EP4673213A1 - Pyridazinyl amino derivatives as alk5 inhibitors - Google Patents

Abstract

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

Description

PYRIDAZINYL AMINO DERIVATIVES AS ALK5 INHIBITORS

FIELD OF THE INVENTION

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 use 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.

BACKGROUND OF THE INVENTION

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, immunosuppression, cancerogenesis and extracellular matrix production. 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). 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)). Several studies have linked an excessive and/or dysregulated TGF P 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 J Respir 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). 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). 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). 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. 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.

Various compounds have been described in the literature as ALK5 and/or ALK4 receptor inhibitors. Pyridazinyl amino derivatives have been disclosed in WO 2022/013307 as potent ALK5 inhibitors.

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

Several efforts have been made 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.

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 across species, low plasma stability, in order to minimize the systemic exposure and correlated safety issues.

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.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein A is group Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3-carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3-yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -((l-oxo-lH-isochromen-3-yl)methyl)sulfanyl) and -[(l-oxo-3,4- dihy dro- 1 H-2-benzopyran-3 -yl)methyl] sulfanyl ; R₂ is -NR₃C(O)R₄;

RJ is H;

R4 is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; - (Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo.

Preferably, the invention relates to a compound of formula (I) and pharmaceutically acceptable salts thereof, wherein

A is group Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3- carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3- yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -((l-oxo-lH-isochromen-3- yl)methyl)sulfanyl) and -[(l-oxo-3,4-dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R2 is -NR₃C(O)R₄;

R3 is H;

R₄ is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo, and wherein when (if) Ri is -[(2-hydroxyethyl)sulfanyl],

R₄ is -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3- C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo, and

R₄ is not -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3- C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl.

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, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use as a medicament.

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.

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.

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).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

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.

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.

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.

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.

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.

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

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.

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 (TUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

The term "(C_x-C_y)alkyl", wherein x and y are integers, refers to a straight (linear) 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.

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

The term “(C_x-C_y)heterocycloalkyl”, wherein x and y are integers, refers to saturated or partially unsaturated monocyclic (C_x-C_y)cycloalkyl groups in which at least one ring carbon atom is replaced by at least one heteroatom (e.g. N, S or O) or may bear an -oxo (=0) substituent group. Said heterocycloalkyl may be further optionally substituted on the available positions in the ring, namely on a carbon atom, or on a heteroatom available for substitution. Substitution may be on a carbon atom including spiro di substitution, forming bicyclic system where two (C_x- C_y)heterocycloalkyl rings, or one (C_x-C_y)heterocycloalkyl and one (C_x-C_y)cycloalkyl ring, are connected through a single carbon atom. Substitution may be as well as on two adjacent carbon atoms forming an additional condensed 5 to 6 membered heterocycloalkyl ring.

The term “(C_x-C_y)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.

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.

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

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)-.

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(0)2- to disambiguate e.g. with respect to the sulfinic group -S(0)0- The compounds of the invention are active as inhibitors of ALK5 receptor, they are potent and show improved properties such as good inhalatory profile, low microsomal stability and they are able to minimize the systemic exposure and correlated safety issues.

The present invention relates to novel compounds differing from the structures disclosed in the art at least for a common new core scaffold. In fact, the invention relates to compounds that are (pyridazin-4-yl)amino derivatives bearing specific sulfanyl groups on the pyridazinyl ring, which are inhibitors of receptor ALK5 that have therapeutically desirable characteristics, particularly promising for some fibrosis, including idiopathic pulmonary fibrosis (TPF).

In this respect, the state of the art does not describe or suggest pyridazinyl amino derivatives of general formula (I) of the present invention, characterized by low microsomal stability, which represents a solution to the aforementioned need.

The state of the art does not describe or suggest pyridazinyl amino derivatives of general formula (I) of the present invention having low microsomal stability, which represents a solution to the aforementioned need.

In more details, the present invention refers to a series of compounds represented by the general formula (I) as herein below described in details, which are endowed with inhibitory activity on ALK5 receptor and low microsomal stability, corresponding to microsomal half-life below 5 minutes across species, such as mouse and human, 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 disease, disorder and condition from fibrosis.

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.

As indicated in the experimental part, in particular in Table 3, the compounds of formula (I) of the present invention show a microsomal half-life below 5 minutes across species such as mouse and human, allowing to minimize the systemic exposure and correlated safety issues.

Advantageously, the compounds of the present invention are endowed by a very high potency, they could be administered in human at a lower dosage respect to the compounds of the prior art, thus reducing the adverse events that typically occur administering higher dosages of drug.

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.

Thus, in one aspect the present invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein A is group Al

Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3-carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3-yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -(((l-oxo-lH-isochromen-3-yl)methyl)sulfanyl) and -[(l-oxo-3,4- dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R2 is -NR₃C(O)R₄;

RJ is H;

R4 is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; - (Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo.

Preferably, the invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein A is group Al

Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3- carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3- yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -(((l-oxo-lH-isochromen-3- yl)methyl)sulfanyl) and -[(l-oxo-3,4-dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R2 is -NR₃C(O)R₄;

R3 is H;

R4 is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo; and wherein the compound of formula (I) is not

Example No. 22, 23, 24, 25, 26, 27, 60, 61, 82, 83, 84, 87, 88, 89, 90, 91, 92, 153, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 183, 189, 191, 193 or 204 of international application No. WO2023046698. Preferably, the invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein A is group Al

Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3- carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3- yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -(((l-oxo-lH-isochromen-3- yl)methyl)sulfanyl) and -[(l-oxo-3,4-dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R₂ is -NR₃C(O)R₄;

R3 is H;

R4 is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo; and wherein the compound of formula (I) is not

Example No. 22, 23, 24, 25, 60, 153, 178 or 193 of international application No. WO2023046698.

Preferably, the invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof,

wherein A is group Al

Al

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3- carboxylate, -(2-oxo-2H-pyran-6-yl)methylsulfanyl, -(2-(l-(l-oxo-lH-isochromen-3- yl)ethoxy)ethylsulfanyl), -[(2-hydroxyethyl)sulfanyl], -(((l-oxo-lH-isochromen-3- yl)methyl)sulfanyl) and -[(l-oxo-3,4-dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R₂ is -NR₃C(O)R₄;

R3 is H;

R₄ is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl; -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo; and wherein when (if) Ri is -[(2-hydroxyethyl)sulfanyl],

R₄ is (Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3- C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo, and

R₄ is not -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C₃- C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl.

Preferably, the invention refers to at least one of the compounds of Formula (I) listed in Table 1 below and pharmaceutically acceptable salts thereof. Table 1: List of preferred compounds of Formula (I) 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. 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 particular 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.

In some cases, a step is needed in order 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).

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. In this respect, it has now been found that the compounds of formula (I) of the present invention have an inhibitory drug potency, expressed as pICso (negative logarithm of IC50, half maximal inhibitory concentration) and subsequently converted to pKi (negative logarithm of dissociate function Ki), equal or higher than 9.4 on ALK5, as shown in the experimental part, Table 2.

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.

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.

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.

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.

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.

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).

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.

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.

In one embodiment, the invention refers to a pharmaceutical composition of 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.

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, intrastemally and by infusion) and by inhalation. Preferably, the compounds of the present invention are administered orally or by inhalation. Preferably, the compounds of the present invention are administered by inhalation.

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.

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

In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage forms 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.

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.

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.

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.

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.

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

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.

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.

All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and apply as well mutatis mutandis. The compounds according to formula (I), including all the compounds or at least one of the above listed, can be generally prepared gollowing the procedure outlined in detail in the Schemes shown below, using generally known methods.

Scheme 1

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

Compounds of formula (III) may be obtained by reacting commercially available compound (II) with appropriate thiol under nucleophilic aromatic substitution (SNAr). Typical reaction conditions comprise a suitable base, such as NaH, a proper solvent as DMF, and an appropriate temperature, usually between 0 °C and room temperature. Reaction of compounds (III) under metal-catalyzed cross coupling conditions afforded compounds (IV). Typical cross-coupling reaction may be Suzuki coupling, or similar as described in “Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004. Representative Suzuki reaction conditions includes reacting compound (III) with a suitable boronic acid, in the presence of base, such as K2CO3 and Pd catalyst, as PdCl(PPh3)2 DCM, in a mixture of solvents, such as 1,2 dimethoxy ethane and water, at an appropriate temperature, such as, for example, 100 °C. A compound of formula (V) may be obtained by reacting a compound of formula (IV) with a suitable halide under standard Buchwald-Hartwig amination conditions. 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 as, for example, 1,2 -dimethoxy ethane and at an appropriate temperature, such as, for example, 100 °C. Deprotection of compound (V) following standard literature conditions, such as the use of tetrabutyl ammonium fluoride (TBAF) in a suitable solvent, as THF, and at an appropriate temperature, such as room temperature, may lead to compound (VI). Finally, a compound of formula (I) may be obtained by reacting a compound of formula (VI) with a suitable carboxylic acid under standard coupling conditions. Typical conditions involve the presence of a coupling agent, such as HATU, a suitable base, such as DIPEA, in an appropriate solvent such as, for example, DCM and at an appropriate temperature, such as room temperature. Alternatively, compounds of formula (I) can be obtained deprotecting compound (V) following standard literature conditions, such as the use of TFA in a suitable solvent, as DCM, and at an appropriate temperature, such as room temperature

In another embodiment, compounds of formula (I) can be prepared as described in Scheme 2.

Compounds of formula (VII) may be obtained by reacting commercially available compound (II) with appropriate thiol under nucleophilic aromatic substitution (SNAr) as described above. Reaction of compound (VII) with the suitable boronic acid under Suzuki cross coupling conditions, as described above, can lead to compound (VIII). Introduction of A group to afford compound (IX) may be achieved using, for example, metal -catalyzed cross coupling reaction such as Buchwald-Hartwig amination of with the suitable halide, as described above. S-deprotection of compound (IX) under standard literature conditions such as by reaction with tetrabutyl ammonium fluoride (TB AF), in a suitable solvent such as THF at an appropriate temperature, such as room temperature, afforded compound (X). Finally, a compound (I) might be prepared from a compound of formula (X) by means of a suitable alkylating agent, in a suitable solvent, such as MeCN, in presence of a suitable base such as K2CO3, at an appropriate temperature, such as room temperature.

PREPARATIONS OF INTERMEDIATES AND EXAMPLES

Chemical Names of the compounds were generated with Structure To Name Marvin Sketch Iodine.1 version 21.15.1. 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.

Abbreviation - meaning

Aq.= Aqueous; CF3SO3Ag= Silver trifluoromethanesulfonate; cHex= Cyclohexane; Cs2CO3= Cesium carbonate; DCM= Dichloromethane; DIPEA= N,N-Diisopropylethylamine; DME= 1,2 dimethoxy ethane; DMF= Dimethylformamide; DMSO= Dimethylsulfoxide; EtOAc= Ethyl acetate; h= hour; H2= Hydrogen; HC1= Hydrochloric acid; HCOOH= Formic acid; H2O= Water; HATU= l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; K3PO4= Potassium phosphate tribasic; LC-MS= Liquid chromatography/mass spectrometry; MeCN= Acetonitrile; MeOH= Methanol; Min= Minutes; N2= Nitrogen; Na2SO4= Sodium sulfate; NaHCCh = Sodium bicarbonate; NH3= Ammonia; NH4CN ammonium chloride; Pd/C= Palladium on carbon; Pd2(dba)3= Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)C12= [1,1'-

Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OAc)2= Palladium(II) acetate; Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0); RT= Room temperature; Sat.= Saturated; SCX= Strong Cation Exchange; TBAF= Tetrabutylammonium fluoride; TEA= Triethylamine; TFA= Trifluoroacetic acid; THF= Tetrahydrofuran; Xantphos= 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene; ZnCh= zinc chloride.

General Experimental Details and methods

Analytical method

Instruments, materials and methods employed for analyses

'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 AgilentVNMRS-500 or on a Bruker Avance 400 spectrometers. Chemical shifts are reported as 6 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, br. dd= broad doublet-doublet, br. t= broad triplet, dd= double-doublet, ddd= double-double-doublet, dt= double triplet, td= triple doublet, quin= quintuplet).

LC/UV/MS Analytical Methods

LC/MS retention times are 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:

Method 7, low pH conditions column: Acquity CSH C18 2.1x50mm 1.7um, 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 1 mL/min. The gradient table was t=0 min 97% A 3% B, t=l .5 min 0.1% A 99.9% B, t=l .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 1500 AMU.

Method 2, high pH conditions: column: Acquity Kinetex 1.7 um EVO Cl 8 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=l .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+/ES- range was 100 to 1000 AMU.

PREPARATIONS OF INTERMEDIATES

Intermediate 1 : 2 - [(tert - butyldimethylsilyl)oxy] ethane - 1 - thiol

To a stirred solution of 2 -mercaptoethanol (1.8 mL, 25.6 mmol) and imidazole (3.49 g, 51.2 mmol) in DCM (20 mL), tert-butyl-chloro-dimethylsilane (4.24 g, 28.16 mmol) was added. The reaction was stirred at RT overnight. H2O was added, phases were separated, and the organic layer was washed with more water. Combined organics were filtered through a phase separator and evaporated under vacuum. The crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 20% EtOAc), to give the title compound (3.70 g, 19.24 mmol, 76% yield). 'H NMR (400 MHz, Chloroform-d) 6 ppm 3.74 (t, J = 6.38 Hz, 2H) 2.64 (dt, J = 8.36, 6.38 Hz, 2H) 1.50 - 1.60 (m, IH) 0.84 - 1.00 (m, 9H) 0.05 - 0.13 (m, 6H).

Intermediate 2: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-chloropyridazin- 4-amine

To an ice cooled solution of Intermediate 1 (2.99 g, 15.55 mmol) in DMF (33.2 mL), NaH (60% suspension in oil) (622 mg, 15.55 mmol) was added and the mixture was stirred at RT for Ih, before slowly adding 3,6-dichloropyridazin-4-amine (1.7 g, 10.37 mmol) dissolved in DMF (8.3 mL). The reaction was stirred at RT for 3h. The reaction was diluted with sat. aq. NaHCCL and EtOAc. Phases were separated, the organic phase was washed with sat. aq. NaHCCL (2^X), filtered through a phase separator and concentrated under vacuum. The crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 20 % EtOAc) affording the title compound (2.56 g, 8.01 mmol, 77% yield). LC-MS (ESI): m/z (M+l): 320.2 (Method 1).

Intermediate 3: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2- fluorophenyl)pyridazin-4-amine

In a round bottom flask, a mixture of Intermediate 2 (2.95 mg, 9.22 mmol), 5-chloro- 2-fluorobenzeneboronic acid (2.41 g, 13.83 mmol), K2CO3 (3.82 g, 27.66 mmol) and Pd(dppf)C12 (1.35 g, 1.84 mmol) in DME (72 mL) and H2O (5.3 mL) was degassed then heated at 100 °C (external temperature) for 5h. The mixture was diluted with EtOAc, filtered through a Celite® pad, washed with EtOAc. The organic phase was washed with brine, separated, filtered through a phase separator and evaporated under vacuum. The crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 20 % EtOAc) to give title compound (2.01 g, 4.85 mmol, 53% yield). LC-MS (ESI): mlz (M+l): 414.1 (Method 1).

Intermediate 4: N-(4-bromopyridin-2-yl)prop-2-enamide

A mixture of 4-bromo-2-pyridinamine (3.0 g, 17.34 mmol) and TEA (7.25 mL, 52.02 mmol) in dry DCM (80 mL) was stirred under nitrogen at 0 °C, then a solution of 3- chloropropanoyl chloride (1.83 mL, 19.07 mmol) in DCM (20 mL) was added dropwise. The resulting mixture was stirred at 0 °C for Ih. Water was added, and the organic solution was separated and washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated to give a yellow oil which was purified by flash chromatography on Biotage silica cartridge (from cHex to 25% EtOAc) to afford title compound (2.4 g, 10.57 mmol, 61% yield). LC- MS (ESI): mlz (M+l): 228.9 (Method 1).

Intermediate 5: N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-l-yl)propanamide

Intermediate 4 (1.8 g, 6.90 mmol) was dissolved in THF (8 mL) and 1 -methylpiperazine (1.15 mL, 10.35 mmol) was added. The resulting solution was stirred at 65 °C for 3h. Volatiles were removed under vacuum and the residue was purified by flash chromatography on Biotage silica NH cartridge (from cHex to 50% EtOAc) to afford title compound (2.4 g, 7.33 mmol, recovery assumed quantitative). LC-MS (ESI): mlz (M+l): 327.2 (Method 1)

Intermediate 6: N-(4 -{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro- 2-fluorophenyl)pyridazin-4 - yl]amino}pyridin - 2 - yl) - 3 - (4 - methylpiperazin - 1 - yl)propanamide A mixture of Intermediate 3 (800 mg, 1.93 mmol), Intermediate 5 (696 mg, 2.13 mmol), Pd(0Ac)2 (26.03 mg, 0.120 mmol), Xantphos (134.17 mg, 0.230 mmol) and CS2CO3 (1.26 g, 3.86 mmol) in DME (16 mL) was degassed (vaciiiiml^ii and stirred at 100 °C for 2h. The mixture was filtered through a Celite® pad washed with EtOAc. The organic phase was washed with sat. aq. NaHCCE solution, separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 2% MeOH) to afford title compound (1.18 g, 1.79 mmol, 92% yield). LC-MS (ESI): m/z (M+l): 660.2 (Method 2).

Intermediate 7: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2- hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-l- yl)propanamide

To a solution of Intermediate 6 (134 mg, 0.20 mmol) in THF (2.5 mL), IM TBAF in THF (0.22 mL, 0.22 mmol) was added and the mixture was stirred at RT for 3h. Volatiles were evaporated under reduced pressure and the crude material was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 2% MeOH). Proper fractions were evaporated and further purified by HPLC preparative in basic conditions to afford title compound (65 mg, 0.12 mmol, 59% yield). LC-MS (ESI): m/z (M+l): 546.2 (Method 2).

Intermediate 8: 6 - chloro - 3 - {[2 - (trimethylsilyl)ethyl]sulfanyl}pyridazin - 4 - amine

Intermediate 8 was prepared following the procedure used for the synthesis of Intermediate 2 starting from 3,6-dichloropyridazin-4-amine (2.17 g, 13.23 mmol) and 2- (trimethylsilyl)-ethanethiol (2.31 g, 17.2 mmol) to afford the title compound (2.7 g, 10.30 mmol, 78% yield). LC-MS (ESI): m/z (M+l): 262.1 (Method 1). Intermediate 9: 6-(5-chloro-2-fluorophenyl)-3-{[2-

(trimethylsilyl)ethyl]sulfanyl}pyridazin-4 - amine

Intermediate 9 was prepared following the procedure used for the synthesis of Intermediate 3 starting from Intermediate 8 (2.7 g, 10.30 mmol) and using 5-chloro-2- fluorobenzeneboronic acid (2.70 g, 15.48 mmol) to afford the title compound (2.27 g, 6.38 mmol, 62% yield). LC-MS (ESI): m/z (M+l): 356.2 (Method 1).

Intermediate 10: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[2-

(trimethylsilyl)ethyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-l- yl)propanamide

To a mixture of Intermediate 9 (500 mg, 1.4 mmol), Intermediate 5 (506 mg, 1.55 mmol), K3PO4 (605 mg, 2.81 mmol), and Xantphos (122 mg, 0.21 mmol) in DME (16 m ), Pd2(dba)3 (129 mg, 0.14 mmol) was added. N2 was bubbled for 5 min, then the vial was sealed and heated at 100 °C for 3h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography on Biotage silica cartridge (from DCM to 20 % MeOH) to afford the title compound (722 mg, 1.20 mmol, 85% yield. LC-MS (ESI): m/z (M+l): 602.3 (Method 2).

Intermediate 11: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-sulfanylpyridazin-4- yl]amino}pyridin-2-yl) - 3 - (4 - methylpiperazin - 1 - yl)propanamide

IM TBAF in THF (0.71 mL, 0.71 mmol) was added to a solution of Intermediate 10 (390 mg, 0.65 mmol) in THF (8 mL). The mixture was stirred at RT for 5h, then volatiles were removed under vacuum to afford a residue that was triturated with water. The solid was collected by filtration and dried under vacuum to afford the title compound (295 mg, 0.59 mmol, 91% yield). LC-MS (ESI): m/z (M+l): 502.3 (Method 2).

Intermediate 12: 6 - (bromomethyl) - 2H - pyran - 2 - one

In a vial, a mixture of 2-propynoic acid (132.0 pL, 2.14 mmol), 3 -bromo- 1 -propyne 80% w/w in toluene (1.2 mL, 10.79 mmol) and chloro(triphenylphosphine)gold (I) (54. mg, 0.11 mmol) was dissolved in DCM (8 mL), then CFsSCLAg (28 mg, 0.11 mmol) was added, the vial was sealed and heated overnight at 50 °C. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 30% EtOAc) to give the title compound (134 mg, 0.71 mmol, 33% yield). LC-MS (ESI): m/z (M+l): 189.1 (Method 1).

Intermediate 13: 3 - (1 - hydroxyethyl) - 1H - isochromen - 1 - one

To a solution of 4-bromo-3-(l-hydroxyethyl)-lH-2-benzopyran-l-one (W02020200918, 1.0 g, 3.72 mmol) in DMF (9.23 mL) under N₂, TEA (1.55 mL, 11.15 mmol), HCOOH (0.28 mL, 7.43 mmol), Pd(OAc)₂ (42 mg, 0.19 mmol) and PPI13 (97 mg, 0.37 mmol) were added. The mixture was heated at 60 °C for Ih. After cooling, the mixture was poured in sat. NH4CI solution and extracted with EtOAc. Organic layer was separated, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on Biotage silica cartridge (from cHex to 40% EtOAc) to afford the title compound (670 mg, 3.52 mmol, 95% yield). LC-MS (ESI): m/z (M+l): 191.1 (Method 2).

Intermediate 14: 3 - [1 - (2 - hydroxyethoxy)ethyl] - 1H - isochromen - 1 - one

Toluene-4-sulfonic acid monohydrate (360 mg, 1.89 mmol) was added to a solution of Intermediate 13 (360 mg, 1.89 mmol) in ethane- 1,2-diol (3.0 mL, 53.65 mmol) at RT. The reaction was warmed at 90 °C for 3h. After cooling, the mixture was poured in water and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on Biotage silica cartridge (from cHex to 30% EtOAc) to afford the title compound (300 mg, 1.28 mmol, 68% yield). LC-MS (ESI): m/z (M+l): 234.2 (Method 2).

Intermediate 15: 3 - [1 - (2 - iodoethoxy)ethyl] - 1H - isochromen - 1 - one

Iodine (302 mg, 1.19 mmol) was added to a stirred solution of Intermediate 14 (200 mg, 0.79 mmol), PPI13 (312 mg, 1.19 mmol) and imidazole (81 mg, 1.19 mmol) in DCM (4.7 mL) at 0 °C under N2. After 10 min the reaction was warmed to RT and stirred for Ih. The mixture was diluted with DCM, washed with water and then with thiosulfate aqueous solution. Organic layer was separated, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on Biotage silica cartridge (from cHex to 10% EtOAc) to afford the title compound (200 mg, 0.58 mmol, 73% yield). LC-MS (ESI): m/z (M+l): 345.1 (Method 2).

Intermediate 16: benzyl 4 - [(2 - oxooxolan - 3 - yl)methyl]piperazine - 1 - carboxylate

To a solution of 1-Cbz-piperazine (0.98 mL, 5.1 mmol) in THF (8 mL), a-methylene- y-butyrolactone (500 mg, 5.1 mmol) was added. The reaction mixture was vigorously stirred at RT for 2 days, then it was concentrated under reduced pressure and the crude material was purified by flash chromatography on Biotage NH silica cartridge (from cHex to 40% EtOAc) to give the title compound (1.3 g, 4.1 mmol, 80% yield). LC-MS (ESI): m/z (M+l): 320.0 (Method 2).

Intermediate 17: benzyl 4- [(3-methyl-2-oxooxolan-3-yl)methyl] piperazin e-1- carboxylate

Lithium bis(trimethylsilyl)amide IM in THF (5.31 mL, 5.31 mmol) was added dropwise at -78 °C to a solution of Intermediate 16 (1.3 g, 4.08 mmol) in THF (21.1 mL) under a N2. After 30 min at the same temperature, iodomethane (0.35 mL, 5.62 mmol) was added dropwise. The resulting reaction mixture was stirred for 10 min at -78 °C then was slowly warmed to RT and stirred for Ih. The reaction mixture was diluted with EtOAc and sat. aq. NaHCCL was added. The mixture was extracted with more EtOAc, the organic phase was washed with H2O, dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on Biotage NH silica cartridge (from cHex to 25% EtOAc) to give the title compound (960 mg, 2.89 mmol, 71% yield). LC- MS (ESI): m/z (M+l): 332.9 (Method 2).

Intermediate 18: 3 - methyl - 3 - [(piperazin - 1 - yl)methyl]oxolan - 2 - one

To a stirred solution of Intermediate 17 (960 mg, 2.89 mmol) in EtOAc (21.9 mL), 10% Pd/C (922 mg, 0.87 mmol) was added at RT and the resulting mixture was stirred under H2 overnight. The mixture was filtered over Celite® pad, and the filtrate was concentrated under reduced pressure to give the title compound (390 mg, 1.97 mmol, 68% yield). LC-MS (ESI): m/z (M+l): 198.8 (Method 2).

Intemrediate 19: N-(4-bromopyridin-2-yl)-3-{4-[(3-methyl-2-oxooxolan-3- yl)methyl]piperazin-l-yl}propanamide

Intermediate 19 was prepared following the procedure used for the synthesis of Intermediate 5 starting from Intermediate 4 (100 mg, 0.44 mmol) and using Intermediate 18 (105 mg, 0.53 mmol) to afford the title compound (130 mg, 0.31 mmol, 69% yield). LC-MS (ESI): m/z (M+l): 426.2 (Method 2).

Intermediate 20: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5- chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-{4-[(3-methyl-2-oxooxolan-3- yl)methyl]piperazin-l-yl}propanamide

Intermediate 20 was prepared following the procedure used for the synthesis of Intermediate 6 starting from Intermediate 3 (100 mg, 0.24 mmol) and using Intermediate 19 (123 mg, 0.29 mmol) to afford the title compound (100 mg, 0.13 mmol, 55% yield). LC-MS (ESI): m/z (M+l): 758.5 (Method 2).

Intermediate 21: 3 - (hydroxymethyl) - 1H - isochromen - 1 - one

To a solution of 2-iodobenzoic acid (600 mg, 2.42 mmol), 2-propyn-l-ol (0.42 mL, 7.26 mmol) and TEA (1.7 mL, 12.2 mmol) in DMF (6 mL), Pd(PPh3)4 (141 mg, 0.12 mmol) and ZnCb (330 mg, 2.42 mmol) were subsequently added. The mixture was degassed by bubbling N2 then the resulting reaction mixture was stirred at 60 °C for 20 h. EtOAc and water were added to the mixture, the organic phase was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 50% EtOAc) to give the title compound (200 mg, 1.13 mmol, 47% yield). LC-MS (ESI): m/z (M+l): 177.1 (Method 1).

Intermediate 22: 3 - (iodomethyl) - 1H - isochromen - 1 - one

Intermediate 22 was prepared following the procedure used for the synthesis of Intermediate 15 starting from Intermediate 21 (200 mg, 1.13 mmol) to afford the title compound (324 mg, 1.13 mmol, quantitative yield). LC-MS (ESI): m/z (M+l): 287.0 (Method 1).

Intermediate 23: 3 - (bromomethyl) - 3,4 - dihydro - 1H - 2 - benzopyran - 1 - one

To a stirred solution of 4-methylmorpholine A-oxide (2 mg, 0.07 mmol) and A- bromosuccinimide (264 mg, 1.48 mmol) in DCM (4.8 mL), at RT, 2 -allylbenzoic acid (200 mg, 1.23 mmol) was added portion-wise and the resulting reaction mixture was stirred at RT for 2h. Sat. aq. Na2SOs solution was added, and the mixture was stirred for 10 min. Phases were separated and the organic one was concentrated under reduced pressure. The crude material was purified by flash chromatography on Biotage silica cartridge (from cHex to 30% EtOAc) to give the title compound (265 mg, 1.10 mmol, 89% yield). LC-MS (ESI): m/z (M+l): 241.1 (Method 1).

PREPARATIONS OF EXAMPLES

Example 1: 2-{[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-l- yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]sulfanyl}ethyl 5-oxooxolane-3- carboxylate

To a suspension of HATU (54 mg, 0.14 mmol) and Intermediate 7 (100 mg, 0.18 mmol) in DCM (2 mL), 5 -ox otetrahydrofuran-3 -carboxylic acid (18 mg, 0.14 mmol) and DIPEA (55 jiL, 0.320 mmol) were added. The reaction was stirred at RT overnight. The reaction was filtered to remove part of residual SM, the mother liquor was diluted with DCM and washed with sat. aq. NaHCCh solution. The organic phase was filtered through a phase separator and concentrated under vacuum. The residue material was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 3% MeOH) to afford title compound (12 mg, 0.02 mmol, 10% yield). LC-MS (ESI): mlz (M+l): 658.4 (Method 2). NMR (400 MHz, Chloroform-d) 5 ppm 11.28 (br. s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 8.16 (dd, J = 6.7, 2.6 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.40 (ddd, J = 8.7, 4.1, 2.7 Hz, 1H), 7.14 (dd, J = 10.5, 9.0 Hz, 1H), 6.92 (dd, ./ - 5.5, 2.0 Hz, 1H), 6.33 (s, 1H), 4.57 (t, J = 6.1 Hz, 2H), 4.46 - 4.57 (m, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.45 - 3.57 (m, 1H), 2.75 - 2.98 (m, 2H), 2.50 - 2.78 (m, 12H), 2.37 (s, 3H).

Example 2: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(2-oxo-2H-pyran-6- yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-l- yl)propanamide

To a mixture of Intermediate 11 (100 mg, 0.20 mmol), Intermediate 12 (30 mg, 0.16 mmol) and K2CO3 (28 mg, 0.20 mmol), MeCN (4 mL) was added, and the resulting reaction mixture was stirred at RT for 6h. The reaction mixture was diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on Biotage silica NH cartridge (from cHex to 100% EtOAc) to give the title compound (31 mg, 0.05 mmol, 32% yield). LC-MS (ESI): m!z (M+l): 610.3 (Method 2). ^TH NMR (400 MHz, Chloroform-d 8 ppm 11.11 (br. s, 1H), 8.21 (d, J = 5.6 Hz, 1H), 8.11 (dd, J = 6.6, 2.6 Hz, IH), 8.06 (d, J = 1.5 Hz, 1H), 7.71 (s, 1H), 7.39 (dt, J = 8.6, 3.5 Hz, IH), 7.20 - 7.29 (m, 1H), 7.05 - 7.18 (m, IH), 6.85 (dd, J = 5.5, 1.9 Hz, IH), 6.43 (d, J = 6.5 Hz, IH), 6.34 (s, IH), 6.22 (d, J = 9.3 Hz, IH), 4.53 (s, 2H), 2.73 - 2.80 (m, 2H), 2.55 (br. t, J = 5.8 Hz, 2H), 2.46 - 3.15 (m, 8H), 2.42 (s, 3H).

Example 3: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({2-[l-(l-oxo-lH-isochromen-3- yl)ethoxy]ethyl}sulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-l- yl)propanamide

Example 3 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 11 (52 mg, 0.10 mmol) and Intermediate 15 (30 mg, 0.09 mmol) to afford the title compound (43 mg, 0.06 mmol, 69% yield). LC-MS (ESI): m!z (M+l): 718.5 (Method 2). ^lH NMR (400 MHz, Chloroform-d) 8 ppm 10.57 (br. s, IH), 9.15 (s, IH), 8.22 (d, J = 6.1 Hz, 2H), 8.18 (s, IH), 7.82 (dd, J = 6.5, 2.6 Hz, IH), 7.67 (t, J = 7.6 Hz, IH), 7.46 (t, J= 7.7 Hz, IH), 7.43 (s, IH), 7.38 (dt, J= 8.8, 3.4 Hz, IH), 7.34 (d, J= 7.8 Hz, IH), 7.13 (t, J = 9.6 Hz, IH), 6.92 (dd, J = 5.5, 1.8 Hz, IH), 6.49 (s, IH), 5.14 - 5.23 (m, IH), 5.03 - 5.13 (m, IH), 4.33 (q, J = 6.5 Hz, IH), 4.22 - 4.30 (m, IH), 4.15 (dt, J = 10.7, 5.5 Hz, IH), 2.85 - 2.90 (m, 2H), 2.76 - 3.19 (m, 8H), 2.57 - 2.66 (m, 5H), 1.50 (d, J= 6.5 Hz, 3H).

Example 4: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin- 4-yl]amino}pyridin-2-yl)-3-{4-[(3-methyl-2-oxooxolan-3-yl)methyl]piperazin-l- yl}propanamide

To a solution of Intermediate 20 (100 mg, 0.13 mmol) in DCM (3 mL), TFA (0.10 mL, 1.32 mmol) was added, and the mixture was stirred at RT for 4h. The reaction was diluted with sat. aq. NaHCCL solution and DCM. Phases were separated, the organic one was dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography on Biotage silica NH cartridge (from cHex to 5% MeOH in EtOAc) to afford title compound (80 mg, 0.12 mmol, 91% yield). LC-MS (ESI): mlz (M+l): 644.4 (Method 2). ‘H NMR (500 MHz, Chloroform-d) 6 ppm 11.26 (s, 1H), 8.23 (d, J = 5.5 Hz, IH), 8.14 (dd, J = 6.6, 2.7 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 0.8 Hz, IH), 7.34 - 7.44 (m, 1H), 7.13 (dd, J = 10.4, 8.8 Hz, 1H), 6.90 (dd, J = 5.5, 2.2 Hz, 1H), 6.50 (s, IH), 4.40 (td, J - 8.6, 5.5 Hz, 1H), 4.24 - 4.34 (m, IH), 4.07 (br. d, J = 4.7 Hz, 2H), 3.60 - 3.70 (m, 2H), 3.35 (br. s, IH), 2.80 - 2.87 (m, 1H), 2.70 - 2.74 (m, 2H), 2.51 - 2.58 (m, 3H), 2.50 - 2.83 (m, 8H), 2.48 (d, J = 13.7 Hz, 1H), 2.01 (ddd, J = 12.8, 7.8, 5.5 Hz, 1H), 1.20 (s, 3H).

Example 5: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(l-oxo-lH-isochromen-3- yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-l- yl)propanamide

To a stirred solution of Intermediate 10 (140 mg, 0.23 mmol) in THF (2 mL), at RT, a solution IM TBAF in THF (0.26 mL, 0.26 mmol) was added dropwise then the resulting reaction mixture was stirred overnight at RT. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (2 mL) then a solution of Intermediate 22 (60 mg, 0.21 mmol) in DMF (0.50 mL) was added dropwise and the resulting reaction mixture was stirred at RT for Ih. The mixture was concentrated under reduced pressure and the residue was taken up with EtOAc and sat. aq. NaHCOs solution. The organic phase was washed with water, dried over NazSOy and evaporated. The crude material was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 4% MeOH) to afford the title compound (33 mg, 0.05 mmol, 24% yield). LC-MS (ESI): mlz (M+l): 660.4 (Method 2). ^TH NMR (400 MHz, DMS0~d₆) 8 ppm 10.60 (s, IH), 9.02 (s, IH), 8.08 - 8.16 (m, 2H), 7.97 - 8.04 (m, 2H), 7.79 - 7.86 (m, IH), 7.69 (br. s, IH), 7.54 - 7.66 (m, 3H), 7.42 (dd, J = 10.3, 9.0 Hz, IH), 6.89 - 6.95 (m, 2H), 4.64 (s, 2H), 2.55 - 2.63 (m, 2H), 2.47 - 2.53 (m, 2H), 2.19 - 2.54 (m, 8H), 2.13 (s, 3H).

Example 6: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(l-oxo-3,4-dihydro-lH-2- benzopyran-3-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin- l-yl)propanamide

Example 6 was prepared following the procedure used for the synthesis of Example 5 starting from Intermediate 10 (155 mg, 0.26 mmol) and using Intermediate 27 (55 mg, 0.23 mmol) to afford the title compound (38 mg, 0.06 mmol, 25% yield). LC-MS (ESI): m/z (M+l): 662.3 (Method 2). ^ NMR (500 MHz, Chloroform-d) 6 ppm 10.73 (br. s, 1H), 8.17 (d, J = 5.6 Hz, 1H), 8.11 - 8.14 (m, 2H), 8.09 (dd, J = 7.8, 0.8 Hz, 1H), 7.74 (d, J - 1.2 Hz, 1H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.37 - 7.43 (m, 2H), 7.26 - 7.30 (m, 1H), 7.13 (dd, J = 10.5, 8.9 Hz, 1H), 6.90 (dd, J = 5.7, 2.1 Hz, 1H), 6.52 (br. s, 1H), 4.94 - 5.05 (m, 1H), 4.09 (dd, J = 14.2, 3.9 Hz, 1H), 3.82 (dd, J = 14.3, 7.4 Hz, 1H), 3.16 - 3.26 (m, 2H), 2.85 - 2.89 (m, 2H), 2.70 - 3.15 (m, 8H), 2.59 (s, 3H), 2.59 - 2.63 (m, 2H).

PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION

In vitro Assay

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 2 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 IC50) 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.

As it can be appreciated, all the compounds of Table 2 show pKi values greater than 9.4 when tested in the biochemical ALK5 assay.

Table 2

Determination of Microsomes Stability

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.

The results for individual compounds are provided below in Table 3, wherein the compounds are classified in term of microsomal stability in human and in mouse. Results were expressed as half-life (ti/2, min). The lower the ti/2, the higher the hepatic metabolism of the tested compound.

As it can be appreciated, all the compounds of Table 3 show a half-life (ti/2) below 5 minutes, in human and in mouse.

Table 3

Claims

1. A compound of formula (I) or pharmaceutically acceptable salts thereof wherein A is group Al l

Ri is selected from the group consisting of -[2-(sulfanyl)ethyl]-5-oxooxolane-3-carboxylate, -(2-oxo-2H-pyran-6-yl)m ethyl sulfanyl, -(2-(l-(l-oxo-lH-isochromen-3- yl)ethoxy)ethyl sulfanyl), -[(2-hydroxyethyl)sulfanyl], -(((l-oxo-lH-isochromen-3- yl)methyl)sulfanyl) and -[(l-oxo-3,4-dihydro-lH-2-benzopyran-3-yl)methyl]sulfanyl;

R2 is -NR3C(O)R4; RJ is H;

R4 is selected from the group consisting of -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci- Ce)alkyl; -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene-(C3-

C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo.

2. The compound of formula (I) according to claim 1, wherein when Ri is -[(2- hydroxyethyl)sulfanyl], R4 is -(Ci-C6)alkylene-(C3-C6)heterocycloalkyl-(Ci-C6)alkylene- (C3-C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl and oxo; and R4 is not -(Ci-Ce)alkylene-(C3- C6)heterocycloalkyl, wherein said -(C3-C6)heterocycloalkyl is optionally substituted by one or more -(Ci-Ce)alkyl.

3. The compound of formula (I) according to claim 1 selected from at least one of:

2-{ [6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-l- yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl] sulfanyl} ethyl 5-oxooxolane-3- carb oxy late;

N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(2-oxo-2H-pyran-6- yl)methyl]sulfanyl }pyridazin-4-yl]amino}pyridin-2-yl)-3 -(4-methylpiperazin- 1- yl)propanamide;

N-(4-{ [6-(5-chloro-2-fluorophenyl)-3 -({2-[ 1 -(1-oxo- lH-isochromen-3 - yl)ethoxy ] ethyl } sulfanyl)pyridazin-4-yl ]amino}pyridin-2-yl)-3 -(4-methylpiperazin- 1 - yl)propanamide;

N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4- yl]amino}pyridin-2-yl)-3-{4-[(3-methyl-2-oxooxolan-3-yl)methyl]piperazin-l- yl}propanamide;

N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(l-oxo-lH-isochromen-3- yl)methyl] sulfanyl }pyridazin-4-yl]amino}pyri din-2 -yl)-3 -(4-methylpiperazin- 1- yl)propanamide;

N-(4-{ [6-(5-chloro-2-fluorophenyl)-3-{[(l -oxo-3, 4-dihydro-lH-2-benzopyran- 3-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3 -(4-methylpiperazin- 1- yl)propanamide.

4. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims from 1 to 3, in admixture with one or more pharmaceutically acceptable carrier or excipient.

5. The pharmaceutical composition according to claim 4 for administration by inhalation.

6. A compound of formula (I) according to any one of claims from 1 to 3 or a pharmaceutical composition according to claims 4 or 5 for use as a medicament.

7. A compound of formula (I) or a pharmaceutical composition for use according to claim 6 in the prevention and/or treatment of a disease, disorder or condition mediated by ALK5 signaling pathway in mammals.

8. A compound of formula (I) or a pharmaceutical composition for use according to claims 6 or 7 in the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions that involve fibrosis.

9. A compound of formula (I) or a pharmaceutical composition for use according to claim 8 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.

10. A compound of formula (I) or a pharmaceutical composition for use according to claim 8 in the prevention and/or treatment idiopathic pulmonary fibrosis (IPF).