.26 (s, 3 H), 1.75 (quin, J = 5.9 Hz, 2 H).

[0186] PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION

[0187] In vitro Assay

[0188] The enzymatic activity of compounds of the present invention was monitored measuring the formation of ADP using the ADP-GLO Kinases assay. Following the incubation of the purified enzyme, a substrate and ATP, the produced ADP was converted into ATP, which in turn was converted into light by Ultra-Gio Luciferase. The luminescent signal positively correlated with ADP amount and kinase activity. Briefly, the kinase reaction was performed by incubating 2.6 nM of the purified, commercially available human ALK5 (recombinant TGF pi N-term GST-tagged, 80-end), a final concentration of TGFpi peptide 94.5 pM (Promega, T36-58) and ultra-pure ATP (Promega V915B). The ATP concentration was set at the Km value (concentration of substrate which permits the enzyme to achieve half maximal velocity (Vmax)) of ALK5 (0.5pM). Compound and ALK5 kinase were mixed and incubated for 15 minutes. Reactions were initiated by addition of ATP at a final concentration in the assay of 0.83 pM. After an incubation of 120 minutes, the reaction was stopped, and ADP production detected with ADP-Glo kit according to manufacturer’s indications. All reaction and incubation steps were performed at 25 °C and the assays were performed in 384-well format and validated using a selection of reference compounds tested in 11 -point concentration-response curve. The results for individual compounds are provided below in Table 5 wherein the compounds are classified in term of potency with respect to their inhibitory activity on ALK5 receptor. Results were expressed as pICso (negative logarithm of ICso) and subsequently converted to pKi (negative logarithm of dissociate function Ki) using the Cheng-Prusoff equation. The higher the value of pKi, the greater the inhibition of ALK5 activity.

[0189] As it can be appreciated, all the compounds of Table 5 show pKi values > 9.3 when tested in the biochemical ALK5 assay.

[0190] Table 5

[0191] Determination of Microsomes Stability

[0192] Test compound was incubated, in duplicate, at the concentration of 0.5 pM with liver microsomes (0.5 mg protein / mL) in phosphate buffer (pH 7.4) at 37 °C in the presence of NADPH regenerating system. At different time points (0, 3, 10, 15, 30, and 45 min), 50pl- aliquots were taken and acetonitrile containing internal standard (150pl) was added to stop the reaction. Samples were centrifuged (3000 rpm, lOmin) and the supernatants were analyzed by LC-MS / MS monitoring the test items and the internal standards. Dextromethorphan and Verapamil at the concentration of 0.5 pM were used as positive control. Rate constant (k) for parent degradation was calculated by determining the slope of the graph line of the natural log of the percentage parent remaining versus incubation time. Half-life (ti / 2) of the test item, which represents the time required for the parent compound abundance to decrease to one-half its initial value, was calculated as follow: ti / 2 = 0.693 / k.

[0193] The results for individual compounds are provided below in Table 6, wherein the compounds are classified in term of microsomal stability in human. Results were expressed as half-life (ti / 2, min). The lower the ti / 2, the higher the hepatic metabolism of the tested compound.

[0194] As it can be appreciated, all the compounds of Table 6 show a half-life (ti / 2) < 11 minutes in human.

[0195] Table 6

Claims

CLAIMS1. A compound of formula (I)whereinRi is selected from the group consisting of -(Ci-Ce)alkylene-(C3- C7)heterocycloalkyl, wherein said -(C3-C7)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci- Ce)alkyl;R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3- C6)heterocycloalkyl, -(Ci-Ce)hydroxyalkyl, -(Ci-C6)alkylene-O-(Ci-C6)hydroxyalkyl; or pharmaceutically acceptable salts thereof.

2. The compound of formula (I) according to claim 1 wherein Ri is selected from the group consisting of -(Ci-C6)alkylene-(C3-C7)heterocycloalkyl, said -(C3-C7)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkyl, said -(C3-C6)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3- C6)heterocycloalkyl, and -(Ci-C6)alkylene-O-(Ci-C6)hydroxyalkyl.

3. The compound of formula (I) according to claim 2, wherein Ri is selected from the group consisting of (N-4-methylpiperazin-l-yl)ethyl, (N-4-methylpiperazin-l-yl)cyclobutan-l-yl, 3 -morpholinopropyl, 2-morpholinoethyl and (3,5-dimethylpiperazin-l-yl)propyl; R2 is selected from the group consisting of methyl, tetrahydrothiophen-2-yl and (2- hy droxy ethoxy)methyl .

4. The compound of formula (I) according to claims 2 or 3, selected from at least one of the following:N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin-4- yl)-3-(4-methylpiperazin-l-yl)propanamide;(ls,3s)-N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4- yl)amino)pyrimidin-4-yl)-3 -(4-methylpiperazin- 1 -yl)cyclobutane- 1 -carboxamideN-(6-((6-(5-chloro-2-fluorophenyl)-3-((2-hydroxyethoxy)methyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-4-morpholinobutanamide;(ls,3s)-N-(6-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2- yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3-(4-methylpiperazin-l-yl)cyclobutane-l- carboxamide;N-(6-((6-(5-chloro-2-fluorophenyl)-3-((2-hydroxyethoxy)methyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-3-morpholinopropanamide;N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin-4- yl)-3-((3S,5R)-3,5-dimethylpiperazin-l-yl)propenamide.

5. The compound of formula (I) according to claim 1, wherein Ri is selected from the group consisting of -(Ci-C6)alkylene-(C3-C7)heterocycloalkyl, said -(C3-C7)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; and -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkyl, said -(C3-C6)heterocycloalkyl being optionally substituted by one or more -(Ci-Ce)alkyl; R2 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3- C6)heterocycloalkyl and -(Ci-C6)hydroxyalkyl.

6. The compound of formula (I) according to claim 5, wherein Ri is selected from the group consisting of 3 -morpholinopropyl, 2-morpholinoethyl, (3,5-dimethylpiperazin-l- yl)cyclobut-l-yl and (4-methyl-l,4-diazepan-l-yl)methyl; R2 is selected from the group consisting of methyl, tetrahydrothiophen-2-yl, and hydroxymethyl.

7. The compound of formula (I) according to claims 5 or 6 selected from at least one of the following:N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin-4- yl)-4-morpholinobutanamide;N-(6-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyrimidin-4- yl)-3-morpholinopropanamide;(ls,3s)-N-(6-((6-(5-chloro-2-fluorophenyl)-3-(tetrahydrothiophen-2- yl)pyridazin-4-yl)amino)pyrimidin-4-yl)-3-((3S,5R)-3,5-dimethylpiperazin-l- yl)cyclobutane- 1 -carboxamide;N-(6-((6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4- yl)amino)pyrimidin-4-yl)-2-(4-m ethyl- 1 ,4-diazepan- 1 -yl)acetamide.

8. A pharmaceutical composition comprising a compound of formula (I) according to claims any one of claims from 1 to 7, in admixture with one or more pharmaceutically acceptable carrier or excipient.

9. The pharmaceutical composition according to claim 8 for administration by inhalation.

10. The compound of formula (I) according to any one of claims from 1 to 7 or the pharmaceutical composition according to claim 8 or 9, for use as a medicament.

11. The compound of formula (I) or the pharmaceutical composition for use according to claim 10 in the prevention and / or treatment of a disease, disorder or condition mediated by ALK5 signaling pathway in mammals.

12. The compound of formula (I) or the pharmaceutical composition for use according to claim 10 or 11 in the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions that involve fibrosis.

13. The compound of formula (I) or the pharmaceutical composition for use according to claim 12, in the prevention and / or treatment of fibrosis including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

14. The compound of formula (I) or the pharmaceutical composition for use according to claim 13 in the prevention and / or treatment idiopathic pulmonary fibrosis (IPF).

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