EP4673214A1 - Pyridazinyl amino derivatives as alk5 inhibitors - Google Patents

Pyridazinyl amino derivatives as alk5 inhibitors

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Publication number
EP4673214A1
EP4673214A1 EP24707794.4A EP24707794A EP4673214A1 EP 4673214 A1 EP4673214 A1 EP 4673214A1 EP 24707794 A EP24707794 A EP 24707794A EP 4673214 A1 EP4673214 A1 EP 4673214A1
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EP
European Patent Office
Prior art keywords
chloro
fluorophenyl
amino
pyrimidin
carbamoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24707794.4A
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German (de)
French (fr)
Inventor
Daniela PIZZIRANI
Paolo RONCHI
Daniele PALA
Donatella RESCIGNO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chiesi Farmaceutici SpA
Original Assignee
Chiesi Farmaceutici SpA
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Publication date
Application filed by Chiesi Farmaceutici SpA filed Critical Chiesi Farmaceutici SpA
Publication of EP4673214A1 publication Critical patent/EP4673214A1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention generally relates to compounds inhibiting the transforming growth factor ⁇ (TGF ⁇ ) type I receptor (ALK5) (hereinafter ALK5 inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
  • TGF ⁇ transforming growth factor ⁇
  • ALK5 inhibitors transforming growth factor ⁇ type I receptor
  • the compounds of the invention may be useful for instance in the treatment of many disease, disorder, or condition associated with ALK5 signaling pathway.
  • TGF ⁇ Transforming Growth Factor ⁇
  • TGF ⁇ is a protein belonging to the TGF ⁇ superfamily.
  • TGF ⁇ superfamily also includes, among others, other members known as activins (Acts) (see e.g. Hinck AP, FEBS Letters 586 (2012); 1860–1870).
  • Acts activins
  • the binding of the peptide initiates the TGF ⁇ signalling cascade through the formation of a heterotetrameric complex composed of two different serine/threonine kinases receptors: type 1 (TGF ⁇ R1/ALK5) and type 2 (TGF ⁇ R2).
  • TGF ⁇ R1/ALK5 is recruited and activated through the phosphorylation of its intracellular domain by TGF ⁇ R2, 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).
  • R receptor-activated
  • ALK4 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 ⁇ activity with many diseases including cancer and fibrosis (see e.g.
  • TGF ⁇ 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.
  • TGF ⁇ is expressed in several cell types, like epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts. These cell populations may produce excess of TGF ⁇ in IPF human lung tissue. Moreover, high levels of TGF ⁇ 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). TGF ⁇ gene expression and TGF ⁇ 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.
  • TGF ⁇ signalling inhibition obtained by employing knockout (KO) animals can inhibit fibrosis development through TGF ⁇ -linked mechanisms (see e.g. Bonniaud P et al., Am J Respir Crit Care Med (2005);171:889–898; 34).
  • TGF ⁇ plays a key role in the development and functionality of cardiac valves. It is therefore clear the importance of a selective regulation of TGF ⁇ 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 antiTGF ⁇ 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.
  • ALK5 receptor 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 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.
  • 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.
  • the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O-(C1- C 6 )hydroxyalkyl and -(C 1 -C 6 )hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C 6 )heterocycloalkylene-(C 1 -C 6 )alkylene-(C 3 -C 6 )heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the compound of formula (I) of the present invention is intended to include also stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof.
  • pharmaceutically acceptable salts 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 sal ts 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).
  • (Cx-Cy)alkylene refers to a (Cx-Cy)alkyl radical having in total two unsatisfied valencies, such as a divalent methylene radical.
  • (Cx-Cy)cycloalkyl refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • (Cx-Cy)heterocycloalkyl refers to saturated or partially unsaturated monocyclic or bicyclic (Cx-Cy)cycloalkyl groups in which at least one ring carbon atom is replaced by at least one heteroatom (e.g.
  • 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 disubstitution, forming bicyclic system where two heterocyclic rings or a heterocycloalkyl and a cycloalkyl ring are connected through a single carbon atom.
  • Substitution may also be on two adjacent carbon atoms forming an additional condensed 5 to 6 membered heterocycloalkyl ring.
  • said heterocycloalkyl may be a diazabicyclo ring.
  • 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 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–.
  • 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.
  • the invention relates to compounds that are (pyridazin-4-yl)amino pyrimidin ⁇ 4 ⁇ yl derivatives, which are inhibitors of receptor ALK5 that have therapeutically desirable characteristics, particularly promising for some fibrosis, including idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the state of the art does not describe or suggest pyridazinyl amino pyrimidin ⁇ 4 ⁇ yl derivatives of general formula (I) of the present invention having low microsomal stability, which represents a solution to the aforementioned need.
  • 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.
  • 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.
  • 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.
  • the compounds of formula (I) of the present invention show a short microsomal half-life across species, below 5 minutes, allowing to minimize the systemic exposure and correlated safety issues.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is -NR 3 C(O)R 4 ; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O-(C1- C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C6)heterocycloalkylene-(C1-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C 1 -C 6 )alkyl and oxo; -(C 1 -C 6 )alkylene-(C 3 -C 6 )heterocycloalkylene-C(O)O-(C 1 -C
  • the invention refers to at least one of the compounds of Formula (I) listed in the Table 1 below and pharmaceutically acceptable salts thereof.
  • Table 1 List of preferred compounds of Formula (I) Example No. Structure Chemical Name cis 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ methylpyridazin ⁇ 1 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl 4 ⁇ methylpiperazine ⁇ 1 ⁇ carboxylate cis tert ⁇ butyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ 2 (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidin e ⁇ 4 ⁇ carboxylate cis ethyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇
  • the compound of formula (I) is selected from at least one of: cis 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ methylpyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl 4 ⁇ methylpiperazine ⁇ 1 ⁇ carboxylate; cis tert ⁇ butyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate; cis ethyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidazin
  • the compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures 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.
  • process conditions i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • the compounds of formula (I) of the present invention have an inhibitory drug potency, expressed as pIC50 (negative logarithm of IC50, half maximal inhibitory concentration) and subsequently converted to pK i (negative logarithm of dissociate function K i ), equal or higher than 9.4 on ALK5, as shown in the experimental part, table 8.
  • the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • 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.
  • 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.
  • 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.
  • fibrosis 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.
  • 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. 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).
  • IPF idiopathic pulmonary fibrosis
  • safety 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.
  • 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, intrasternally and by infusion) and by inhalation.
  • the compounds of the present invention are administered orally or by inhalation. More preferably, the compounds of the present invention are administered by inhalation.
  • 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.
  • 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.
  • 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.
  • 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.
  • inhalers for administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized.
  • 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 jet 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 multi-dose dry powder inhaler or a metered dose inhaler. All preferred groups or embodiments described above for compounds of formula (I) may be combined among each other and apply as well mutatis mutandis.
  • the compounds of formula (I) including all the compounds or at least one of the above listed can be generally prepared according to 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) when R2 is -(C1-C6)alkyl e. g. -Me.
  • Compound of formula (III) may be prepared by reacting compound (II) and (5-chloro-2-fluorophenyl) boronic acid in a cross-coupling reaction, such as Suzuki cross couplings in presence of a Pd catalyst, such as Pd(dppf)Cl2, in the presence of a suitable base such as Cs2CO3, in a mixture of solvents, such as 1,4 dioxane and water, at an appropriate temperature, such as, for example, 100 °C.
  • a compound of formula (V) may be prepared reacting a compound of formula (III) with a compound (IV) (Teoc-NH2, 2-(trimethylsilyl)ethyl carbamate) under Buchwald-Hartwig cross coupling conditions.
  • Typical Buchwald-Hartwig conditions involve the presence of a suitable base, such as cesium carbonate, a suitable ligand reagent, such as Xantphos, and a suitable catalyst such as Pd2(dba)3, in an appropriate solvent such as 1,4-dioxane and at an appropriate temperature, such as at 100 °C.
  • a suitable base such as cesium carbonate
  • a suitable ligand reagent such as Xantphos
  • Pd2(dba)3 a suitable catalyst
  • Cleavage of Teoc (2-(trimethylsilyl)ethoxy carbonyl) using cesium fluoride in DMF afforded compounds (VI).
  • compound (VIII) under standard literature conditions such as by reaction with TFA, in a suitable solvent such as DCM at an appropriate temperature, such as room temperature, afforded compound (IX).
  • a suitable solvent such as DCM
  • Compound of formula (I) may be synthesized by activation of compound (IX) with CDI in a suitable solvent, such as in THF, at an appropriate temperature, such as between 0 and 60 °C, followed by addiction of a suitable amine or alcoholate, in the presence of an appropriate base, such as DIPEA.
  • compound of formula (I) can be obtained by reaction of alcohol (IX) with an appropriate carboxylic acid in presence of an activating agent such as DCC, catalytic amount of DMAP, in an appropriate solvent, such as THF at an appropriate temperature, such as 45 °C.
  • an activating agent such as DCC, catalytic amount of DMAP
  • an appropriate solvent such as THF
  • Compound of formula (VII) might be obtained as described in Scheme 2.
  • Typical conditions involve the presence of an appropriate base, such as n-BuLi, in an appropriate solvent, such as THF, and at an appropriate temperature, such as, from -78 °C to room temperature.
  • an appropriate base such as n-BuLi
  • THF an appropriate solvent
  • an appropriate temperature such as, from -78 °C to room temperature.
  • compounds of formula (I) can be prepared as described in Scheme 3.
  • Scheme 3 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)hydroxyalkyl, e.g. -CH2OH.
  • Compound of formula (XIV) may be obtained from commercially available compound (XIII) by SNAr substitution with commercially available 2,4-dimethoxybenzylamine (Dmb) in a suitable solvent, such as MeCN, in presence of a suitable base such as N,N-diisopropylethylamine, typically at room temperature.
  • Dmb 2,4-dimethoxybenzylamine
  • a suitable solvent such as MeCN
  • a suitable base such as N,N-diisopropylethylamine
  • Typical Suzuki conditions comprise reacting compound (XIV) with (5-chloro-2-fluorophenyl) boronic acid, in the presence of a suitable base such as K2CO3 and a Pd catalyst, such as Pd(dppf)Cl 2 , in a suitable solvent, such as 1,2- dimethoxyethane and water, at an appropriate temperature, such as, for example, 85 °C.
  • a suitable base such as K2CO3 and a Pd catalyst, such as Pd(dppf)Cl 2
  • a suitable solvent such as 1,2- dimethoxyethane and water
  • Typical Buchwald-Hartwig conditions comprise reacting compound (XVIII) with the intermediate(XIX), which preparation is detailed in schemes 4- 7, in the presence of a Pd catalyst, as described above.
  • Deprotection of compound (XX) under standard literature conditions such as by reaction with TBAF, in a suitable solvent such as THF and at an appropriate temperature, such as room temperature, afforded compound (I).
  • Compound of formula (XIX) might be obtained as described in Scheme 4, 5, 6 and 7.
  • Typical Buchwald-Hartwig conditions comprise reacting compound (XXV) with 4,6-dichloropyrimidine (XXVI), in the presence of a Pd catalyst, such as Pd(OAc) 2 , in the presence of a suitable base, such as cesium carbonate, a suitable ligand reagent, such as Xantphos, in an appropriate solvent such as 1,2 - dimethoxyethane and at an appropriate temperature, such as 80 °C.
  • a Pd catalyst such as Pd(OAc) 2
  • a suitable base such as cesium carbonate
  • a suitable ligand reagent such as Xantphos
  • XXV Amide (XXV) might be also obtained by alkylation of an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person (XXI), such as tert-butyl piperidine-4-carboxylate with 2- chloroacetamide (XXVII) in an appropriate solvent, such as a MeCN, in the presence of a suitable base, such as DIPEA, at an appropriate temperature, such as 70 °C. Reaction of (XXV) with (XXVI) under Buchwald-Hartwig cross coupling conditions described above afforded compound (XIX).
  • Tosylate (XXIX) could react with an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person (XXI), such as tert ⁇ butyl piperidine ⁇ 3 ⁇ carboxylate, in an appropriate solvent, such as a DMF, in the presence of a suitable base, such as potassium carbonate, at an appropriate temperature, such as 95 °C, to afford compound (XXIII) with inversion of configuration. Reaction of (XXIII) with (XII) under Buchwald-Hartwig cross coupling conditions described above afforded compound (XIX).
  • compounds of formula (I) can be prepared as described in Scheme 8.
  • Scheme 8 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)alkylene-O-(C1-C6)hydroxyalkyl, eg. -CH2OCH2CH2OH.
  • the alcohol (XVI) may be activated using for example methanesulfonic anhydride in presence of an appropriate base, such as DIPEA, in an appropriate solvent such as DCM at an appropriate temperature, such as, for example, 0 °C. Reaction of the mesylate intermediate with an appropriate alcohol, such as ethane-1,2 diol, afforded compound (XXX).
  • ester (XXXII), being (XXXII) compound (XX), where R4 is L-piperidinyl-4-tertbutylcarboxylate and L is an alkyl or cycloalkyl linker, such as CH 2 or cyclobutyl, to afford carboxylic acid (XXXIII) can be achieved by reaction with trimethylsilyl trifluoromethanesulfonate in presence of a base such as 2,6-dimethylpyridine, at an appropriate temperature, such as RT.
  • LC-MS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on Waters LC/PDA/MS Acquity TM system coupled with Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative electron spray ES ionization mode. LC/MS retention times are estimated to be affected by an experimental error of +0.5 min.
  • the UV detection range was 210-350 nm and ES+/ES- range was 100 to 1500 AMU.
  • the UV detection range was 210-350 nm and ES+/ES- range was 100 to 1000 AMU.
  • Purification Methods Some compounds were purified by FCC using Biotage® columns and conditions specified in each Example. Biotage® columns used are herein described with their abbreviations used in the synthetic procedures: Sfär silica: Silica column Biotage® Sfär silica D Duo 60 ⁇ M; Sfär amino: amino-functionalized silica column Biotage® Sfär KP-amino D Duo 50 ⁇ M; Sfär C18: C18 derivatized silica column Biotage® Sfär C18 D Duo 100 ⁇ 30 ⁇ M.
  • the mixture was degassed (N2/vacuum) then heated at 100 °C for 2 hrs.
  • the mixture was diluted with EtOAc, then filtered over a celite® pad.
  • the solvents were removed under reduced pressure, the residue loaded onto a SCX cartridge (10 g) and eluted with 1 N NH3 in MeOH. Collected fractions were concentrated under reduced pressure and the residue treated with DCM (3 mL) and TFA (2.38 mL, 31 mmol) and stirred overnight at RT.
  • the mixture was coevaporated with toluene under reduced pressure.
  • the residue loaded onto a SCX cartridge (10 g) and eluted with 1 N NH3 in MeOH.
  • Step B In a suitable vial, a mixture of 4,6-dichloropyrimidine (110 mg, 0.74 mmol), Pd(OAc)2 (10 mg, 0.04 mmol), tert-butyl 1-(3-amino-3-oxo-propyl)piperidine-4-carboxylate (from Step A, 0.7 mmol), Cs 2 CO 3 (242 mg, 0.76 mmol), Xantphos (51 mg, 0.08 mmol) in DME (5.3 mL) was degassed (N2/ vacuum) then stirred at 80 °C for 1 h.
  • reaction mixture was vigorously stirred at RT for 2 days, then it was concentrated under reduce pressure and the crude material was purified by FCC on Biotage NH silica cartridge (from cHex to 40% EtOAc) to give the title compound (1.3 g, 4.1 mmol, 80% yield).
  • the resulting reaction mixture was stirred for 10 min at -78 °C then was slowly warmed to RT and stirred for 1h.
  • the reaction mixture was diluted with EtOAc and sat. aq. NaHCO 3 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 FCC on Biotage NH silica cartridge (from cHex to 25% EtOAc) to give the title compound (960 mg, 2.89 mmol, 71% yield).
  • Step B Intermediate 35 was prepared following the procedure used for the synthesis of Intermediate 10 starting from intermediate from Step A (125 mg, 0.42 mmol) and using 6- chloro-4-pyrimidinamine (88 mg, 0.68 mmol) to afford the title compound (60 mg, 0.15 mmol, 36% yield).
  • Example listed below in Table 6 were prepared from the suitable reagents in analogy to the procedures followed for Example 2.
  • Table 6 Example Structure & Reagents and N° IUPAC Name Solvents Product Amount (Yield)/ Analytical Data/Purification 21
  • Example 3 cis ethyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 3 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 17 (10 mg, 0.01 mmol) and purifying by extraction in DMC/water to afford the title compound (3 mg, 0.005 mmol, 36% yield).
  • Example 4 tert ⁇ butyl 1 ⁇ 2 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]ethyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 4 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 19 (140 mg, 0.20 mmol) and purifying by extraction in EtOAc/water to afford the title compound (95 mg, 0.016 mmol, 81% yield).
  • LC-MS (ESI): m/z (M+1): 586.3 (Method 2), t R 1.10.
  • Example 5 cis (3R) ⁇ 1 ⁇ methylpyrrolidin ⁇ 3 ⁇ yl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 5 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 20 (43 mg, 0.06 mmol) and purifying by FCC on Biotage NH silica cartridge eluting with cHex/EtOAc/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:70:30 to afford the title compound (22 mg, 0.03 mmol, 60% yield).
  • Example 6 cis 3 ⁇ hydroxy ⁇ 2,2 ⁇ dimethylpropyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 6 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 21 (33 mg, 0.04 mmol) and purifying by FCC on Biotage NH silica cartridge (cHex/EtOA/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:95:5 to afford the title compound (23 mg, 0.03 mmol, 82% yield).
  • Example 7 cis 2,2 ⁇ dimethylpropyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 7 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 22 (54 mg, 0.07 mmol) and purifying by FCC on Biotage SFAR 5g column eluting with cHex/EtOAc/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:95:5 to afford the title compound (24 mg, 0.04 mmol, 53% yield).
  • Example 8 cis 3 ⁇ methylbutan ⁇ 2 ⁇ yl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 8 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 23 (54 mg, 0.07 mmol) and purifying by FCC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (24 mg, 0.04 mmol, 53% yield).
  • Example 9 N ⁇ (6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl) ⁇ 3 ⁇ 4 ⁇ [(3 ⁇ methyl ⁇ 2 ⁇ oxooxolan ⁇ 3 ⁇ yl)methyl]piperazin ⁇ 1 ⁇ yl ⁇ propanamide
  • Example 9 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 28 (120 mg, 0.17 mmol) and purifying by FCC on Biotage NH cartrige from cHex to 100% (EtOAc/MeOH 90:10) to afford the title compound (60 mg, 0.10 mmol, 60% yield).
  • Example 10 cis (3S) ⁇ 1 ⁇ (2,2,2 ⁇ trifluoroethyl)pyrrolidin ⁇ 3 ⁇ yl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 10 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 29 (117 mg, 0.14 mmol) and purifying by FC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (53 mg, 0.07 mmol, 53% yield).
  • Example 11 cis oxetan ⁇ 3 ⁇ yl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 11 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 30 (51 mg, 0.07 mmol) and purifying by FC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (13 mg, 0.02 mmol, 30% yield).
  • Example 12 cis methyl 3 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ 3 ⁇ azabicyclo[3.1.1]heptane ⁇ 6 ⁇ carboxylate
  • Example 12 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 33 (140 mg, 0.20 mmol) to afford the title compound (70 mg, 0.12 mmol, 60% yield).
  • LC-MS (ESI): m/z (M+1): 582.3 (Method 2), tR 1.05.
  • Example 13 cis tert ⁇ butyl 1 ⁇ 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl ⁇ piperidine ⁇ 3 ⁇ carboxylate
  • Example 12 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 36 (35 mg, 0.05 mmol) to afford the title compound (70 mg, 0.12 mmol, 60% yield).
  • LC-MS (ESI): m/z (M+1): 612.3 (Method 2), t R 1.07.
  • Example listed in table 7 were prepared from the suitable reagents in analogy to the procedures followed for Example 14.
  • Example 16 cis 3 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ methylpyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]cyclobutyl 1 ⁇ methylpiperidine ⁇ 4 ⁇ carboxylate 1-Methylpiperidine-4-carboxylic acid (17 mg, 0.12 mmol), DCC (36 mg, 0.17 mmol), DMAP (21 mg, 0.17 mmol), and Intermediate 14 (50 mg, 0.12 mmol) were mixed in THF (1.5 mL) and stirred 45 °C for 8h.
  • Example 18 (3R) ⁇ 1 ⁇ methylpyrrolidin ⁇ 3 ⁇ yl 1 ⁇ [(6 ⁇ [6 ⁇ (5 ⁇ chloro ⁇ 2 ⁇ fluorophenyl) ⁇ 3 ⁇ (hydroxymethyl)pyridazin ⁇ 4 ⁇ yl]amino ⁇ pyrimidin ⁇ 4 ⁇ yl)carbamoyl]methyl ⁇ piperidine ⁇ 4 ⁇ carboxylate
  • Example 18 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 47 (35 mg, 0.05 mmol) and purifying by FCC on Biotage NH cartridge eluting with cHex/EtOAc/(EtOAc/EtOH 3:1) from 100:0:0 to 0:100:0 to 0:50:50 to afford the title compound (19 mg, 0.03 mmol, 65% yield).
  • the produced ADP was converted into ATP, which in turn was converted into light by Ultra-Glo Luciferase.
  • the luminescent signal positively correlated with ADP amount and kinase activity.
  • the kinase reaction was performed by incubating 2.6 nM of the purified, commercially available human ALK5 (recombinant TGF ⁇ 1 N-term GST-tagged, 80-end), a final concentration of TGF ⁇ 1 peptide 94.5 ⁇ M (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 (0.5 ⁇ M).
  • 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 ⁇ M. 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 oC and the assays were performed in 384-well format and validated using a selection of reference compounds tested in 11-point concentration-response curve.
  • Microsomes Stability Test compound was incubated, in duplicate, at the concentration of 0.5 ⁇ M 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), 50 ⁇ l- aliquots were taken and acetonitrile containing internal standard (150 ⁇ l) was added to stop the reaction. Samples were centrifuged (3000 rpm, 10min) 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 ⁇ M 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.
  • Table 9 The results for individual compounds are provided below in Table 9 wherein the compounds are classified in term of microsomal stability in human and in mouse. Results were expressed as half-life (t1/2, min). The lower the t1/2, the higher the hepatic metabolism of the tested compound. As it can be appreciated, all the compounds of Table 9 show a half-life (t 1/2 ) lower than 5 minutes, in human and in mouse. Table 9 Example No.

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Abstract

The present invention generally relates to compounds (I) 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 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 disease, disorder, or condition associated with ALK5 signaling pathway. BACKGROUND OF THE INVENTION The Transforming Growth Factor β (TGFβ) is a protein belonging to the TGFβ superfamily. It is involved in several processes, both cellular, such as proliferation, migration and differentiation, and biological, including wound healing, immunesuppression, cancerogenesis and extracellular matrix production. The TGFβ 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 TGFβ signalling cascade through the formation of a heterotetrameric complex composed of two different serine/threonine kinases receptors: type 1 (TGFβR1/ALK5) and type 2 (TGFβR2). TGFβR1/ALK5 is recruited and activated through the phosphorylation of its intracellular domain by TGFβR2, 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 TGFβ 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 TGFβ 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 TGFβ 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, TGFβ expression is increased in fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), and in chronic inflammatory conditions, such as chronic obstructive pulmonary disease and asthma (see e.g. Thomas BJ et al., Am J Respir Cell Mol Biol. (2016);(55):759–766). In lung, TGFβ is expressed in several cell types, like epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts. These cell populations may produce excess of TGFβ in IPF human lung tissue. Moreover, high levels of TGFβ 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). TGFβ gene expression and TGFβ 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 TGFβ expression is sufficient to induce progressive fibrosis in rodents (see e.g. Sime PJ et al., J Clin Invest (1997);100:768-776; Kim KK et al.). Contrarily, TGFβ signalling inhibition obtained by employing knockout (KO) animals can inhibit fibrosis development through TGFβ-linked mechanisms (see e.g. Bonniaud P et al., Am J Respir Crit Care Med (2005);171:889–898; 34). Similar results have been achieved with inhibition of TGFβR1 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 TGFβ, 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 TGFβ 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 TGFβ in angiogenesis and vascular morphogenesis. Moreover, TGFβ plays a key role in the development and functionality of cardiac valves. It is therefore clear the importance of a selective regulation of TGFβ 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 antiTGFβ 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 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. 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 a good selectivity across the kinome. SUMMARY OF THE INVENTION In a first aspect the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O-(C1- C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C6)heterocycloalkylene-(C1-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C1- C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3- C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3- C7)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C3-C6)cycloalkylene-OC(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and -(C1-C6)haloalkyl; -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkylene-C(O)O-(C1-C6)hydroxyalkyl; -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkylene-(C1-C3)alkylene-C(O)O-(C3-C6)alkyl; and -(C3-C6)cycloalkylene- O-C(O)-(C3-C6)heterocycloalkylene-(C1-C3)alkylene-(C3-C5)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)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 of 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 stereoisomer, tautomer or pharmaceutically acceptable salt or solvate 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 sal ts 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 (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)). The term “(Cx-Cy)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 "(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. 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. The term “(Cx-Cy)heterocycloalkyl”, wherein x and y are integers, refers to saturated or partially unsaturated monocyclic or bicyclic (Cx-Cy)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 (=O) 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 disubstitution, forming bicyclic system where two heterocyclic rings or a heterocycloalkyl and a cycloalkyl ring are connected through a single carbon atom. Substitution may also be on two adjacent carbon atoms forming an additional condensed 5 to 6 membered heterocycloalkyl ring. Moreover, said heterocycloalkyl may be a diazabicyclo ring. 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(O)– as an alternative to the other common representations such as –CO–, –(CO)– or –C(=O)– 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–. 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 pyrimidin‐4‐yl derivatives, which are inhibitors of receptor ALK5 that have therapeutically desirable characteristics, particularly promising for some fibrosis, including idiopathic pulmonary fibrosis (IPF). In this respect, the state of the art does not describe or suggest pyridazinyl amino pyrimidin‐ 4‐yl 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 9, the compounds of formula (I) of the present invention show a short microsomal half-life across species, below 5 minutes, 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, the present invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O-(C1- C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C6)heterocycloalkylene-(C1-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C1- C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3- C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3- C7)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C3-C6)cycloalkylene-OC(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and -(C1-C6)haloalkyl; -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkylene-C(O)O-(C1-C6)hydroxyalkyl; -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkylene-(C1-C3)alkylene-C(O)O-(C3-C6)alkyl; and -(C3-C6)cycloalkylene- O-C(O)-(C3-C6)heterocycloalkylene-(C1-C3)alkylene-(C3-C5)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl. Preferably, the invention refers to at least one of the compounds of Formula (I) listed in the Table 1 below and pharmaceutically acceptable salts thereof. Table 1: List of preferred compounds of Formula (I) Example No. Structure Chemical Name cis 3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐ 1 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 4‐ methylpiperazine‐1‐carboxylate cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐ 2 (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis ethyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐ 3 (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐ 2‐fluorophenyl)‐3‐ 4 (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]ethyl}piperidine‐4‐ carboxylate cis (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐ 5 (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis 3‐hydroxy‐2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐ 6 (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis 2,2‐dimethylpropyl 1‐{3‐[(6‐ {[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis 3‐methylbutan‐2‐yl 1‐{3‐[(6‐ {[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate N‐(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)‐3‐{4‐ [(3‐methyl‐2‐oxooxolan‐3‐ yl)methyl]piperazin‐1‐ yl}propanamide cis (3S)‐1‐(2,2,2‐ trifluoroethyl)pyrrolidin‐3‐yl 1‐{3‐ [(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐ 3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis oxetan‐3‐yl 1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis methyl 3‐{3‐[(6‐{[6‐(5‐chloro‐ 2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}‐3‐ azabicyclo[3.1.1]heptane‐6‐ carboxylate cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐3‐carboxylate cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐ 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate cis 3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐ 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐ methylpiperidin‐4‐yl carbonate cis 3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐ 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐ methylpiperidine‐4‐carboxylate cis (2R)‐3‐methylbutan‐2‐yl 1‐{3‐ [(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐ 3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐ 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin e‐4‐carboxylate (3R)‐1‐methylpyrrolidin‐3‐yl 1‐ {[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]methyl}piperidine‐ 4‐carboxylate cis 3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐ 4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 3,5‐ dimethylpiperazine‐1‐carboxylate cis 3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐ 4‐yl]amino}pyrimidin‐4‐ 20 yl)carbamoyl]cyclobutyl 4‐[(1‐ methylpiperidin‐4‐ yl)methyl]piperazine‐1‐ carboxylate cis tert‐butyl 2‐(1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐ 21 (hydroxymethyl)pyridazin-4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin ‐4yl)acetate tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐ 2‐fluorophenyl)3‐[(2‐ 22 hydroxyethoxy)methyl]pyridazin‐ 4‐yl]amino}pyrimidin-4- yl)carbamoyl]ethyl}piperidine‐4‐ carboxylate Preferably, the invention relates to a compound of general formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O-(C1- C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C6)heterocycloalkylene-(C1-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C1- C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O)-(C3C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3- C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3- C7)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C3-C6)cycloalkylene-OC(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and -(C1-C6)haloalkyl; and -(C3-C6)cycloalkylene-(C3- C6)heterocycloalkylene-C(O)O-(C1-C6)hydroxyalkyl. Preferably, the compound of formula (I) is selected from at least one of: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 4‐methylpiperazine‐1‐carboxylate; cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis ethyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]ethyl}piperidine‐4‐carboxylate; cis (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 3‐hydroxy‐2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; N‐(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)‐3‐{4‐[(3‐methyl‐2‐oxooxolan‐3‐yl)methyl]piperazin‐1‐ yl}propanamide; cis (3S)‐1‐(2,2,2‐trifluoroethyl)pyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis oxetan‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐ 4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis methyl 3‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}‐3‐azabicyclo[3.1.1]heptane‐6‐ carboxylate; cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐3‐carboxylate; cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐methylpiperidin‐4‐yl carbonate; cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐methylpiperidine‐4‐carboxylate; cis (2R)‐3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]methyl}piperidine‐4‐ carboxylate. 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 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 to 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 pIC50 (negative logarithm of IC50, half maximal inhibitory concentration) and subsequently converted to pK i (negative logarithm of dissociate function Ki), equal or higher than 9.4 on ALK5, as shown in the experimental part, table 8. 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. 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). 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, 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. 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 jet 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 multi-dose dry powder inhaler or a metered dose inhaler. All preferred groups or embodiments described above for compounds of formula (I) may be combined among each other and apply as well mutatis mutandis. The compounds of formula (I) including all the compounds or at least one of the above listed can be generally prepared according to 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) when R2 is -(C1-C6)alkyl e. g. -Me. Compound of formula (III) may be prepared by reacting compound (II) and (5-chloro-2-fluorophenyl) boronic acid in a cross-coupling reaction, such as Suzuki cross couplings in presence of a Pd catalyst, such as Pd(dppf)Cl2, in the presence of a suitable base such as Cs2CO3, in a mixture of solvents, such as 1,4 dioxane and water, at an appropriate temperature, such as, for example, 100 °C. A compound of formula (V) may be prepared reacting a compound of formula (III) with a compound (IV) (Teoc-NH2, 2-(trimethylsilyl)ethyl carbamate) under Buchwald-Hartwig cross coupling conditions. Typical Buchwald-Hartwig conditions involve the presence of a suitable base, such as cesium carbonate, a suitable ligand reagent, such as Xantphos, and a suitable catalyst such as Pd2(dba)3, in an appropriate solvent such as 1,4-dioxane and at an appropriate temperature, such as at 100 °C. Cleavage of Teoc (2-(trimethylsilyl)ethoxy carbonyl) using cesium fluoride in DMF afforded compounds (VI). Reaction of compound (VI) with the protected intermediate VII, which preparation is detailed in Scheme 2, afforded compound (VIII) under typical Buchwald-Hartwig cross coupling conditions as described above. Deprotection of compound (VIII) under standard literature conditions such as by reaction with TFA, in a suitable solvent such as DCM at an appropriate temperature, such as room temperature, afforded compound (IX). Compound of formula (I) may be synthesized by activation of compound (IX) with CDI in a suitable solvent, such as in THF, at an appropriate temperature, such as between 0 and 60 °C, followed by addiction of a suitable amine or alcoholate, in the presence of an appropriate base, such as DIPEA. Otherwise, compound of formula (I) can be obtained by reaction of alcohol (IX) with an appropriate carboxylic acid in presence of an activating agent such as DCC, catalytic amount of DMAP, in an appropriate solvent, such as THF at an appropriate temperature, such as 45 °C. Compound of formula (VII) might be obtained as described in Scheme 2. Scheme 2 Protection of commercially available compound (X), under standard literature conditions such as by reaction with tert-butyl(chloro)dimethylsilane, in presence of imidazole and catalytic amount of DMAP, carrying out the reaction in a suitable solvent, such as DCM at room temperature, afforded compound (XI) where PG is, for example, tert- butyl(chloro)dimethylsilyl or other silyl group or other suitable protecting group. Compounds of formula (VII) may be obtained, for example, reacting the ester (XI) with the commercially available 6-chloro-4-pyrimidinamine (XII). Typical conditions involve the presence of an appropriate base, such as n-BuLi, in an appropriate solvent, such as THF, and at an appropriate temperature, such as, from -78 °C to room temperature. In another embodiment, compounds of formula (I) can be prepared as described in Scheme 3.
Scheme 3 Scheme 3 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)hydroxyalkyl, e.g. -CH2OH. Compound of formula (XIV) may be obtained from commercially available compound (XIII) by SNAr substitution with commercially available 2,4-dimethoxybenzylamine (Dmb) in a suitable solvent, such as MeCN, in presence of a suitable base such as N,N-diisopropylethylamine, typically at room temperature. Compound of formula (XV) may be achieved obtained, for example, with a cross coupling reaction, such as Suzuki cross couplings in presence of a Pd catalyst. Typical Suzuki conditions comprise reacting compound (XIV) with (5-chloro-2-fluorophenyl) boronic acid, in the presence of a suitable base such as K2CO3 and a Pd catalyst, such as Pd(dppf)Cl2, in a suitable solvent, such as 1,2- dimethoxyethane and water, at an appropriate temperature, such as, for example, 85 °C. Reduction of compound (XV) with a suitable reducing agent such as lithium aluminum hydride, in a suitable solvent, such as THF, at an appropriate temperature, such as between 0 °C and room temperature, afforded compound (XVI). N-deprotection of compound (XVI) under acidic conditions, such as, for example, TFA solution in DCM at room temperature, allowed to obtain compounds of formula (XVII). Protection of compound (XVII) under standard literature conditions such as by reaction with tert-butyl(chloro)dimethylsilane, in presence of a suitable base such as triethylamine and catalytic amount of DMAP, carrying out the reaction in a suitable solvent, such as a mixture of DCM and DMF at room temperature, afforded compound (XVIII) where PG is, for example, tert-butyldimethylsilyl or other silyl group or other suitable protecting group.Reaction of compound (XVIII) under Buchwald-Hartwig cross coupling conditions afforded compound (XX). Typical Buchwald-Hartwig conditions comprise reacting compound (XVIII) with the intermediate(XIX), which preparation is detailed in schemes 4- 7, in the presence of a Pd catalyst, as described above. Deprotection of compound (XX) under standard literature conditions such as by reaction with TBAF, in a suitable solvent such as THF and at an appropriate temperature, such as room temperature, afforded compound (I). Compound of formula (XIX) might be obtained as described in Scheme 4, 5, 6 and 7. Scheme 4 Reductive amination of (XXI)which is an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person,, such as tert‐butyl piperidine‐4‐carboxylate, methyl 3-azabicyclo[3.1.1]heptane-6- carboxylate, tert-butyl 2-(4-piperidyl)acetate, with the appropriate commercially available ester (XXII) where X is, for example, methyl or ethyl, under standard literature conditions, such as using NaBH(OAc)3 in an suitable solvent such as DCM, at an appropriate temperature, such as room temperature, afforded compound (XXIII). Compounds of formula (XIX) may be obtained, for example, by reacting the appropriate ester (XXIII) and the commercially available 6-chloro-4-pyrimidinamine (XII) as described above. Scheme 5 Michael addition of (XXI), which is an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person, such as tert-butyl piperidine-4-carboxylate or 3‐methyl‐3‐[(piperazin‐1‐ yl)methyl]oxolan‐2‐one, to 2-propenamide (XXIV) in an appropriate solvent, such as a mixture of MeCN and water, at an appropriate temperature, such as room temperature, afforded compound (XXV). Compound (XXV) can be reacted under Buchwald-Hartwig cross coupling conditions afforded compound (XIX). Typical Buchwald-Hartwig conditions comprise reacting compound (XXV) with 4,6-dichloropyrimidine (XXVI), in the presence of a Pd catalyst, such as Pd(OAc)2, in the presence of a suitable base, such as cesium carbonate, a suitable ligand reagent, such as Xantphos, in an appropriate solvent such as 1,2 - dimethoxyethane and at an appropriate temperature, such as 80 °C. Amide (XXV) might be also obtained by alkylation of an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person (XXI), such as tert-butyl piperidine-4-carboxylate with 2- chloroacetamide (XXVII) in an appropriate solvent, such as a MeCN, in the presence of a suitable base, such as DIPEA, at an appropriate temperature, such as 70 °C. Reaction of (XXV) with (XXVI) under Buchwald-Hartwig cross coupling conditions described above afforded compound (XIX). Scheme 7 Commercially available hydroxy ester (XXVIII), such as the one where X is methyl or ethyl, can be activated as tosylate (XXIX) by reaction with4-methylbenzenesulfonyl chloride under standard literature condition, such as in presence of catalytic amount of DMAP, in presence of a suitable base, such as DIPEA, in a suitable solvent, such as DCM, and at an appropriate temperature, such as between 0 °C and room temperature. Tosylate (XXIX) could react with an appropriate commercially available amine or an amine properly derivatized following syntheic procedures well known to the skilled person (XXI), such as tert‐butyl piperidine‐3‐carboxylate, in an appropriate solvent, such as a DMF, in the presence of a suitable base, such as potassium carbonate, at an appropriate temperature, such as 95 °C, to afford compound (XXIII) with inversion of configuration. Reaction of (XXIII) with (XII) under Buchwald-Hartwig cross coupling conditions described above afforded compound (XIX). In another embodiment, compounds of formula (I) can be prepared as described in Scheme 8.
Scheme 8 Scheme 8 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)alkylene-O-(C1-C6)hydroxyalkyl, eg. -CH2OCH2CH2OH. The alcohol (XVI) may be activated using for example methanesulfonic anhydride in presence of an appropriate base, such as DIPEA, in an appropriate solvent such as DCM at an appropriate temperature, such as, for example, 0 °C. Reaction of the mesylate intermediate with an appropriate alcohol, such as ethane-1,2 diol, afforded compound (XXX). N- deprotection of compound (XXX) under acidic conditions, such as, for example, TFA solution in DCM at room temperature, allowed to obtain compounds of formula (XXXI). Finally, reaction of compound (XXXI) with a suitable halide (XIX) under Buchwald-Hartwig cross coupling conditions described above afforded compound (I). In another embodiment, compounds of formula (I) can be prepared as described in Scheme 9. Scheme 9 Scheme 9 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)hydroxyalkyl, e.g.-CH2OH. Hydrolysis of ester (XXXII), being (XXXII) compound (XX), where R4 is L-piperidinyl-4-tertbutylcarboxylate and L is an alkyl or cycloalkyl linker, such as CH2 or cyclobutyl, to afford carboxylic acid (XXXIII) can be achieved by reaction with trimethylsilyl trifluoromethanesulfonate in presence of a base such as 2,6-dimethylpyridine, at an appropriate temperature, such as RT. Reaction of carboxylic acid (XXXIII) with a commercially available alcohol, such as, for example, ethanol, (R)-(-)-1-methyl-3-pyrrolidinol, 2,2-dimethylpropane-1,3-diol, 2,2- dimethylpropane-1,3-diol, 3-methylbutan-2-ol, (3S)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ol, 3-oxetanol, under standard esterification conditions, for example in presence of an appropriate coupling agent, such as HATU, in the presence of a suitable base, such as DIPEA, in an appropriate solvent such as DMF and at an appropriate temperature, such as RT, afforded ester (XXXIV). Finally, deprotection of compound (XXXIV) under standard literature conditions as described above, afforded compound (I). In another embodiment, compounds of formula (I) can be prepared as described in Scheme 10. Scheme 10 Scheme 10 provides possible synthetic route for the preparation of a compound of formula (I) when R2 is -(C1-C6)alkylene-O-(C1-C6)hydroxyalkyl, eg. -CH2OCH2CH2OH. Compound (XXXV), being (XXXV) compound I synthesized following Scheme 8, where L is an alkyl or cycloalkyl linker, such as cyclobutyl. is protected under standard literature conditions by reaction with a suitable protecting group such as tert- butyl(chloro)dimethylsilane or other silyl group, in presence of a suitable base such as triethylamine and catalytic amount of DMAP, carrying out the reaction in a suitable solvent, such as a mixture of DCM and DMF at room temperature, affording compound (XXXVI). Hydrolysis of ester (XXXVI) to afford carboxylic acid (XXXVII) can be achieved by reaction with trimethylsilyl trifluoromethanesulfonate in presence of a base such as 2,6- dimethylpyridine, at an appropriate temperature, such as RT. Reaction of carboxylic acid (XXXVII) with a commercially available alcohol, such as 3-methylbutan-2-ol, under standard esterification conditions, for example in presence of an appropriate coupling agent, such as EDC*HCl, in the presence of catalytic amount of DMAP, in an appropriate solvent such as NMP and at an appropriate temperature, such as 50 °C, afforded ester (XXXVIII) . Finally, deprotection of compound (XXXVIII) under standard literature conditions as described above, afforded compound (I). 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. In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step number. This is provided merely for assistance to the skilled chemist. A “similar” or “analogous” procedure means that such a procedure may involve minor variations, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions. All the Intermediates and the Examples reported were analytically characterized by LC-MS and/or 1H-NMR as described therein, the optimal proton frequency and solvent conditions may vary and can be readily determined by those skilled in the art by routine optimization procedures. Abbreviations – meaning Aq. = Aqueous; Boc= tert-Butyloxycarbonyl; Cbz= 1-(Benzyloxycarbonyl); CDI= 1,1′- Carbonyldiimidazole; cHex= Cyclohexane; Cs2CO3= Cesium carbonate; CsF= Cesium fluoride; DCC= N,N'-Dicyclohexylcarbodiimide; DCM= Dichloromethane; DIPEA= N,N- Diisopropylethylamine; DMAP= 4-(Dimethylamino)pyridine; DME= 1,2 dimethoxyethane; DMF= Dimethylformamide; DMSO= Dimethylsulfoxide; EDC= N-(3- Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc= Ethyl acetate; FCC = flash chromatography; h= hour; H2= Hydrogen; HCl= Hydrochloric acid; HCOOH= Formic acid; H2O= Water; HATU= 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate; K3PO4= Potassium phosphate tribasic; LC-MS= Liquid chromatography-mass spectrometry; MeCN= Acetonitrile; MeOH= Methanol; MW= microwave; Min= Minutes; N2= Nitrogen; NaBH(OAc)3=sodium triacetoxyborohydride; NaOH= Sodium hydroxide; Na2SO4= Sodium sulfate; NaHCO3 = Sodium bicarbonate; NH3= Ammonia; NH4Cl= ammonium chloride; NH4OH= ammonium hydroxide; NMP= N-Methyl- 2-pyrrolidone; Pd/C= Palladium on carbon; Pd2(dba)3= Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2= [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; Teoc = 2-(trimethylsilyl)ethoxycarbonyl. General Experimental Details and methods Analytical method Instruments, materials and methods employed for analyses 1H-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 1H/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 δ 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). 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. LC-MS: LC-MS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on Waters LC/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. LC/MS retention times are estimated to be affected by an experimental error of +0.5 min. LC/UV/MS Analytical Methods 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 1= low pH conditions, column Acquity CSH C182.1x50mm 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=1.5 min 0.1% A 99.9% B, t=1.9 min 0.1% A 99.9% B and t=2 min 97% A 3% B. The UV detection range was 210-350 nm and ES+/ES- range was 100 to 1500 AMU. 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+/ES- range was 100 to 1000 AMU. Purification Methods Some compounds were purified by FCC using Biotage® columns and conditions specified in each Example. Biotage® columns used are herein described with their abbreviations used in the synthetic procedures: Sfär silica: Silica column Biotage® Sfär silica D Duo 60 μM; Sfär amino: amino-functionalized silica column Biotage® Sfär KP-amino D Duo 50 μM; Sfär C18: C18 derivatized silica column Biotage® Sfär C18 D Duo 100 Å 30 μM. PREPARATIONS OF INTERMEDIATES Intermediate 1: 2-(trimethylsilyl)ethyl carbamate CDI (9.9 g, 60.9 mmol) was added to a stirred suspension of 2-(trimethylsilyl)ethanol (6.0 g, 50.7 mmol) in dry toluene (50 mL). The reaction was stirred at RT for 5h, before adding NH4OH solution (28 wt% NH4OH in H2O, 10 mL). This mixture was vigorously stirred overnight. Phases were separated, the organic phase was washed with brine, then filtered through a phase separator and concentrated under vacuum. The residue was taken - up with EtOAc and washed with brine (5×), then filtered and evaporated to afford the title compound (7.5 g, 46.5 mmol, 92% yield). 1H NMR (400 MHz, Chloroform-d) δ ppm 4.52 (br. s, 2H), 4.10 - 4.22 (m, 2H), 0.93 - 1.07 (m, 2H), 0.05 (s, 9H). Intermediate 2: 4-chloro-6-(5-chloro-2-fluorophenyl)-3-methylpyridazine 4,6-dichloro-3-methylpyridazine (630 mg, 3.87 mmol), (5-chloro-2-fluorophenyl) boronic acid (674 mg, 3.87 mmol), Cs2CO3 (3.17 g, 9.66 mmol) and Pd(dppf)Cl2 (110 mg, 0.190 mmol) were mixed in 1,4-dioxane (15 mL)/H2O (5 mL). The mixture was degassed with N2 for 5 min before adding Pd(OAc)2 (44 mg, 0.190 mmol), the resulting mixture was heated at 60 ºC for 1h. EtOAc and H2O were added, the product was extracted with EtOAc several times, organic phases were collected, dried and evaporated. The residue was purified by FCC on Biotage silica cartridge (from cHex to 15% EtOAc) to afford the title compound (665 mg, 2.59 mmol, 67% yield). LC-MS (ESI): m/z (M+1): 257.1 (Method 1) Intermediate 3: 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine In a suitable vial, Intermediate 2 (500 mg, 1.94 mmol), Intermediate 1 (361 mg, 2.24 mmol), Xantphos (171 mg, 0.30 mmol) and K3PO4 (837 mg, 3.89 mmol) were mixed in 1,4- dioxane (15 mL). N2 was bubbled for 2 min before adding Pd2(dba)3 (184 mg, 0.20 mmol), then the vial was sealed and irradiated with MW at 100 °C for 5h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by FCC on Biotage silica NH cartridge (from cHex to 15% EtOAc) to afford the Teoc product intermediate (400 mg) which was mixed with CsF (297 mg, 1.94 mmol) in DMF (5 mL), and heated at 45 °C overnight. The mixture was cooled to RT and charged on SCX cartridge (20g) washing with MeOH and eluting with 1 N NH 3 in MeOH. Basic fractions were collected and evaporated and the residue was purified by FCC on Biotage silica NH cartridge (from DCM to 3% MeOH) to afford the title compound (170 mg, 0.71 mmol, 37% yield). LC-MS (ESI): m/z (M+1): 238.0 (Method 1). Intermediate 4: methyl 6-chloro-4-{[(2,4- dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate 1-(2,4-dimethoxyphenyl)methanamine (8.71 mL, 58 mmol) was added to a stirred solution of methyl 4,6-dichloropyridazine-3-carboxylate (10 g, 48.3 mmol) and TEA (7.43 mL, 53.14 mmol) in dry MeCN (70 mL) at RT under N2, and the reaction was stirred for 3h, a precipitate formed. The suspension was filtered washing with MeCN and the solids collected to give title compound (15 g, 44.4 mmol, 92 % yield). LC-MS (ESI): m/z (M+1): 338.1 (Method 1) Intermediate 5: methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate In a 100 mL flask equipped with a reflux condenser, a mixture of 5-chloro-2- fluorobenzeneboronic acid (2.06 g, 11.84 mmol), Pd(dppf)Cl2 (434.46 mg, 0.59 mmol), K2CO3 (2.45 g, 17.76 mmol) and Intermediate 4 (2 g, 5.92 mmol) in dry 1,2-dimethoxyethane (33.7 mL) and H2O (4.8 mL) was degassed with N2 for 2 min, then the mixture was gently stirred at 85 °C for 1.5h. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3. The organic phase was separated, dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by FCC on Biotage silica cartridge (from cHex to 50 % EtOAc) to give title compound (1.14 g, 2.64 mmol, 45% yield). LC-MS (ESI): m/z (M+1): 432.2 (Method 1) Intermediate 6: [6-(5-chloro-2-fluorophenyl)-4-{[(2,4- dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol 2 M solution of lithium aluminum hydride in THF (6.26 mL, 12.52 mmol) was added dropwise to a stirred solution of Intermediate 5 (4.7 g, 10.88 mmol) in dry THF (94 mL) at 0 ºC under N2. After 1h, the reaction was warmed to RT and stirred for 1h. The mixture was then cooled at 0 ºC and, in sequence, were added 0.24 mL of H2O, 0.24 mL of NaOH 15% and 0.72 mL of H2O. The reaction was warmed to RT and stirred for 1h. The mixture was filtered on Celite® pad and washed with THF. The solvent was removed by reduced pressure and the residue was purified by FCC on Biotage silica cartridge (from cHex to 60 % EtOAc) to give title compound (4.20 g, 10.4 mmol, 95% yield). LC-MS (ESI): m/z (M+1): 404.2 (Method 1) Intermediate 7: [4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol TFA (18.77 mL, 245.12 mmol) was added to a stirred solution of Intermediate 6 (3.1 g, 7.68 mmol) in DCM (42 mL) at RT under N2. The reaction was stirred for 24h. The solvents were removed under reduced pressure, toluene was added and evaporated again under vacuum. The residue was charged on SCX, washed with MeOH, and eluted with 1N NH3 in MeOH. Basic fractions were collected and evaporated to afford ti tle compound (1.85 g, 7.29 mmol, 95% yield). LC-MS (ESI): m/z (M+1): 254.1 (Method 1) Intermediate 8: 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2- fluorophenyl)pyridazin-4-amine Tert-butyl(chloro)dimethylsilane (985 mg, 6.53 mmol) was added to a stirred solution of Intermediate 7 (1.1 g, 4.34 mmol), imidazole (503 mg, 7.39 mmol) and DMAP (105 mg, 0.86 mmol) in DCM (13.8 mL)/DMF (13.8 mL) at RT. After 2h the mixture was diluted with DCM, washed with a concentrated solution of NaHCO3 and water. The organic phase was dried over Na2SO4, filtered and the solvent removed under reduced pressure. The residue was purified by FCCon Biotage silica cartridge (from cHex to 20 % EtOAc) to afford the title compound (1.04 g, 2.82 mmol, 65 % yield). LC-MS (ESI): m/z (M+1): 369.1 (Method 2) Intermediate 9: cis tert‐butyl 1‐[3‐(ethoxycarbonyl)cyclobutyl]piperidine‐4‐ carboxylate A solution of ethyl 3-oxocyclobutane-1-carboxylate (1.5 g, 10.55 mmol) and tert-butyl piperidine-4-carboxylate hydrochloride (2.34 g, 10.55 mmol) in DCM (51.4 mL) was stirred for 15 min at RT, then NaBH(OAc)3 (3.45 g, 16.28 mmol) was added portion-wise and the resulting reaction mixture was stirred at RT for 4h. The mixture was concentrated under reduced pressure, then methanol (30 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with sat. aq. NaHCO3. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC on Biotage silica cartridge (from cHex to 25 % EtOAc) to give the title compound (1.46 g, 4.69 mmol, 44% yield). LC-MS (ESI): m/z (M+1): 311.9 (Method 2) Intermediate 10: cis tert‐butyl 1‐{3‐[(6‐chloropyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate To a stirred solution of 6-chloro-4-pyrimidinamine (0.98 g, 7.55 mmol) in THF (30 mL), at -78 °C and under a N2 atmosphere, n-Butyllithium 2.5 N/hexanes (2.3 mL, 5.75 mmol) was added portion-wise over 10 min then the reaction mixture was stirred at -78 °C for 50 min. A solution of Intermediate 9 (1.46 g, 4.96 mmol) in THF (9 mL) was added dropwise over the course of 5 min at -78 °C. After 5 min, the cooling bath was removed and the resulting reaction mixture was allowed to reach RT and stirred for 20h . The mixture was diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude was taken-up with DCM, the solids filtered, and the obtained solution concentrated under reduced pressure. The crude product was purified by FCC on Biotage silica cartridge (from cHex to 100% EtOAc) to give the title compound (883 mg, 2.24 mmol, 48% yield). LC-MS (ESI): m/z (M+1): 395.1 (Method 2) Intermediate 11: cis methyl 3‐[(tert‐butyldimethylsilyl)oxy]cyclobutane‐1‐ carboxylate Intermediate 11 was prepared following similar procedure used for the synthesis of Intermediate 8, starting from cis methyl 3-hydroxycyclobutanecarboxylate (1 g, 7.68 mmol). The mixture was diluted with DCM, washed with H2O and sat. aq. solution of NH4Cl affording title compound (7.68 mmol, recovery assumed quantitative). 1H NMR (400 MHz, Chloroform-d) δ ppm 4.13 - 4.20 (m, 1H), 3.68 (s, 3H), 2.39 - 2.59 (m, 3H), 2.13 - 2.30 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H). Intermediate 12: cis 3‐[(tert‐butyldimethylsilyl)oxy]‐N‐(6‐chloropyrimidin‐4‐ yl)cyclobutane‐1‐carboxamide Intermediate 12 was prepared following the procedure used for the synthesis of Intermediate 10 starting from 6-chloro-4-pyrimidinamine (711 mg, 5.49 mmol) and Intermediate 11 (776 mg, 3.43 mmol) to afford the title compound (470 mg, 1.37 mmol, 42% yield). LC-MS (ESI): m/z (M+1): 342.2 (Method 2) Intermediate 13: cis 3‐[(tert‐butyldimethylsilyl)oxy]‐N‐(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐yl)cyclobutane‐1‐ carboxamide In a vial, to a mixture of Intermediate 3 (150 mg, 0.63 mmol), Intermediate 12 (237 mg, 0.69 mmol), K3PO4 (268 mg, 1.26 mmol), and Xantphos (55 mg, 0.15 mmol) in DME (4.2 mL), Pd2(dba)3 (58 mg, 0.06 mmol) was added. N2 was bubbled for 5 min, then the vial was sealed and heated at 100 °C for 1h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by FCC on Biotage silica cartridge (from cHex to 60 % EtOAc) to afford the title compound (280 mg, 0.52 mmol, 82% yield). LC-MS (ESI): m/z (M+1): 543.1 (Method 2) Intermediate 14: cis N‐(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)‐3‐hydroxycyclobutane‐1‐carboxamide To a solution of Intermediate 13 (280 mg, 0.52 mmol) in DCM (2.6 mL), TFA (0.39 mL, 5.16 mmol) was added. The reaction was stirred for 2h. Volatiles were removed under vacuum. The residue was taken up with MeOH and loaded on SCX (2g, washing with MeOH, and eluting with ammonia solution 1M in MeOH). Basic fraction was evaporated. The residue was taken up with DCM and the resulting solids were collected affording a first crop (95 mg). The filtrate was evaporated and triturated with acetone affording a second crop which was combined with the first one to afford the title compound (180 mg, 0.42 mmol, 81% yield). LC-MS (ESI): m/z (M+1): 429.2 (Method 2) Intermediate 14 (Alternative synthesis): cis N‐(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐yl)‐3‐ hydroxycyclobutane‐1‐carboxamide Step A: cis methyl 3‐(oxan‐2‐yloxy)cyclobutane‐1‐carboxylate A mixture of cis-methyl-3-hydroxycyclobutane-1-carboxylate (1.43 g, 11 mmol), 3,4- dihydro-2H-pyran (1.2 mL, 13.2 mmol) and pyridinium p-toluenesulfonate (552 mg, 2.2 mmol) in DCM (36 mL) was stirred overnight at 23 °C. The mixture was diluted with DCM, then washed with sat. aq. NaHCO3 and water. 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 20% EtOAc) to give the title compound (2.36 g, 11 mmol, quantitative recovery). LC-MS (ESI): m/z (M+1): 215.2 (Method 2) Step B: N‐(6‐chloropyrimidin‐4‐yl)‐3‐(oxan‐2‐yloxy)cyclobutane‐1‐ carboxamide Title compound (3.04 g, 9.75 mmol, 88% yield). was prepared following the procedure used for the synthesis of Intermediate 10 starting from 6-chloro-4-pyrimidinamine (2.43 g, 18.7 mmol) and cis methyl 3‐(oxan‐2‐yloxy)cyclobutane‐1‐carboxylate (from Step A, 2.36 g, 11 mmol) to afford the title compound. LC-MS (ESI): m/z (M+1): 312.2 (Method 2) Step C: N‐(6‐chloropyrimidin‐4‐yl)‐3‐(oxan‐2‐yloxy)cyclobutane‐1‐ carboxamide (Intermediate 14) In a suitable vial, a mixture of N‐(6‐chloropyrimidin‐4‐yl)‐3‐(oxan‐2‐ yloxy)cyclobutane‐1‐carboxamide (from Step B, 717 mg, 2.28 mmol), 6-(5-chloro-2- fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 3, 507 mg, 2.07 mmol), K3PO4 (439 mg, 2.07 mmol), Pd2(dba)3 (189 mg, 0.21 mmol) and xanthphos (180 mg, 0.31 mmol) was suspended in DME (12 mL). The mixture was degassed (N2/vacuum) then heated at 100 °C for 2 hrs. The mixture was diluted with EtOAc, then filtered over a celite® pad. The solvents were removed under reduced pressure, the residue loaded onto a SCX cartridge (10 g) and eluted with 1 N NH3 in MeOH. Collected fractions were concentrated under reduced pressure and the residue treated with DCM (3 mL) and TFA (2.38 mL, 31 mmol) and stirred overnight at RT. The mixture was coevaporated with toluene under reduced pressure. The residue loaded onto a SCX cartridge (10 g) and eluted with 1 N NH3 in MeOH. Collected fractions were concentrated under reduced pressure and the crude product was purified by FCC on Biotage silica cartridge (from DCM to 10% MeOH) to give the title compound (709 mg, 1.65 mmol, 80% yield). LC-MS (ESI): m/z (M+1): 429.2 (Method 2) Intermediate 15: cis tert‐butyl 1‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐ 6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 15 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 10 (446 mg, 1.13 mmol), and Intermediate 8 (300 mg, 0.81 mmol) to afford the title compound (422 mg, 0.58 mmol, 72% yield). LC-MS (ESI): m/z (M+1): 726.5 (Method 1) Intermediate 16: cis 1‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐ chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylic acid A solution of Intermediate 15 (532 mg, 0.73 mmol) and 2,6-dimethylpyridine (0.68 mL, 5.86 mmol) in DCM (7.1 mL) was treated with trimethylsilyl trifluoromethanesulfonate (0.53 mL, 2.93 mmol) at RT. The mixture was stirred for 3h, then diluted with DCM and gently washed with H2O. The organic phase was separated and left standing over weekend in the fridge. A solid formed, which was filtered and dried under vacuum to give the title compound (412 mg, 0.615 mmol, 84% yield). LC-MS (ESI): m/z (M+1): 670.4 (Method 2) Intermediate 17: cis ethyl 1‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐ chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate To solution of ethanol (0.02 mL, 0.37 mmol) and DIPEA (0.03 mL, 0.15 mmol) in DMF (0.34 mL), Intermediate 16 (25 mg, 0.04 mmol) was added and stirred for 5 min. Afterwards, HATU (20 mg, 0.05 mmol) was added, and the mixture stirred at RT overnight. The mixture was quenched by adding sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated and washed with sat. aq. NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC on Biotage silica cartridge (from cHex to 65 % EtOAc) to give the title compound (10 mg, 0.014 mmol, 38% yield). LC-MS (ESI): m/z (M+1): 698.4 (Method 2) Intermediate 18: tert‐butyl 1‐{2‐[(6‐chloropyrimidin‐4‐ yl)carbamoyl]ethyl}piperidine‐4‐carboxylate Step A Tert-butyl piperidine-4-carboxylate hydrochloride (156 mg, 0.70 mmol), TEA (0.1 mL, 0.70 mmol) and 2-propanamide (50 mg, 0.70 mmol) were mixed in H2O (1 mL) and MeCN (0.17 mL) and stirred at RT for 8h. Volatiles were removed under vacuum to afford the title compound used as such (0.7 mmol, recovery assumed quantitative). Step B In a suitable vial, a mixture of 4,6-dichloropyrimidine (110 mg, 0.74 mmol), Pd(OAc)2 (10 mg, 0.04 mmol), tert-butyl 1-(3-amino-3-oxo-propyl)piperidine-4-carboxylate (from Step A, 0.7 mmol), Cs2CO3 (242 mg, 0.76 mmol), Xantphos (51 mg, 0.08 mmol) in DME (5.3 mL) was degassed (N2/ vacuum) then stirred at 80 °C for 1 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 silica cartridge (from EtOAc to 40% MeOH) to afford the title compound (115 mg, 0.31 mmol, 44% yield). LC-MS (ESI): m/z (M+1): 369.2 (Method 2) Intermediate 19: tert‐butyl 1‐[2‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐ (5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)ethyl]piperidine‐4‐carboxylate Intermediate 19 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 18 (110 mg, 0.3 mmol) and Intermediate 8 (100 mg, 0.27 mmol) to afford the title compound (140 mg, 0.20 mmol, 74% yield). LC-MS (ESI): m/z (M+1): 700.5 (Method 2) Intermediate 20: cis (3R)‐1‐methylpyrrolidin‐3‐yl 1‐[3‐({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 20 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (102 mg, 0.15 mmol) and using (R)-1-methyl- 3-pyrrolidinol (31 mg, 0.30 mmol) to afford the title compound (46 mg, 0.06 mmol, 36% yield). LC-MS (ESI): m/z (M+1): 753.6 (Method 2) Intermediate 21: cis 3‐hydroxy‐2,2‐dimethylpropyl 1‐[3‐({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 21 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (185 mg, 0.27 mmol) and using 2,2- dimethylpropane-1,3-diol (287 mg, 2.76 mmol) to afford the title compound (33 mg, 0.04 mmol, 16% yield). LC-MS (ESI): m/z (M+1): 756.6 (Method 2) Intermediate 22: cis 2,2‐dimethylpropyl 1‐[3‐({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxy late Intermediate 22 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (130 mg, 0.19 mmol) and using 2,2-dimethyl- 1-propanol (171 mg, 1.94 mmol) to afford the title compound (48 mg, 0.06 mmol, 31% yield). LC-MS (ESI): m/z (M+1): 740.6 (Method 2) Intermediate 23: cis 3‐methylbutan‐2‐yl 1‐[3‐({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 23 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (130 mg, 0.19 mmol) and using 3- methylbutan-2-ol (342 mg, 3.88 mmol) to afford the title compound (17 mg, 0.02 mmol, 12% yield). LC-MS (ESI): m/z (M+1): 740.6 (Method 2) Intermediate 24: 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), α-methylene- γ-butyrolactone (500 mg, 5.1 mmol) was added. The reaction mixture was vigorously stirred at RT for 2 days, then it was concentrated under reduce pressure and the crude material was purified by FCC 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+1): 320.0 (Method 2) Intermediate 25: benzyl 4‐[(3‐methyl‐2‐oxooxolan‐3‐yl)methyl]piperazine‐1‐ carboxylate Lithium bis(trimethylsilyl)amide 1M in THF (5.31 mL, 5.31 mmol) was added dropwise at -78 °C to a solution of Intermediate 24 (1.3 g, 4.08 mmol) in THF (21.1 mL) under N2 atmosphere. 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 1h. The reaction mixture was diluted with EtOAc and sat. aq. NaHCO3 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 FCC 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+1): 332.9 (Method 2) Intermediate 26: 3‐methyl‐3‐[(piperazin‐1‐yl)methyl]oxolan‐2‐one To a stirred solution of Intermediate 25 (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 atmosphere 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+1): 198.8 (Method 2) Intermediate 27: N‐(6‐chloropyrimidin‐4‐yl)‐3‐{4‐[(3‐methyl‐2‐oxooxolan‐3‐ yl)methyl]piperazin‐1‐yl}propanamide Intermediate 27 was prepared following the procedure used for the synthesis of Intermediate 18 starting from Intermediate 26 (279 mg, 1.41 mmol) to afford the title compound (260 mg, 0.68 mmol, 49% yield). LC-MS (ESI): m/z (M+1): 382.3 (Method 2) Intermediate 28: N‐{6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐ fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐yl}‐3‐{4‐[(3‐methyl‐2‐oxooxolan‐3‐ yl)methyl]piperazin‐1‐yl}propanamide Intermediate 28 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 27 (104 mg, 0.27 mmol) and Intermediate 8 (100 mg, 0.27 mmol) to afford the title compound (120 mg, 0.17 mmol, 62% yield). LC-MS (ESI): m/z (M+1): 713.3 (Method 2) Intermediate 29: cis (3S)‐1‐(2,2,2‐trifluoroethyl)pyrrolidin‐3‐yl 1‐[3‐({6‐[(3‐ {[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 29 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (150 mg, 0.22 mmol) and using (3S)-1-(2,2,2- trifluoroethyl)pyrrolidin-3-ol (114 mg, 0.67 mmol) to afford the title compound (117 mg, 0.14 mmol, 64% yield). LC-MS (ESI): m/z (M+1): 821.5 (Method 2) Intermediate 30: cis oxetan‐3‐yl 1‐[3‐({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]piperidine‐4‐carboxylate Intermediate 30 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 16 (80 mg, 0.12 mmol) and using 3-oxetanol (38 µL, 0.60 mmol) to afford the title compound (51 mg, 0.07 mmol, 59% yield). LC-MS (ESI): m/z (M+1): 726.5 (Method 2) Intermediate 31: cis methyl 3‐[3‐(ethoxycarbonyl)cyclobutyl]‐3‐ azabicyclo[3.1.1]heptane‐6‐carboxylate Intermediate 31 was prepared following the procedure used for the synthesis of Intermediate 9 starting from cis ethyl 3-oxocyclobutane-1-carboxylate (570 mg, 4.02 mmol), and methyl 3-azabicyclo[3.1.1]heptane-6-carboxylate hydrochloride (770 mg, 4.02 mmol) to afford the title compound (780 mg, 2.77 mmol, 69% yield). LC-MS (ESI): m/z (M+1): 282.9 (Method 2) Intermediate 32: cis methyl 3‐{3‐[(6‐chloropyrimidin‐4‐yl)carbamoyl]cyclobutyl}‐ 3‐azabicyclo[3.1.1]heptane‐6‐carboxylate Intermediate 32 was prepared following the procedure used for the synthesis of Intermediate 10 starting from Intermediate 31 (780 mg, 2.77 mmol) and using 6-chloro-4- pyrimidinamine (578 mg, 4.46 mmol) to afford the title compound (260 mg, 0.71 mmol, 26% yield). LC-MS (ESI): m/z (M+1): 365.3 (Method 2) Intermediate 33: cis metyl 3‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐ (5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐yl}carbamoyl)cyclobutyl]‐ 3‐azabicyclo[3.1.1]heptane‐6‐carboxylate Intermediate 33 was prepared following the procedure used for the synthesis of Intermediate 13, starting from Intermediate 8 (100 mg, 0.27 mmol) and Intermediate 32 (119 mg, 0.33 mmol) to afford the title compound (140 mg, 0.20 mmol, 74% yield). LC-MS (ESI): m/z (M+1): 696.5 (Method 2) Intermediate 34: trans methyl 3‐[(4‐methylbenzenesulfonyl)oxy]cyclobutane‐1‐ carboxylate To a stirred solution of trans methyl 3-hydroxycyclobutanecarboxylate (500 mg, 3.84 mmol) in DCM (10 mL), TEA (0.69 mL, 4.97 mmol) and DMAP (94 mg, 0.77 mmol) were added, the solution was cooled to 0 °C, then 4-methylbenzenesulfonyl chloride (806 mg, 4.23 mmol) was added portion-wise. After 5 min the ice-bath was removed, and the resulting reaction mixture was stirred at RT for 4h. The mixture was diluted with DCM, washed with a sat. NaHCO3 solution, the organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by FCC on Biotage silica cartridge (from cHex 20% EtOAc) affording the title compound (760 mg, 2.67 mmol, 70% yield). 1H NMR (Chloroform-d) ^^ ppm: 7.80 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 8.6, 0.7 Hz, 2H), 4.97-5.10 (m, 1H), 3.70 (s, 3H), 3.03-3.12 (m, 1H), 2.47 (s, 7H). Intermediate 35: cis tert‐butyl 1‐{3‐[(6‐chloropyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐3‐carboxylate Step A A solution of Intermediate 34 (200 mg, 0.70 mmol), tert-butyl piperidine-3-carboxylate (130 mg, 0.70 mmol) and K3CO2 (194 mg, 1.41 mmol) was stirred at 95 °C for 36h. The reaction mixture was dissolved with EtOAc and washed with sat . NaHCO3 solution. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by FCC on Biotage silica cartridge (from cHex 20% EtOAc) to give cis tert‐butyl 1‐[3‐(methoxycarbonyl)cyclobutyl]piperidine‐3‐carboxylate (125 mg, 0.42 mmol, 60% yield). Step B Intermediate 35 was prepared following the procedure used for the synthesis of Intermediate 10 starting from intermediate from Step A (125 mg, 0.42 mmol) and using 6- chloro-4-pyrimidinamine (88 mg, 0.68 mmol) to afford the title compound (60 mg, 0.15 mmol, 36% yield). LC-MS (ESI): m/z (M+1): 395.2 (Method 2) Intermediate 36: cis tert‐butyl 1‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐ 6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidine‐3‐carboxylate Intermediate 36 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 8 (55 mg, 0.15 mmol) and Intermediate 35 (60 mg, 0.15 mmol) to afford the title compound (35 mg, 0.05 mmol, 33% yield). LC-MS (ESI): m/z (M+1): 726.5 (Method 2) Intermediate 37: 2‐{[6‐(5‐chloro‐2‐fluorophenyl)‐4‐{[(2,4‐ dimethoxyphenyl)methyl]amino}pyridazin‐3‐yl]methoxy}ethan‐1‐ol A solution of Intermediate 6 (500 mg, 1.24 mmol) in DCM (15 mL) cooled at 0 °C was treated with methanesulfonic anhydride (302 mg, 1.73 mmol). DIPEA (560 µL, 3.22 mmol) was added and the reaction stirred at 0 °C. After 45 min, ethane-1,2-diol (1.9 g, 30.95 mmol) was added, the mixture allowed to reach RT and stirred for 24h. The reaction was diluted with DCM and washed with sat. NaHCO3 solution. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC on Biotage silica cartridge (from cHex 100% EtOAc) to give the title compound (360 mg, 0.80 mmol, 65% yield). LC-MS (ESI): m/z (M+1): 447.8 (Method 2) Intermediate 38: 2‐{[4‐amino‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐3‐ yl]methoxy}ethan‐1‐ol Intermediate 38 was prepared following the procedure used for the synthesis of Intermediate 7 starting from Intermediate 37 (360 mg, 0.80 mmol) to afford the title compound (0.80 mmol, recovery assumed quantitative). LC-MS (ESI): m/z (M+1): 298.5 (Method 2) Intermediate 39: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl 1H‐imidazole‐1‐carboxylate A suspension of Intermediate 14 (42 mg, 0.10 mmol) in MeCN (3.3 mL) was treated with CDI (48 mg, 0.29 mmol). The reaction was stirred at 60 °C overnight. The mixture was diluted with DCM and washed with water, the organic phase dried with Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (42 mg, 0.08 mmol, 82% yield). LC-MS (ESI): m/z (M+1): 523.2 (Method 2) Intermediate 40: cis tert‐butyl 1‐{3‐[(6‐{[3‐({2‐[(tert‐ butyldimethylsilyl)oxy]ethoxy}methyl)‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Intermediate 40 was prepared following the procedure used for the synthesis o f Intermediate 8 starting from Example 14 (180 mg, 0.27 mmol) to afford the title compound (200 mg, 0.26 mmol, 95% yield). LC-MS (ESI): m/z (M+1): 770.5 (Method 2) Intermediate 41: cis 1‐{3‐[(6‐{[3‐({2‐[(tert‐butyldimethylsilyl)oxy]ethoxy}methyl)‐ 6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylic acid Intermediate 41 was prepared following the procedure used for the synthesis of Intermediate 16 starting from Intermediate 40 (200 mg, 0.26 mmol) to afford the title compound (0.26 mmol, recovery assumed quantitative). LC-MS (ESI): m/z (M+1): 714.5 (Method 2) Intermediate 42: cis (2R)‐3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[3‐({2‐[(tert‐ butyldimethylsilyl)oxy]ethoxy}methyl)‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate EDC HCl (58 mg, 0.30 mmol) was added to a stirred mixture of Intermediate 41 (120 mg, 0.13 mmol), (2R)-3-methylbutan-2-ol (118 mg, 1.34 mmol) and DMAP (19 mg, 0.16 mmol) in NMP (2 mL) at RT. The reaction was heated at 50 °C for 6h. The mixture was dissolved with water and extracted with EtOAc. Organic layer was separated, dried over Na2SO4, and evaporated. The crude material was purified by FCC on Biotage NH silica cartridge (from DCM to 2 % MeOH) to afford the title compound (20 mg, 0.02 mmol, 19 % yield). LC-MS (ESI): m/z (M+1): 784.5 (Method 2) Intermediate 43: tert‐butyl 1‐(carbamoylmethyl)piperidine‐4‐carboxylate To a mixture of 4-piperidine carboxylic acid tert-butyl ester hydrochloride (330 mg, 1.49 mmol) and 2-chloroacetamide (127 mg, 1.35 mmol) in MeCN (6 mL), DIPEA (0.78 mL, 4.47 mmol) was added, and the reaction was stirred overnight at 70 °C. Volatiles were removed under vacuum. The crude material was purified by FCC on Biotage NH silica cartridge (from DCM to 2 % MeOH) affording the title compound (276 mg, 1.14 mmol, 767% yield). LC-MS (ESI): m/z (M+1): 242.9 (Method 2) Intermediate 44: tert‐butyl 1‐{[(6‐chloropyrimidin‐4‐ yl)carbamoyl]methyl}piperidine‐4‐carboxylate In a suitable vial, a mixture of 4,6-dichloropyrimidine (130 mg, 0.87 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), Intermediate 43 (225 mg, 0.93 mmol), Cs2CO3 (286 mg, 0.87 mmol), Xantphos (61 mg, 0.10 mmol) in DME (5.8 mL) was degassed (N2/ vacuum) then stirred at 80 °C for 1h. The mixture was diluted with EtOAc, filtered through a Celite® pad washed with EtOAc. The filtrate was evaporated under vacuum. The crude material was purified by FCC on Biotage NH silica cartridge (from EtOAc to 40% MeOH) to afford the title compound (256 mg, 0.72 mmol, 83% yield). LC-MS (ESI): m/z (M+1): 355.2 (Method 2) Intermediate 45: tert‐butyl 1‐[({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐ chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)methyl]piperidine‐4‐carboxylate Intermediate 45 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 8 (240 mg, 0.65 mmol) and Intermediate 44 (255 mg, 0.72 mmol) to afford the title compound (347 mg, 0.51 mmol, 78% yield). LC-MS (ESI): m/z (M+1): 686.5 (Method 2) Intermediate 46: 1‐[({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐ fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐yl}carbamoyl)methyl]piperidine‐ 4carboxylic acid Intermediate 46 was prepared following the procedure used for the synthesis of Intermediate 16 starting from Intermediate 45 (300 mg, 0.44 mmol) to afford the title compound (270 mg, 0.43 mmol, 98% yield). LC-MS (ESI): m/z (M+1): 630.4 (Method 2) Intermediate 47: (3R)‐1‐methylpyrrolidin‐3‐yl 1‐[({6‐[(3‐{[(tert‐ butyldimethylsilyl)oxy]methyl}‐6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐yl}carbamoyl)methyl]piperidine‐4‐carboxylate Intermediate 47 was prepared following the procedure used for the synthesis of Intermediate 17 starting from Intermediate 46 (30 mg, 0.05 mmol) and using (R)-(-)-1- methyl-3-pyrrolidinol (10 µL, 0.09 mmol) in DCM (0.5 mL) to afford the title compound (35 mg, 0.05 mmol, recovery assumed quantitative). LC-MS (ESI): m/z (M+1): 713.4 (Method 2) Intermediate 48: ethyl 3‐{4‐[2‐(tert‐butoxy)‐2‐oxoethyl]piperidin‐1‐ yl}cyclobutane‐1‐carboxylate The Intermediate listed below in Table 2 was prepared from the suitable reagents in analogy to the procedures followed for Intermediate 9. Table 2 Intermediate Stru Reagents/Amount, Analytical N° cture & IUPAC Name yield data tert-butyl 2-(4- piperidyl)acetate LC-MS (ESI): m/z 48 ethyl 3- (M+1): ethyl 3‐{4‐[2‐(tert‐butoxy)‐2‐ oxocyclobutane-1- 327.2 oxoethyl]piperidin‐1‐ carboxylate (Method 2) yl}cyclobutane‐1‐carboxylate 582 mg, 85% yield Intermediate 49: tert‐butyl 2‐(1‐{3‐[(6‐chloropyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin‐4‐yl)acetate The Intermediate listed below in Table 3 was prepared from the suitable reagents in analogy to the procedures followed for Intermediate 10. Table 3 Intermediate Structure & IUPAC Reagents/Amount, Analytical N° Name yield data Intermediate 48 LC-MS (ESI): m/z 49 6-chloro-4- (M+1): 409.7 tert‐butyl 2‐(1‐{3‐[(6‐ pyrimidinamine (Method 2) chloropyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidi n‐4‐yl)acetate Intermediate 50: tert‐butyl 2‐{1‐[3‐({6‐[(3‐{[(tert‐butyldimethylsilyl)oxy]methyl}‐ 6‐(5‐chloro‐2‐fluorophenyl)pyridazin‐4‐yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidin‐4‐yl}acetate The Intermediate listed below in Table 4 was prepared from the suitable reagents in analogy to the procedures followed for Intermediate 13. Table 4 Interm. Struc Analytical N° ture & IUPAC Name Reagents data Intermediate 49 LC-MS 50 (ESI): m/z tert‐butyl 2‐{1‐[3‐({6‐[(3‐{[(tert‐ Intermediate (M+1): 740.5 butyldimethylsilyl)oxy]methyl}‐6‐(5‐ 8 (Method 2) chloro‐2‐fluorophenyl)pyridazin‐4‐ yl)amino]pyrimidin‐4‐ yl}carbamoyl)cyclobutyl]piperidin‐4‐ yl}acetate PREPARATIONS OF EXAMPLES Example 1: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl 4‐methylpiperazine‐1‐ carboxylate A suspension of Intermediate 14 (57 mg, 0.13 mmol) in MeCN (5.3 mL) was treated with CDI (54 mg, 0.33 mmol). The reaction was stirred at 60 °C overnight. DIPEA (0.07 mL, 0.40 mmol) was added followed by 1-methylpiperazine (0.04 mL, 0.33 mmol) and the reaction stirred at 60 °C for 5h. The mixture was diluted with DCM, washed with sat. aq. NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC on Biotage NH silica cartridge (from cHex to 100% EtOAc) and then by reverse phase FCC on Biotage C18 cartridge (from H2O+0.1% HCOOH to 30% MeCN+0.1% HCOOH). Collected fractions were treated with sat. aq. NaHCO3 and extracted with DCM, the organic phase separated and dried with Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (51 mg, 0.09 mmol, 69% yield). LC-MS (ESI): m/z (M+1): 555.3 (Method 2), tR=0.87. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.98 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.15 (dd, J = 6.6, 2.6 Hz, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.38 - 7.44 (m, 1H), 7.16 (dd, J = 10.4, 8.9 Hz, 1H), 6.75 (s, 1H), 4.97 (quin, J = 7.5 Hz, 1H), 3.43 - 3.58 (m, 4H), 2.80 (s, 3H), 2.74 - 2.82 (m, 1H), 2.68 - 2.77 (m, 2H), 2.43 - 2.51 (m, 2H), 2.38 (br. s, 4H), 2.31 (s, 3H). The Examples listed below in Table 5 were prepared from the suitable reagents in analogy to the procedures followed for Example 1. Table 5 Structure & Example IUPAC Name Reagents and Solvents N° Product Amount (Yield)/ Analytical Data/Purification cis-2,6- cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ dimethylpiperazine, 3 eq methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ Intermediate 14, 1 eq yl)carbamoyl]cyclobutyl 3,5‐ dimethylpiperazine‐1‐carboxylate 19 85 mg, 43% yield LC-MS (ESI): m/z (M+1): 569.2 (Method 2), tR=0.91 ¹H NMR (500 MHz, DMSO-d6): δ ppm 10.73 (br s, 1H), 9.33 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.04 (s, 1H), 7.97 (dd, J = 6.4, 2.6 Hz, 1H), 7.60 - 7.66 (m, 1H), 7.47 (t, J = 9.6 Hz, 1H), 4.79 (quin, J = 7.6 Hz, 1H), 3.77 (br. D., J = 11.9 Hz, 2H), 3.00 (quin, J = 8.6 Hz, 1H), 2.73 (s, 3H), 2.55 - 2.62 (m, 2H), 2.48 - 2.54 (m, 2H), 2.11 - 2.38 (m, 5H), 0.94 (d, J = 6.2 Hz, 6H). FCC on Biotage-NH cartrige eluting with EtOAc/ EtOAc-EtOH 3-1 from 100:0 to 95:5 1-((1-methylpiperidin- cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ 4-yl)methyl)piperazine, methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ 3 eq yl)carbamoyl]cyclobutyl 4‐[(1‐ methylpiperidin‐4‐ Intermediate 14, 1 eq yl)methyl]piperazine‐1‐carboxylate 20 110 mg, 48% yield LC-MS (ESI): m/z (M+1): 652.3 (Method 2), tR=1.16 ¹H NMR (500 MHz, DMSO-d6): δ 10.72 (br s, 1H), 9.33 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.04 (br s, 1H), 7.97 (dd, J=6.4, 2.7 Hz, 1H), 7.63 (dt, J=8.8, 3.4 Hz, 1H), 7.47 (dd, J=10.2, 9.2 Hz, 1H), 4.80 (quin, J=7.5 Hz, 1H), 3.27 - 3.42 (m, 4H), 2.94 - 3.08 (m, 1H), 2.73 (s, 3H), 2.70 (br d, J=11.4 Hz, 2H), 2.46 - 2.57 (m, 2H), 2.27 (br t, J=4.9 Hz, 4H), 2.16 - 2.23 (m, 2H), 2.11 (s, 3H), 2.09 - 2.13 (m, 2H), 1.78 (td, J=11.4, 1.6 Hz, 2H), 1.63 (br d, J=11.8 Hz, 2H), 1.36 - 1.47 (m, 1H), 1.07 (qd, J=12.0, 3.6 Hz, 2H) FCC on Biotage NH cartridge eluting with cHex/EtOAc 50:50 to EtOAc/( EtOAc-EtOH 3-1) 90:10 Example 2: cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate A solution of Intermediate 15 (150 mg, 0.21 mmol) in THF (2.1 mL) was treated with 1M TBAF in THF (0.23 mL, 0.23 mmol) and the reaction stirred for 1h at RT. The mixture was concentrated under reduced pressure, then diluted with DCM and washed with H2O. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC on Biotage NH silica cartridge (from cHex to 100% EtOAc then 1% of EtOAc/MeOH 10/1) to give the title compound (107 mg, 0.18 mmol, 85% yield). LC-MS (ESI): m/z (M+1): 612.3 (Method 2), tR=1.09. 1H NMR (500 MHz, Chloroform-d) δ ppm 9.92 (br. s, 1H), 9.14 (d, J = 0.8 Hz, 1H), 9.00 (s, 1H), 8.46 - 8.57 (m, 1H), 8.07 (dd, J = 6.6, 2.6 Hz, 1H), 7.58 (s, 1H), 7.35 - 7.45 (m, 1H), 7.14 (dd, J = 10.0, 9.1 Hz, 1H), 5.28 (s, 2H), 5.16 - 6.26 (m, 1H), 2.91 (quin, J = 8.1 Hz, 1H), 2.77 - 2.89 (m, 2H), 2.69 - 2.78 (m, 1H), 2.41 - 2.53 (m, 2H), 2.24 - 2.34 (m, 1H), 2.13 - 2.23 (m, 2H), 1.85 - 2.04 (m, 6H), 1.46 (s, 9H). The Example listed below in Table 6 were prepared from the suitable reagents in analogy to the procedures followed for Example 2. Table 6 Example Structure & Reagents and N° IUPAC Name Solvents Product Amount (Yield)/ Analytical Data/Purification 21 Intermediate 50 cis tert‐butyl 2‐(1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐(hydroxymethyl)pyridazin4‐ yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidin‐4yl)acetate 92 mg, 90% yield LC-MS (ESI): m/z (M+1): 626.4 (Method 2), tR=1.12. ¹H NMR (500 MHz, CDCl3): δ ppm 10.03 (s, 1H), 9.18 (d, J = 1.2 Hz, 1H), 8.98 (s, 1H), 8.53 (d, J = 0.7 Hz, 1H), 8.09 (dd, J = 6.6, 2.7 Hz, 1H), 7.54 (d, J = 0.7 Hz, 1H), 7.40 (ddd, J = 8.7, 4.2, 2.9 Hz, 1H), 7.15 (dd, J = 10.2, 8.8 Hz, 1H), 5.30 (s, 2H), 2.91 (br d, J = 11.0 Hz, 2H), 2.83 - 2.90 (m, 1H), 2.70 (quin, J = 7.0 Hz, 1H), 2.38 - 2.49 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.07 - 2.18 (m, 2H), 1.79 - 1.87 (m, 3H), 1.72 - 1.80 (m, 2H), 1.45 (s, 9H), 1.37 - 1.45 (m, 2H). FCC on Biotage NH cartrige eluting with cHex/EtOAc from 100:0 to 100:0 then washing with EtOAc/(EtOAc/MeOH 10:1) 90:10 Example 3: cis ethyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 3 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 17 (10 mg, 0.01 mmol) and purifying by extraction in DMC/water to afford the title compound (3 mg, 0.005 mmol, 36% yield). LC-MS (ESI): m/z (M+1): 584.3 (Method 2), tR=0.98. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 9.37 (br. s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.56 (d, J = 0.8 Hz, 1H), 7.98 (dd, J = 6.6, 2.7 Hz, 1H), 7.93 (s, 1H), 7.62 - 7.69 (m, 1H), 7.49 (dd, J = 10.4, 8.9 Hz, 1H), 5.90 (br. s, 1H), 5.03 (s, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.96 - 3.06 (m, 1H), 2.70 (br. d, J = 10.8 Hz, 2H), 2.56 - 2.63 (m, 1H), 2.24 - 2.31 (m, 1H), 2.18 - 2.25 (m, 2H), 1.92 - 2.03 (m, 2H), 1.70 - 1.87 (m, 4H), 1.46 - 1.59 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). Example 4: tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]ethyl}piperidine‐4‐ carboxylate Example 4 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 19 (140 mg, 0.20 mmol) and purifying by extraction in EtOAc/water to afford the title compound (95 mg, 0.016 mmol, 81% yield). LC-MS (ESI): m/z (M+1): 586.3 (Method 2), tR=1.10. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (br. s, 1H), 9.87 (br. s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 7.97 (dd, J = 6.5, 2.7 Hz, 1H), 7.90 (s, 1H), 7.65 (ddd, J = 8.8, 4.1, 2.9 Hz, 1H), 7.48 (dd, J = 10.4, 9.0 Hz, 1H), 5.91 (br. s, 1H), 5.02 (s, 2H), 2.82 (br. d, J = 11.3 Hz, 2H), 2.54 - 2.65 (m, 4H), 2.13 - 2.23 (m, 1H), 1.97 - 2.07 (m, 2H), 1.71 - 1.80 (m, 2H), 1.46 - 1.60 (m, 2H), 1.39 (s, 9H). Example 5: cis (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 5 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 20 (43 mg, 0.06 mmol) and purifying by FCC on Biotage NH silica cartridge eluting with cHex/EtOAc/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:70:30 to afford the title compound (22 mg, 0.03 mmol, 60% yield). LC-MS (ESI): m/z (M+1): 639.4 (Method 2), tR=0.96. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.73 (s, 1H), 9.36 (br. s, 1H), 9.02 (s, 1H), 8.56 (s, 1H), 7.98 (dd, J = 6.6, 2.7 Hz, 1H), 7.93 (s, 1H), 7.60 - 7.68 (m, 1H), 7.44 - 7.52 (m, 1H), 5.91 (br. s, 1H), 4.96 - 5.11 (m, 3H), 2.91 - 3.05 (m, 1H), 2.69 (br. d, J = 10.4 Hz, 2H), 2.55 - 2.65 (m, 3H), 2.47 (br. dd, J = 10.6, 2.3 Hz, 1H), 2.22 (s, 3H), 2.11 - 2.30 (m, 5H), 1.92 - 2.03 (m, 2H), 1.71 - 1.85 (m, 4H), 1.59 - 1.69 (m, 1H), 1.44 - 1.56 (m, 2H). Example 6: cis 3‐hydroxy‐2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 6 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 21 (33 mg, 0.04 mmol) and purifying by FCC on Biotage NH silica cartridge (cHex/EtOA/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:95:5 to afford the title compound (23 mg, 0.03 mmol, 82% yield). LC-MS (ESI): m/z (M+1): 642.3 (Method 2), tR=0.92. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 9.37 (br. s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.56 (d, J = 0.8 Hz, 1H), 7.98 (dd, J = 6.6, 2.7 Hz, 1H), 7.93 (s, 1H), 7.60 - 7.69 (m, 1H), 7.49 (dd, J = 10.3, 8.9 Hz, 1H), 5.91 (br. s, 1H), 5.03 (s, 2H), 4.60 (t, J = 5.4 Hz, 1H), 3.80 (s, 2H), 3.17 (d, J = 5.5 Hz, 2H), 2.93 - 3.07 (m, 1H), 2.69 (br. d, J = 10.2 Hz, 2H), 2.56 - 2.64 (m, 1H), 2.27 - 2.34 (m, 1H), 2.14 - 2.26 (m, 2H), 1.92 - 2.03 (m, 2H), 1.71 - 1.87 (m, 4H), 1.46 - 1.63 (m, 2H), 0.82 (s, 6H). Example 7: cis 2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 7 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 22 (54 mg, 0.07 mmol) and purifying by FCC on Biotage SFAR 5g column eluting with cHex/EtOAc/(EtOAc/MeOH 10:1) from 100:0:0 to 0:100:0 to 0:95:5 to afford the title compound (24 mg, 0.04 mmol, 53% yield). LC-MS (ESI): m/z (M+1): 626.4 (Method 2), tR=1.15. 1H NMR (400 MHz, Chloroform-d) δ ppm 9.92 (br. s, 1H), 9.12 (d, J = 1.0 Hz, 1H), 8.93 (br. s, 1H), 8.51 (s, 1H), 8.08 (dd, J = 6.6, 2.6 Hz, 1H), 7.64 (s, 1H), 7.35 - 7.47 (m, 1H), 7.08 - 7.20 (m, 1H), 5.26 (s, 2H), 3.81 (s, 2H), 2.91 - 3.00 (m, 1H), 2.90 (br. s, 2H), 2.72 - 2.83 (m, 1H), 2.45 - 2.55 (m, 2H), 2.37 - 2.45 (m, 1H), 2.17 - 2.31 (m, 2H), 1.91 - 2,08 (m, 6H), 0.96 (s, 9H). Example 8: cis 3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 8 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 23 (54 mg, 0.07 mmol) and purifying by FCC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (24 mg, 0.04 mmol, 53% yield). LC-MS (ESI): m/z (M+1): 626.4 (Method 2), tR=1.14. 1H NMR (400 MHz, Chloroform-d) δ ppm 9.98 (br. s, 1H), 9.13 (d, J = 1.2 Hz, 1H), 8.82 (br. s, 1H), 8.53 (s, 1H), 8.09 (dd, J = 6.6, 2.7 Hz, 1H), 7.65 (s, 1H), 7.35 - 7.46 (m, 1H), 7.16 (dd, J = 10.2, 8.9 Hz, 1H), 5.27 (s, 2H), 4.78 (quin, J = 6.2 Hz, 1H), 2.91 - 3.01 (m, 1H), 2.84 - 2.93 (m, 2H), 2.71 - 2.84 (m, 1H), 2.44 - 2.57 (m, 2H), 2.32 - 2.44 (m, 1H), 2.16 - 2.31 (m, 2H), 1.88 - 2.09 (m, 6H), 1.80 (td, J = 13.3, 6.8 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 6H). Example 9: N‐(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)‐3‐{4‐[(3‐methyl‐2‐oxooxolan‐3‐yl)methyl]piperazin‐1‐ yl}propanamide Example 9 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 28 (120 mg, 0.17 mmol) and purifying by FCC on Biotage NH cartrige from cHex to 100% (EtOAc/MeOH 90:10) to afford the title compound (60 mg, 0.10 mmol, 60% yield). LC-MS (ESI): m/z (M+1): 599.3 (Method 2), tR=0.93. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (br. s, 1H), 9.27 (br. s, 1H), 9.02 (d, J = 1.0 Hz, 1H), 8.56 (s, 1H), 7.97 (dd, J = 6.6, 2.7 Hz, 1H), 7.90 (s, 1H), 7.61 - 7.69 (m, 1H), 7.49 (dd, J = 10.2, 9.2 Hz, 1H), 5.88 (br. s, 1H), 5.02 (s, 2H), 4.20 - 4.33 (m, 2H), 2.35 - 2.64 (m, 15H), 1.96 (ddd, J = 12.7, 7.5, 5.5 Hz, 1H), 1.06 (s, 3H). Example 10: cis (3S)‐1‐(2,2,2‐trifluoroethyl)pyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐ chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 10 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 29 (117 mg, 0.14 mmol) and purifying by FC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (53 mg, 0.07 mmol, 53% yield). LC-MS (ESI): m/z (M+1): 707.5 (Method 2), tR=1.06. 1H NMR (500 MHz, Chloroform-d) δ ppm 9.96 (br. s, 1H), 9.15 (d, J = 1.2 Hz, 1H), 8.88 - 9.00 (m, 1H), 8.47 - 8.57 (m, 1H), 8.07 (dd, J = 6.6, 2.6 Hz, 1H), 7.61 (s, 1H), 7.40 (ddd, J = 8.8, 4.1, 2.7 Hz, 1H), 7.15 (dd, J = 10.2, 8.9 Hz, 1H), 5.27 (s, 2H), 5.19 - 5.26 (m, 1H), 4.91 (br. s, 1H), 3.04 - 3.20 (m, 2H), 3.03 - 3.09 (m, 1H), 2.84 - 3.00 (m, 4H), 2.79 - 2.84 (m, 1H), 2.67 - 2.78 (m, 2H), 2.43 - 2.54 (m, 2H), 2.31 - 2.43 (m, 1H), 2.23 - 2.31 (m, 1H), 2.13 - 2.23 (m, 2H), 1.92 - 2.01 (m, 6H), 1.84 - 1.92 (m, 1H). Example 11: cis oxetan‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 11 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 30 (51 mg, 0.07 mmol) and purifying by FC on Biotage SFAR 5g column eluting with EtOAc/MeOH from 100:0 to 95:5 to afford the title compound (13 mg, 0.02 mmol, 30% yield). LC-MS (ESI): m/z (M+1): 612.3 (Method 2), tR=0.91. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.72 (br. s, 1H), 9.01 (s, 1H), 9.35 (br. s, 1H), 8.56 (s, 1H), 7.97 (dd, J = 6.5, 2.7 Hz, 1H), 7.92 (s, 1H), 7.69 – 7.61 (m, 1H), 7.48 (dd, J = 10.2, 9.0 Hz, 1H), 5.91 (br. s, 1H), 5.43 – 5.30 (m, 1H), 5.03 (s, 2H), 4.79 (t, J = 7.1 Hz, 2H), 4.46 (dd, J = 7.3, 5.5 Hz, 2H), 3.01 (quin, J = 8.7 Hz, 1H), 2.71 (br. d, J = 10.6 Hz, 2H), 2.66 – 2.57 (m, 1H), 2.42 – 2.32 (m, 1H), 2.28 – 2.17 (m, 2H), 2.04 – 1.92 (m, 2H), 1.89 – 1.74 (m, 4H), 1.62 – 1.48 (m, 2H). Example 12: cis methyl 3‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}‐3‐ azabicyclo[3.1.1]heptane‐6‐carboxylate Example 12 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 33 (140 mg, 0.20 mmol) to afford the title compound (70 mg, 0.12 mmol, 60% yield). LC-MS (ESI): m/z (M+1): 582.3 (Method 2), tR=1.05. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.68 (s, 1H), 9.34 (br. s, 1H), 9.03 (d, J = 1.2 Hz, 1H), 8.55 (d, J = 0.7 Hz, 1H), 7.97 (dd, J = 6.6, 2.7 Hz, 1H), 7.93 (s, 1H), 7.61 - 7.69 (m, 1H), 7.49 (dd, J = 10.4, 8.9 Hz, 1H), 5.86 (br. s, 1H), 5.02 (s, 2H), 3.62 (s, 3H), 3.04 (br. dd, J = 9.3, 3.4 Hz, 2H), 2.95 - 3.04 (m, 1H), 2.84 - 2.93 (m, 1H), 2.79 (t, J = 5.5 Hz, 1H), 2.50 - 2.56 (m, 1H), 2.18 - 2.23 (m, 2H), 2.12 - 2.19 (m, 2H), 1.94 - 2.01 (m, 1H), 1.83 - 1.93 (m, 2H), 0.98 (d, J = 8.9 Hz, 1H). Example 13: cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐3‐carboxylate Example 12 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 36 (35 mg, 0.05 mmol) to afford the title compound (70 mg, 0.12 mmol, 60% yield). LC-MS (ESI): m/z (M+1): 612.3 (Method 2), tR=1.07. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (br. s, 1H), 9.05 - 9.83 (m, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 7.97 (dd, J = 6.6, 2.7 Hz, 1H), 7.91 (s, 1H), 7.65 (dt, J = 8.7, 3.5 Hz, 1H), 7.48 (dd, J = 10.2, 9.2 Hz, 1H), 5.53 - 6.31 (m, 1H), 5.02 (s, 2H), 3.00 (quin, J = 8.8 Hz, 1H), 2.59 - 2.66 (m, 1H), 2.31 - 2.41 (m, 1H), 2.18 - 2.28 (m, 2H), 1.92 - 2.01 (m, 2H), 1.78 - 2.58 (m, 4H), 1.40 (s, 9H), 0.77 - 1.78 (m, 4H). Example 14: cis 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 14 was prepared following similar procedure used for the synthesis of Intermediate 13, using Intermediate 10 (320 mg, 1.03 mmol) and Intermediate 38 (230 mg, 0.73 mmol) and purifying by on biotage SFAR column eluting with DCM/MeOH/H2O 100:5:0.5 to afford title compound (250 mg, 0.38 mmol, 52% yield). LC-MS (ESI): m/z (M+1): 656.4 (Method 2), tR=1.10. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.68 (br. s, 1H), 9.32 (br. s, 1H), 9.04 (br. s, 1H), 8.54 (br. s, 1H), 7.99 (dd, J = 6.6, 2.7 Hz, 1H), 7.94 (br. s, 1H), 7.57 - 7.71 (m, 1H), 7.49 (dd, J = 10.2, 9.1 Hz, 1H), 5.05 (s, 2H), 4.91 (br. s, 1H), 3.61 (s, 4H), 2.93 - 3.06 (m, 1H), 2.68 (br. d, J = 11.0 Hz, 2H), 2.59 (br. t, J = 7.3 Hz, 1H), 2.18 - 2.26 (m, 2H), 2.11 - 2.18 (m, 1H), 1.90 - 2.02 (m, 2H), 1.67 - 1.83 (m, 4H), 1.43 - 1.56 (m, 2H), 1.39 (s, 9H). The Example listed in table 7 were prepared from the suitable reagents in analogy to the procedures followed for Example 14. Table 7 Structure & Reagents and Example IUPAC Name Solvents N° Product Amount (Yield)/ Analytical Data/Purification Intermediate 18, 1.2 eq tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)3‐ Intermediate 38, 1 [(2‐hydroxyethoxy)methyl]pyridazin‐4‐ eq yl]amino}pyrimidin-4yl)carbamoyl]ethyl}piperidine‐ 22 4‐ carboxylate 68 mg, 36% yield LC-MS (ESI): m/z (M+1): 630.3 (Method 2), tR=1.11 ¹H NMR (400 MHz, CDCl3): δ ppm 11.57 (br. s., 1H), 9.26 (s, 1H), 9.17 (d, J = 1.4 Hz, 1H), 8.57 (s, 1H), 8.12 (dd, J = 6.6, 2.7 Hz, 1H), 7.86 (br. s., 1H), 7.41 (ddd, J = 8.7, 4.2, 2.7 Hz, 1H), 7.17 (dd, J = 10.2, 8.8 Hz, 1H), 5.14 (s, 2H), 3.93 - 4.06 (m, 2H), 3.87 (dd, J = 5.2, 3.2 Hz, 2H), 1.75 - 3.19 (m, 13H), 1.48 (s, 9H) FCCFCC on Biotage silica cartridge eluting with cHex/EtOAc/MeOH from 100:0:0 to 0:90:10 Example 15: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl 1‐methylpiperidin‐4‐yl carbonate A solution of 1-methyl-4-piperidinol (9 mg, 0.08 mmol) in THF (0.40 mL) was treated with lithium bis(trimethylsilyl)amide 1M in THF (0.08 mL, 0.08 mmol) at 0 ºC. The mixture was stirred at 0 ºC for 5 min, then warmed to RT and stirred for 30 min. The obtained solution was added dropwise to a solution Intermediate 39 (42 mg, 0.08 mmol) in THF (0.40 mL) at 0 ºC. The mixture was stirred for 30 min at 0 ºC and then for 5h at RT. The mixture was concentrated under reduced pressure, then DCM and water were added, the mixture was stirred, and the phases separated. The aqueous layer was extracted again with DCM. The combined organic phases were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC on Biotage silica NH cartridge eluting with cHex to 100% EtOAc to give the title compound (3 mg, 0.005 mmol, 6% yield). LC-MS (ESI): m/z (M+1): 570.3 (Method 2), tR=0.99. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.99 (s, 1H), 8.59 (s, 1H), 8.15 (dd, J = 6.6, 2.6 Hz, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.41 (ddd, J = 8.7, 4.2, 2.7 Hz, 1H), 7.16 (dd, J = 10.3, 8.9 Hz, 1H), 6.72 (s, 1H), 4.90 - 5.00 (m, 1H), 4.66 (br. s, 1H), 2.81 (s, 3H), 2.64 - 2.81 (m, 5H), 2.50 - 2.61 (m, 2H), 2.30 (s, 3H), 2.25 (br. s, 2H), 1.94 - 2.05 (m, 2H), 1.74 - 1.88 (m, 2H). Example 16: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl 1‐methylpiperidine‐4‐carboxylate 1-Methylpiperidine-4-carboxylic acid (17 mg, 0.12 mmol), DCC (36 mg, 0.17 mmol), DMAP (21 mg, 0.17 mmol), and Intermediate 14 (50 mg, 0.12 mmol) were mixed in THF (1.5 mL) and stirred 45 °C for 8h. Volatiles were removed under vacuum and the residue by FCC on Biotage silica NH cartridge (from cHex to 100% EtOAc) then by reverse phase FCC on Biotage C18 cartridge eluting with H2O+0.1% HCOOH to 30% MeCN in H2O +0.1% HCOOH. Proper fractions were collected and solvent reduced to lower volume. Then it was passed through solid-phase extraction NaHCO3 cartridge to remove HCOOH, washing with MeCN. Evaporation of the solvent afforded the title compound (23 mg, 0.04 mmol, 36% yield). LC-MS (ESI): m/z (M+1): 554.3 (Method 2), tR=1.01. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 9.32 (s, 1H), 8.84 (d, J = 1.2 Hz, 1H), 8.52 (s, 1H), 8.06 (s, 1H), 7.97 (dd, J = 6.6, 2.7 Hz, 1H), 7.58 - 7.68 (m, 1H), 7.47 (dd, J = 10.5, 8.9 Hz, 1H), 4.88 (quin, J = 7.5 Hz, 1H), 2.97 - 3.11 (m, 1H), 2.74 (s, 3H), 2.62 - 2.71 (m, 2H), 2.51 - 2.61 (m, 2H), 2.15 - 2.29 (m, 3H), 2.13 (s, 3H), 1.89 (td, J = 11.2, 2.0 Hz, 2H), 1.77 (br. dd, J = 12.9, 3.3 Hz, 2H), 1.45 - 1.61 (m, 2H). Example 17: cis (2R)‐3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ [(2‐hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate Example 17 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 42 (17 mg, 0.02 mmol) to afford the title compound (6 mg, 0.01 mmol, 50% yield). LC-MS (ESI): m/z (M+1): 670.4 (Method 2), tR=1.12. 1H NMR (500 MHz, Chloroform-d) δ ppm 9.69 (br. s, 1H), 9.33 (s, 1H), 9.19 (d, J = 1.5 Hz, 1H), 8.54 (s, 1H), 8.12 (dd, J = 6.6, 2.7 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.40 (ddd, J = 8.8, 4.1, 2.7 Hz, 1H), 7.16 (dd, J = 10.3, 8.8 Hz, 1H), 5.14 (s, 2H), 4.77 (quin, J = 6.2 Hz, 1H), 3.96 - 4.05 (m, 2H), 3.82 - 3.92 (m, 2H), 2.82 - 2.99 (m, 4H), 2.71 - 2.81 (m, 1H), 2.45 - 2.56 (m, 2H), 2.31 - 2.41 (m, 1H), 2.17 - 2.30 (m, 2H), 1.87 - 2.08 (m, 6H), 1.62 - 1.84 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 0.92 (dd, J = 6.8, 0.9 Hz, 6H). Example 18: (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]methyl}piperidine‐ 4‐carboxylate Example 18 was prepared following the procedure used for the synthesis of Example 2 starting from Intermediate 47 (35 mg, 0.05 mmol) and purifying by FCC on Biotage NH cartridge eluting with cHex/EtOAc/(EtOAc/EtOH 3:1) from 100:0:0 to 0:100:0 to 0:50:50 to afford the title compound (19 mg, 0.03 mmol, 65% yield). LC-MS (ESI): m/z (M+1): 599.3 (Method 2), tR=0.99. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 9.41 (br. s, 1H), 9.04 (d, J = 1.4 Hz, 1H), 8.59 (d, J = 1.0 Hz, 1H), 7.98 (dd, J = 6.6, 2.7 Hz, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.60 - 7.70 (m, 1H), 7.49 (dd, J = 10.5, 8.9 Hz, 1H), 5.87 (br. s, 1H), 5.04 - 5.09 (m, 1H), 5.03 (s, 2H), 3.22 (s, 2H), 2.79 - 2.87 (m, 2H), 2.58 - 2.67 (m, 2H), 2.39 - 2.54 (m, 1H), 2.23 - 2.34 (m, 4H), 2.22 (s, 3H), 2.12 - 2.21 (m, 1H), 1.82 (br. d, J = 10.6 Hz, 2H), 1.56 - 1.70 (m, 3H). 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-Glo 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 β1 N-term GST-tagged, 80-end), a final concentration of TGFβ1 peptide 94.5 µM (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 (0.5µM). 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 µM. 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 ºC 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 8 wherein the compounds are classified in term of potency with respect to their inhibitory activity on ALK5 receptor. Results were expressed as pIC50 (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 4 show pKi values greater than 9.4 when tested in the biochemical ALK5 assay. Table 8 Example No ALK5 pKi 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21 and 22. ≥ 9.4 Determination of Microsomes Stability Test compound was incubated, in duplicate, at the concentration of 0.5 μM 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), 50μl- aliquots were taken and acetonitrile containing internal standard (150μl) was added to stop the reaction. Samples were centrifuged (3000 rpm, 10min) 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 μM 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 (t1/2) 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: t1/2 = 0.693/k. The results for individual compounds are provided below in Table 9 wherein the compounds are classified in term of microsomal stability in human and in mouse. Results were expressed as half-life (t1/2, min). The lower the t1/2, the higher the hepatic metabolism of the tested compound. As it can be appreciated, all the compounds of Table 9 show a half-life (t1/2) lower than 5 minutes, in human and in mouse. Table 9 Example No. Human t1/2 (min) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. <5 Example No. Mouse t1/2 (min) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22. <5

Claims

CLAIMS 1. A compound of formula (I) or pharmaceutically acceptable salts thereof wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O- (C1-C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-(C1-C6)alkylene-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O)-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3- C6)cycloalkylene-(C3-C7)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C3-C6)cycloalkylene-OC(O)O-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and -(C1-C6)haloalkyl; -(C3- C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)hydroxyalkyl; -(C3- C6)cycloalkylene-(C3-C6)heterocycloalkylene-(C1-C3)alkylene-C(O)O-(C3- C6)alkyl; and -(C3-C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkylene-(C1- C3)alkylene-(C3-C5)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl. 2. The compound of formula (I) according to claim 1 selected from at least one of: cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 4‐methylpiperazine‐1‐carboxylate, (Example 1); cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis ethyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]ethyl}piperidine‐4‐carboxylate; cis (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 3‐hydroxy‐2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 2,2‐dimethylpropyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; cis 3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐ carboxylate; N‐(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)‐3‐{4‐[(3‐methyl‐2‐oxooxolan‐3‐yl)methyl]piperazin‐1‐ yl}propanamide; cis (3S)‐1‐(2,2,2‐trifluoroethyl)pyrrolidin‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐ fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis oxetan‐3‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐ 4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis methyl 3‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}‐3‐azabicyclo[3.1.1]heptane‐6‐ carboxylate; cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin‐4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidine‐3‐carboxylate; cis tert‐butyl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐methylpiperidin‐4‐yl carbonate; cis 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 1‐methylpiperidine‐4‐carboxylate; cis (2R)‐3‐methylbutan‐2‐yl 1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl}piperidine‐4‐carboxylate; (3R)‐1‐methylpyrrolidin‐3‐yl 1‐{[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐ (hydroxymethyl)pyridazin‐4‐yl]amino}pyrimidin‐4‐yl)carbamoyl]methyl}piperidine‐4‐ carboxylate; 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 3,5‐dimethylpiperazine‐1‐carboxylate; 3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐methylpyridazin‐4‐yl]amino}pyrimidin‐4‐ yl)carbamoyl]cyclobutyl 4‐[(1‐methylpiperidin‐4‐yl)methyl]piperazine‐1‐carboxylate; Tert‐butyl 2‐(1‐{3‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)‐3‐(hydroxymethyl)pyridazin4‐ yl]amino}pyrimidin‐4‐yl)carbamoyl]cyclobutyl}piperidin‐4yl)acetate and Tert‐butyl 1‐{2‐[(6‐{[6‐(5‐chloro‐2‐fluorophenyl)3‐[(2‐ hydroxyethoxy)methyl]pyridazin‐4‐yl]amino}pyrimidin-4yl)carbamoyl]ethyl}piperidine‐ 4‐carboxylate. 3. The compound of formula (I) according to claim 1, wherein R1 is -NR3C(O)R4; R2 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-O- (C1-C6)hydroxyalkyl and -(C1-C6)hydroxyalkyl; R3 is H; R4 is selected from the group consisting of -(C1-C6)alkylene-(C3- C6)heterocycloalkylene-(C1-C6)alkylene-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1- C6)alkyl and oxo; -(C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)alkyl; - (C1-C6)alkylene-(C3-C6)heterocycloalkylene-C(O)O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; - (C3-C6)cycloalkylene-O-C(O)-(C3-C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3- C7)heterocycloalkylene-C(O)O-(C1-C6)alkyl; -(C3-C6)cycloalkylene-OC(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; -(C3-C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C3- C6)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl and -(C1-C6)haloalkyl; -(C3- C6)cycloalkylene-(C3-C6)heterocycloalkylene-C(O)O-(C1-C6)hydroxyalkyl. 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 3 or 4 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 9 in the prevention and/or treatment idiopathic pulmonary fibrosis (IPF).
EP24707794.4A 2023-03-02 2024-03-01 Pyridazinyl amino derivatives as alk5 inhibitors Pending EP4673214A1 (en)

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