Pyridazinylamino derivatives as ALK5 inhibitors

Abstract

The present invention relates to compounds of formula (I) that inhibit transforming growth factor-beta (TGF-beta) type 1 receptor (ALK5), methods for preparing such compounds, pharmaceutical compositions containing them, and therapeutic uses thereof. The compounds of the present invention are useful for treating diseases or conditions in mammals associated with dysregulation of the ALK5 signaling pathway.

Description

Field of the Invention

[0001] The present invention generally relates to compounds that inhibit transforming growth factor beta (TGFβ) type I receptor (ALK5) (hereinafter ALK5 inhibitors), methods for preparing such compounds, pharmaceutical compositions containing them, and their therapeutic uses.

[0002] The compounds of the present invention can be used, for example, to treat a number of diseases, disorders or conditions associated with the ALK5 signaling pathway. Background of the Invention

[0004] Transforming growth factor β (TGFβ) is a protein belonging to the TGFβ superfamily.

[0005] It is involved in multiple processes, both cellular, such as proliferation, migration, and differentiation, and biological, including wound healing, immunosuppression, carcinogenesis, and extracellular matrix production.

[0006] The TGFβ superfamily also includes, inter alia, further members known as activins (Act) (see, for example, Hinck AP, FEBS Letters 586 (2012); 1860-1870).

[0007] Binding of the peptide initiates the TGFβ signaling cascade through the formation of a heterotetrameric complex consisting of two distinct serine / threonine kinase receptors, type 1 (TGFβR1 / ALK5) and type 2 (TGFβR2).

[0008] TGFβR1 / ALK5 is recruited and activated by phosphorylation of its intracellular domain by TGFβR2, leading to phosphorylation of the receptor-activated (R)-Smad family, thereby activating target gene transcription (see, e.g., Sheppard D., Proc Am Thorac Soc. (2006); (3): 413-417).

[0009] Similar to TGFβ signaling, the type I receptor for activin, ALK4, leads to activation of target gene transcription (see, eg, Heldin CH et al., Cold Spring Harb Perspect Biol. (2016) Aug 1;8(8)).

[0010] Multiple studies have linked excessive and / or dysregulated TGFβ activity to a number of diseases, including cancer and fibrosis (see, e.g., Syed V, J Cell Biochem. (2016) June; 117(6): 1279-87; Jakowlew SB. Cancer Metastasis Rev. (2006) September; 25(3): 435-57). In fibrotic disorders, an important role for TGFβ in organs such as the lungs, heart, liver, and kidneys has been demonstrated (see, e.g., Alhamad EH, J Thorac Dis. (2015); 7(3): 386-93). Specifically, TGFβ expression is increased in fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and 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).

[0011] In the lung, TGFβ is expressed in several cell types, such as epithelial cells, endothelial cells, connective tissue cells, macrophages, and fibroblasts.

[0012] These cell populations may produce excessive amounts of TGFβ in IPF human lung tissue. In addition, high levels of TGFβ have been detected in lung tissue and BAL of IPF patients (see, eg, Bergeron A et al., Eur Respir J (2003); 22: 69-76).

[0013] TGFβ gene expression and TGFβ protein production have been observed to be increased 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 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.).

[0014] In contrast, inhibition of TGFβ signaling achieved by using knockout (KO) animals can suppress fibrosis development through a TGFβ-related mechanism (see, eg, Bonniaud P et al., Am J Respir Crit Care Med (2005); 171: 889-898; 34).

[0015] Similar results have been obtained by inhibition of TGFβR1 in a mouse bleomycin disease model (see, e.g., Wei Y et al., J Clin Invest. (2017); 127(10): 3675-3688).

[0016] Similar to TGFβ, activin signaling dysregulation is associated with fibroblast proliferation, myofibroblast differentiation and accumulation of extracellular matrix (ECM) (see, e.g., Yamashita et al., J.Am.Soc.Nephrol. (2004) 15, 91-101). In addition, overexpression of activins has been associated with pathological conditions and fibrosis development in different organs such as the liver (see, e.g., Patella et al., Am.J.Physiol.Gastrointest.Liver Physiol. (2006) 290, G137-G144), kidney (see, e.g., Agapova et al., Kidney Int. (2016) 89, 1231-1243), heart (see, e.g., Yndestad et al., Circulation (2004) 109, 1379-1385) and lung (see, e.g., de Kretser et al., Crit.Care (2013) 17: R263).

[0017] Taken together, these data demonstrate the importance of targeting ALK5 for the pharmacological treatment of these diseases associated with dysregulated TGF signaling pathways.

[0018] TGFβ signaling is strongly involved in cardiovascular homeostasis (see, for example, van Meeteren LA et al., Springer (2013)). Several studies in humans and mice have demonstrated a major role for TGFβ in angiogenesis and vascular morphogenesis. In addition, TGFβ plays a key role in the development and function of heart valves. Therefore, the importance of selectively modulating the TGFβ pathway to target pathological effects and avoid inhibition of signaling required for proper homeostasis is obvious.

[0019] The answer to this critical point can be addressed by using the inhalation route to deliver anti-TGFβ drugs.

[0020] The inhalational route would allow treatment of the affected lung compartment, bypassing the issue of cardiac exposure.

[0021] Various compounds have been described in the literature as ALK5 and / or ALK4 receptor inhibitors.

[0022] WO2008 / 006583, WO2009 / 087212, WO2009 / 087224, WO2009 / 087225, WO2009 / 133070, WO2009 / 013335 and WO2009 / 050183 (Novartis) disclose pyrimidine, pyridine, imidazopyridine, pyrrolopyrimidine and pyrrolopyridine, imidazopyridazine, imidazopyridine derivatives that can be used to treat ALK4 or ALK5 mediated diseases (such as inflammatory or obstructive airway diseases, pulmonary hypertension and pulmonary fibrosis).

[0023] WO00 / 61576 and US2003 / 0149277 (Smithkline Beecham Corp) disclose triarylimidazole derivatives as ALK5 inhibitors useful in treating, inter alia, renal disease, wound healing, kidney disease, congestive heart failure, ulcers, impaired neurological function and any disease in which fibrosis is a major component.

[0024] WO 01 / 62756 (Smithkline Beecham PLC) discloses pyridyl imidazole derivatives as ALK5 inhibitors useful in the treatment of, inter alia, renal disease, wound healing, kidney disease, congestive heart failure, ulcers, impaired neurological function and any disease in which fibrosis is a major component.

[0025] WO03 / 087304 (Biogen Inc.) discloses trisubstituted heteroaryls as ALK5 and / or ALK4 inhibitors useful for treating, inter alia, idiopathic pulmonary fibrosis, diabetic nephropathy, liver fibrosis, lung fibrosis, acute lung injury, post-infarction cardiac fibrosis, fibrotic cancers and fibromas.

[0026] WO 2013 / 009140 (SK Chemicals Co) discloses 2-pyridyl substituted imidazole derivatives as ALK5 and / or ALK4 receptor inhibitors, which are useful in the treatment of, inter alia, renal, hepatic or pulmonary fibrosis.

[0027] Pyridazinylamino derivatives have been disclosed in the literature, but not as ALK5 inhibitors.

[0028] WO 2005 / 033105 (Amgen) discloses, among other compounds, pyridazinylamino derivatives as vanilloid receptor ligands for the treatment of a number of diseases and disorders, excluding fibrosis.

[0029] WO 2002 / 022605 and WO 2002 / 022602 (Vertex) describe, inter alia, pyridazine compounds as protein kinase inhibitors which are useful in the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia.

[0030] WO 02 / 24681 (Ortho-McNeil Pharmaceutical Inc.) describes pyridazine compounds as tyrosine kinase inhibitors useful as antitumor agents and in the treatment of diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.

[0031] Notably, inhibition of the ALK5 receptor may be useful in treating fibrosis and diseases, disorders, and conditions resulting from fibrosis.

[0032] Over the past few years, efforts have been made to develop novel ALK5 receptor inhibitors that could be used to treat a variety of diseases, and some of those compounds have also shown efficacy in humans.

[0033] However, there is still potential to develop inhibitors of the receptor ALK5 that are characterized by good potency and that can be used to treat diseases or disorders associated with dysregulation of the ALK5 signaling pathway, in particular fibrosis.

[0034] Specifically, in the respiratory field there is still potential to develop ALK5 receptor inhibitors that can be used to treat diseases or conditions associated with dysregulation of ALK5 signaling, particularly idiopathic pulmonary fibrosis (IPF), which would be administered via the inhalation route and characterized by good inhalation performance, corresponding to good activity in the lungs, good lung retention and low metabolic stability to minimize systemic exposure and associated safety issues.

[0035] In this direction, we have unexpectedly discovered a series of novel compounds of general formula (I) that solve the problem of providing effective ALK5 receptor inhibitors for administration by inhalation, while showing good inhalation performance, low metabolic stability, low systemic exposure, improved safety and tolerability, and good selectivity between kinase groups. SUMMARY OF THE INVENTION

[0037] In a first aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof

[0038]

[0039] in

[0040] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0041] A is selected from the set consisting of: A1, A2, and A3

[0042]

[0043] R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6;

[0044] X1 is C, CH or N;

[0045] R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7;

[0046] R 3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, -C(O)O-(C1-C6)alkyl, and -C(O)NH-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one -(C1-C6)alkyl;

[0047] R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0048] R5 is H or -(C1-C6)alkyl;

[0049] R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A-C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo;

[0050] R7 is selected from the group consisting of:

[0051] -(C1-C6)alkylene-NR A R B ;

[0052] -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups;

[0053] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0054] and

[0055] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C -CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl;

[0056] R A selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0057] R B is a heterocycloalkyl group;

[0058] R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0059] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

[0060] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carriers or excipients.

[0061] In a third aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use as a medicament.

[0062] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in preventing and / or treating a disease, disorder or condition mediated by the ALK5 receptor in a mammal.

[0063] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0064] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in preventing and / or treating idiopathic pulmonary fibrosis (IPF). Detailed Description of the Invention

[0066] definition

[0067] Unless otherwise indicated, the compounds of formula (I) of the present invention are intended to also include stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0068] 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 free acidic or basic groups that may be present into the corresponding addition salts with any base or acid which is conventionally considered pharmaceutically acceptable.

[0069] Suitable examples of such salts may thus include mineral or organic acid addition salts of basic residues such as amino groups and mineral or organic base addition salts of acidic residues such as carboxyl groups.

[0070] Cations of inorganic bases which may be suitably used to prepare salts include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0071] Those obtained by reacting the main compound acting as a base with an inorganic or organic acid to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0072] The term "solvate" refers to a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0073] The term "stereoisomer" refers to isomers that have identical structure but differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0074] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are non-superimposable.

[0075] The term "diastereomers" refers to stereoisomers that are not mirror images.

[0076] The term "racemate" or "racemic mixture" means a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is optically inactive.

[0077] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomer descriptors "R" and "S" are used as described herein to indicate atomic configurations relative to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0078] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0079] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine and iodine atoms.

[0080] The term "(C x -C y )alkyl" (wherein x and y are integers) means a straight or branched chain alkyl group having from x to y carbon atoms. Thus, for example, when x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0081] The term "(C x -C y )alkoxy" (wherein x and y are integers) represents a straight or branched chain hydrocarbon of the specified number of carbons, which is attached to the rest of the molecule through an oxygen bridge.

[0082] The term "(C x -C y ) alkylene (wherein x and y are integers) means a C x -C y Alkyl residues, such as divalent methylene residues.

[0083] The expression “(C x -C y )haloalkyl”(wherein x and y are integers) means the above-defined “C x -C y An "alkyl" group in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different.

[0084] The “(C x -C y Examples of "haloalkyl" groups may thus include halo, polyhalo and perhaloalkyl groups wherein all hydrogen atoms are replaced by halogen atoms, for example trifluoromethyl.

[0085] The term "(C x -C y )cycloalkyl" (wherein x and y are integers) means a saturated cyclic hydrocarbon group containing the specified number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0086] The term "aryl" denotes a monocyclic carbocyclic ring system having 6 ring atoms, wherein the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0087] The term "heteroaryl" means a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N and O, and includes groups having two such monocyclic rings or one such monocyclic ring and a monocyclic aryl ring fused through a common bond.

[0088] The term "(C x -C y )heterocycloalkyl" (wherein x and y are integers) represents a saturated or partially unsaturated monocyclic or bicyclic (C x -C y ) cycloalkyl group, wherein at least one ring carbon atom is replaced by at least one heteroatom (e.g., N, S, or O) or may carry an -oxo (=O) substituent. The heterocycloalkyl group may further optionally be substituted at an available position in the ring (i.e., on a carbon atom or on a heteroatom available for substitution). Substitution may be on a carbon atom, including spirodisubstituted carbon atoms, thereby forming a bicyclic system in which two heterocycles or a heterocycloalkyl and a cycloalkyl ring are connected by a single carbon atom. Substitution may also be on two adjacent carbon atoms forming an additional condensed 5-6 membered heterocycloalkyl ring. In addition, the heterocycloalkyl group may be a diazabicyclic ring.

[0089] The term "-(C x -C y )alkylene-heterocycloalkyl" means a group connected to -(C x -C y) the heterocycloalkyl ring of the alkylene group, both of which are as defined above.

[0090] The term "N-oxide-heterocycloalkyl" refers to a heterocycloalkyl group containing one nitrogen atom having an oxygen atom as a substituent.

[0091] Throughout this specification, the use of an asterisk "*" in the definition of a structural formula indicates the point of attachment of a residue group to the rest of the molecule.

[0092] A dash ("-") that is not between two letters or symbols is intended to represent a point of attachment for a substituent.

[0093] The carbonyl group is preferably represented herein as -C(O)-, as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0094] In general, groups enclosed in parentheses are pendant groups, not included in the chain, and parentheses are used when deemed useful to help disambiguate linear formulae; for example, a sulfonyl group -SO2- might also be represented as -S(O)2- to disambiguate, for example, a sulfinyl group -S(O)O-.

[0095] The present invention relates to novel compounds that differ structurally from those disclosed in the prior art, at least with respect to a common novel core skeleton. In fact, the present invention relates to compounds that are [pyridazin-4-yl]amino derivatives that are inhibitors of the receptor ALK5, which possess therapeutically desirable characteristics and are particularly promising for certain fibroses, including idiopathic pulmonary fibrosis (IPF).

[0096] The compounds of the present invention are active as inhibitors of the ALK5 receptor, they are potent and exhibit improved properties such as good inhalation properties, low metabolic stability, low systemic exposure, improved safety and tolerability and good selectivity across kinase groups.

[0097] In this respect, the prior art does not describe or suggest that the pyridazinylamino derivatives of the general formula (I) according to the present invention have an inhibitory activity towards the receptor ALK5, which would represent a solution to the aforementioned need.

[0098] Amgen has disclosed, among other compounds, pyridazinylamino derivatives. The compounds of formula (I) of the present invention differ from the Amgen compounds in at least the substituents on rings A1, A2, and A3. Amgen has disclosed compounds that are ligands for vanilloid receptors for the treatment of a wide variety of diseases and disorders. Amgen has not disclosed compounds that are ALK5 inhibitors nor compounds that are useful for the treatment of fibrosis.

[0099] Vertex describes, inter alia, pyridazine derivatives. The compounds of formula (I) of the present invention differ from the Vertex compounds by at least the presence of a pyridyl or pyridyl condensation group attached to an amino linker bearing a pyridazine ring, rather than a triazole group. The Vertex compounds are described as protein kinase inhibitors useful for treating cancer, diabetes, Alzheimer's disease, and schizophrenia. Vertex does not describe compounds as ALK5 inhibitors nor compounds useful for treating fibrosis.

[0100] Ortho-McNeil describes pyridazine compounds. The compounds of formula (I) of the present invention differ from the Ortho-McNeil compounds in at least the position of the two nitrogen atoms in the pyridazine ring. The Ortho-McNeil compounds are described as tyrosine kinase inhibitors useful as antitumor agents and for the treatment of diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. Ortho-McNeil does not disclose compounds that are ALK5 inhibitors or compounds that are useful for the treatment of fibrosis.

[0101] More specifically, the present invention relates to a series of compounds represented by the general formula (I) as described in detail below, which have inhibitory activity against the receptor ALK5.

[0102] Advantageously, inhibition of the receptor ALK5 may be effective in treating those diseases in which these receptors play a relevant role in the pathogenesis, such as fibrosis and diseases, disorders and conditions caused by fibrosis.

[0103] Unlike similar compounds in the prior art, the compounds of formula (I) of the present invention can act as antagonists of the ALK5 receptor and have attracted particular attention from technicians when searching for suitable and effective compounds for treating fibrosis, especially idiopathic pulmonary fibrosis.

[0104] As shown in the experimental part, in particular in Table 4, the compounds of formula (I) of the present invention exhibit significant potency in their inhibitory activity against the receptor ALK5, below about 10 nM, confirming their ability to inhibit the ALK5 receptor involved in fibrosis and diseases caused by fibrosis.

[0105] As shown in the experimental part, the comparative examples and in particular in Table 4, it was demonstrated that, in contrast to compounds C1 and C2 characterized by the absence of a pyridyl or pyridyl condensation group attached to an amino group bearing a pyridazine ring, the presence of a pyridyl or pyridyl condensation group attached to an amino group bearing a pyridazine ring in the compounds of the present invention unexpectedly and significantly determines a relevant increase in the inhibitory activity against the ALK5 receptor.

[0106] Furthermore, as shown in the same Table 4, in contrast to compound C3, which is characterized by an NH2 group on the pyridine ring and falls within the general formula of Amgen, the presence of specific substituents on the pyridine ring described in the present invention unexpectedly and specifically determines a relevant increase in the inhibitory activity against the ALK5 receptor.

[0107] Advantageously, the compounds of the present invention have such high potency that they can be administered to humans at lower doses than prior art compounds, thereby reducing adverse events that typically occur when higher doses of the drug are administered.

[0108] In addition to being remarkably potent in terms of their inhibitory activity against the receptor ALK5, the compounds of the invention are characterized by good inhalation properties, which allow effective action in the lung compartment and at the same time low metabolic stability, which allows minimizing the drawbacks associated with systemic exposure, such as safety and tolerability problems.

[0109] Therefore, when searching for suitable and effective compounds that can be used to treat fibrosis, in particular idiopathic pulmonary fibrosis, the compounds of the present invention are of particular interest to the skilled person, which are administered by the inhalation route and are characterized by good inhalation properties, which correspond to good activity on the lungs, good lung retention and low metabolic stability, which minimizes systemic exposure and related safety issues.

[0110] Thus, in one aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof

[0111]

[0112] in

[0113] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0114] A is selected from the set consisting of: A1, A2, and A3

[0115]

[0116] R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6;

[0117] X1 is C, CH or N;

[0118] R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7;

[0119] R3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, -C(O)O-(C1-C6)alkyl, and -C(O)NH-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one -(C1-C6)alkyl;

[0120] R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0121] R5 is H or -(C1-C6)alkyl;

[0122] R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR AR C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo;

[0123] R7 is selected from the group consisting of:

[0124] -(C1-C6)alkylene-NR A R B ;

[0125] -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups;

[0126] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0127] and

[0128] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C -CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl;

[0129] RA selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0130] R B is a heterocycloalkyl group;

[0131] R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0132] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

[0133] In another aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof

[0134]

[0135] in

[0136] R1 is an aryl group optionally substituted by one or more halogen atoms;

[0137] A is selected from the set consisting of: A1, A2, and A3

[0138]

[0139] R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6;

[0140] X1 is C, CH or N;

[0141] R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7;

[0142] R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0143] R5 is H or -(C1-C6)alkyl;

[0144] R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B, cycloalkyl, heterocycloalkyl substituted with one or more -(C1-C6)alkyl, and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups selected from -(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, and oxo;

[0145] R7 is selected from the group consisting of:

[0146] -(C1-C6)alkylene-NR A R B ,

[0147] -heterocycloalkyl substituted by one or more -(C1-C6)alkyl,

[0148] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl, and

[0149] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)haloalkyl and -C(O)-(C1-C6)alkyl;

[0150] R A is -(C1-C6)alkyl;

[0151] R B is a heterocycloalkyl group;

[0152] R8 is H or -(C1-C6)alkyl.

[0153] In a more preferred embodiment, the present invention relates to compounds of formula (I), wherein R1 is phenyl substituted by one or more groups selected from fluoro, chloro, CHF2 and propan-2-yl.

[0154] In another preferred embodiment, R5 is H or -CH3.

[0155] In a particularly preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A is A1

[0156]

[0157] It is represented by formula (Ia)

[0158]

[0159] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0160] R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6;

[0161] R5 is H or -(C1-C6)alkyl;

[0162] R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ,-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo;

[0163] R A is -(C1-C6)alkyl;

[0164] R B is a heterocycloalkyl group;

[0165] R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0166] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

[0167] In an even more preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A is A1a

[0168]

[0169] It is represented by formula (Iaa)

[0170]

[0171] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0172] R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6;

[0173] R5 is H or -(C1-C6)alkyl;

[0174] R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R Cand -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O-(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo;

[0175] R A is -(C1-C6)alkyl;

[0176] R B is a heterocycloalkyl group;

[0177] R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0178] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

[0179] According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (Iaa) listed in Table 1 below and pharmaceutically acceptable salts thereof.

[0180] Table 1: List of preferred compounds of formula (Iaa)

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201] In an even more preferred embodiment, the present invention relates to compounds of formula (Iaa), wherein R2 is -NHC(O)R6; R6 is selected from the group consisting of cyclopropyl, 1-ethylpiperazine, 4-ethylmorpholine, 1-ethyl-4-methylpiperazine, (4-acetylpiperazin-1-yl)ethyl, 4-propylmorpholine, -(3-methyl-1,3-diazinane-1-yl)ethyl, -(3-methylsulfonyl-1,3-diazinane-1-yl)ethyl, 4-methylmorpholine, N-ethyl-N-methyloxetan-3-amine, 1-methylpiperidine, -1-ethyl-(4-methyl-2-oxopiperazin-1-yl), -4-ethyl-(1-methyl-2-oxopiperazine)-1-yl). 1-yl), -(4-methylsulfonylpiperazin-1-yl)ethyl, -(3-acetyl-1,3-diazinane-1-yl)ethyl, -(3-methylsulfonyl-1,3-diazinane-1-yl)ethyl, -[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl, -[3-(2,2,2-trifluoroethyl)-1,3-diazinane-1-yl]ethyl, -1-propyl-4-methylpiperazine, -[4-(2-aminoethyl)piperazin-1-yl]ethyl, -[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]ethyl, -[4-(2-hydroxyethyl)piperazin-1-yl]ethyl, (2-(4-ethylpiperazin-1-yl)ethyl)amino methyl formate, -[4-(2-methylsulfonylethyl)piperazin-1-yl]ethyl, -[4-(2-cyanoethyl)piperazin-1-yl]ethyl, 4-methylpiperazine, 4-ethyl-piperazine-2-carboxylic acid methyl ester, 4-ethyl-piperazine-2-carboxylic acid, -[2-(methylamino)ethyl]amino-ethyl, 4-ethyl-1-methylpiperazine-2-carboxylic acid methyl ester, 4-ethyl-1-methylpiperazine-2-carboxylic acid, 2-(4-methylpiperazin-1-yl)acetate methyl ester, 2-(4-ethylpiperazin-2-yl)acetate methyl ester, 2-(4-ethyl-1-methylpiperazin-2-yl)acetate methyl ester, 1-ethyl-4-methylpiperazine-2-carboxylic acid methyl ester, 2-(1-ethyl-4-methylpiperazine 2-(1-ethyl-piperazin-2-yl)acetic acid methyl ester, 4-[2-(methylamino)ethyl]piperazin-1-yl-ethyl, (2-(4-ethylpiperazin-1-yl)ethyl)-N-methylcarbamic acid methyl ester, 4-[2-(methylamino)ethyl]piperazin-1-yl-methyl, (2-(4-methylpiperazin-1-yl)ethyl)-N-methylcarbamic acid methyl ester, 4-[2-(methylamino)ethyl]piperazin-1-yl-methyl, (2-(4-methylpiperazin-1-yl)ethyl)-N-methylcarbamic acid methyl ester, 4-[4-(2-aminoethyl)piperazin-1-yl]methyl, (2-(4-methylpiperazin-1-yl)ethyl)carbamic acid methyl ester, 4-ethyl 1,1-dimethylpiperazin-1-ium, 4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl]-ethyl, 1-isopropyl-4-ethylpiperazine-2-carboxylic acid methyl ester, 4-ethylthiomorpholine, -(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)-ethyl, 4-ethyl-1-methylpiperazine-2-carboxylic acid ethyl ester, 4-methylmorpholine 4-oxide, 4-ethyl-1-methylpiperazine-2-carboxylic acid propane-2-yl ester, 4-ethyl-1-methylpiperazine-2-carboxylic acid cyclopropyl ester, 4-ethyl-1-methylpiperazine-2-carboxylic acid oxetan-3-yl ester, -(1-oxo-thiomorpholin-4-yl)ethyl, -[4-(2,2,2- 1-yl)ethyl, -(1,1-dioxo-thiomorpholin-4-yl)ethyl, -(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)ethyl, -[4-(2-methanesulfonylaminoethyl)piperazin-1-yl]ethyl, -{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}ethyl, -(4,4-difluoropiperidin-1-yl)ethyl, -(4-hydroxypiperidin-1-yl)ethyl, -2-(4-methylpiperazin-1-yl)ethan-1-amine, -(1-methylpiperidin-4-yl)methylamine, -{6-methyl-2,6-diazaspiro[3.3]heptane-2-yl}ethyl ethyl, -{6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl}ethyl, -{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}ethyl, -2-methyl-2,7-diazaspiro[3.5]nonane, -2-methyl-2,8-diazaspiro[4.5]decane, -2-(1,4-diazacycloheptan-1-yl)methyl, -{1-[2-(methylamino)-1-yl]-2-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl}ethyl, -{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonane, -2-methyl-2,8-diazaspiro[4.5]decane yl)ethyl]-1H-pyrazole}, -{1-[2-(dimethylamino)ethyl]-1H-pyrazole}, -(1-methylpiperidin-4-yl)methyl, -1-propyl-1,4-diazepane, -1-methyl-4-propyl-1,4-diazepane, -[2-(hydroxymethyl)-4-methylpiperazin-1-yl]ethyl, -(4-methylpiperazin-1-yl)cyclobutyl, -2-(piperazin-1-yl)methyl, -1-methyl-4-methyl-1,4-diazepane, -[3-(hydroxymethyl)-4-methylpiperazin-1-yl]ethyl and -1-methyl-4-methylpiperazine.

[0202] In a further preferred embodiment, the present invention relates to compounds of formula (Iaa), wherein R2 is -NR5R6; R6 is selected from the group consisting of -4-(1-methylpiperazine)propyl and -[(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl.

[0203] In an equally preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A is A2

[0204]

[0205] It is represented by formula (Ib)

[0206]

[0207] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms and -(C1-C6)alkyl;

[0208] X1 is C, CH or N;

[0209] R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7;

[0210] R 3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, -C(O)O-(C1-C6)alkyl, and -C(O)NH-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one -(C1-C6)alkyl;

[0211] R5 is H or -(C1-C6)alkyl;

[0212] R7 is selected from the group consisting of:

[0213] -(C1-C6)alkylene-NR A R B ;

[0214] -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups;

[0215] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; and

[0216] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl;

[0217] R A selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0218] R B is a heterocycloalkyl group;

[0219] R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0220] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-OH, and -(C1-C6)haloalkyl.

[0221] In a more preferred embodiment, the present invention relates to compounds of formula (Ib), wherein R3 is -C(O)OR7; R 3’ is H; R7 is 4-ethylmorpholine; R8 is H or -(C1-C6)alkyl.

[0222] According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (Ib) listed in Table 2 below and pharmaceutically acceptable salts thereof.

[0223] Table 2: List of preferred compounds of formula (Ib)

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ib) and pharmaceutically acceptable salts thereof, wherein A is A2a

[0238]

[0239] It is represented by formula (Iba)

[0240]

[0241] R1 is an aryl group optionally substituted by one or more groups selected from halogen atoms and -(C1-C6)alkyl;

[0242] R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7;

[0243] R 3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, and -C(O)O-(C1-C6)alkyl;

[0244] R5 is H or -(C1-C6)alkyl;

[0245] R7 is selected from the group consisting of:

[0246] -(C1-C6)alkylene-NR A R B ,

[0247] -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups;

[0248] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl, and

[0249] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl-(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, and -(C1-C6)alkylene-SO2-(C1-C6)alkyl;

[0250] R A selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0251] R B is a heterocycloalkyl group;

[0252] R cis H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH;

[0253] R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-OH, and -(C1-C6)haloalkyl.

[0254] In a more preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -NHC(O)R7, R 3’ is H, and R7 is 1-ethyl-4-methylpiperazine.

[0255] In a particularly preferred embodiment, the present invention relates to compounds of formula (Iba) and pharmaceutically acceptable salts thereof, wherein R1 is aryl optionally substituted by one or more halogen atoms; R3 is -C(O)NHR7; R 3’ is H; R7 is -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; R8 is H or -(C1-C6)alkyl.

[0256] In a more preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -C(O)NHR7; R 3’ is H; R7 is selected from the group consisting of: 4-ethylmorpholine, 4-ethylpiperazine, 1-ethyl-4-methylpiperazine and 1-ethyl-4-methylpiperidine; R8 is H or -(C1-C6)alkyl.

[0257] In a more preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -C(O)OR7; R 3’ is H; R7 is selected from the group consisting of: 4-ethylmorpholine, N-methylpiperidine and N-methylpyrrolidine; R8 is H or -(C1-C6)alkyl.

[0258] In a further preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -OC(O)R7; R 3’ is H; R7 is a heterocycloalkyl group optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO 2- (C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, and -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups; RA is selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R B is a heterocycloalkyl group; R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R8 is H or -(C1-C6)alkyl.

[0259] In a more preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -OC(O)R7; R 3’ is H; R7 is selected from the group consisting of -4-methylpiperazine, -N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl, -N-methyl-N-[2-(1-methylpiperidin-4-yl)ethyl], -4-(2-methylsulfonylethyl)piperazine, -4-(2-hydroxyethyl)piperazine, -4-[2-(dimethylamino)ethyl]piperazine, -4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine, -4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine, -4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine, -4-[(1-methylpiperidin-4-yl)methyl]piperazine, -4-(1-methylpiperidin-4-yl)piperazine, -2,8-diazaspiro[4.5]decane, -2-methyl-2 ,7-diazaspiro[3.5]nonane, -7-methyl-2,7-diazaspiro[3.5]nonane, -8-methyl-2,8-diazaspiro[4.5]decane, -2-methyl-2,6-diazaspiro[3.4]octane, -(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane, -5-methyl-2,5-diazabicyclo[2. 2.1]heptane, -3-(pyrrolidin-1-yl)azetidine, -4-(azetidin-1-yl)piperidine, -(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane and -3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-3-carboxylate; R8 is H or -(C1-C6)alkyl.

[0260] In a further preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -OR7; R 3’ is H or is selected from the group consisting of: -(C1-C6)alkoxy, -OH and -C(O)O-(C1-C6)alkyl; R7 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl and -SO2-(C1-C6)alkyl; R A is selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R B is a heterocycloalkyl group; R c R8 is H or a member selected from the group consisting of -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R8 is H or a member selected from the group consisting of -(C1-C6)alkyl and -(C1-C6)alkylene-OH.

[0261] In a more preferred embodiment, the present invention relates to compounds of formula (Iba), wherein R3 is -OR7; R 3’R is H or is selected from the group consisting of: -OCH3, -OH and -C(O)O-CH3; R is selected from the group consisting of: -2-(morpholin-4-yl)ethyl, -2-(piperazin-1-yl)ethyl, -2-(4-methylpiperazin-1-yl)ethyl, 2-(1-methylpiperidin-4-yl)ethyl, -3-(4-methylpiperazin-1-yl)propyl, -2-(4-ethylpiperazin-1-yl)ethyl, -4-ethyl-1-(piperazin-1-yl)ethan-1-one, -2-(4-methylpiperidin-4-yl)ethyl sulfonylpiperazin-1-yl)ethyl, -1-(4-methylpiperazin-1-yl)ethan-1-one, -2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl, -2-[methyl(oxetan-3-yl)amino]ethyl, -3-(3-methyl-1,3-diazinane-1-yl)propyl, -2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}ethyl, -1-(3-ethyltetrahydropyrimidin-1(2H)-yl)ethan-1-one, methyl-[4-ethyl-(piperazin- 1-yl)] propionate, -2-(3-methyl-1,3-diazinane-1-yl)ethyl, -3-(4-ethylpiperazin-1-yl)-N-methylpropionamide, -2-[4-(2-aminoethyl)piperazin-1-yl]ethyl, -4-ethyl-[(piperazin-1-yl)ethyl]methanesulfonamide, -4-[2-(dimethylamino)ethyl]piperazin-1-yl-ethyl, N-(2-(4-ethylpiperazin-1-yl)ethyl)acetamide, -3-(4-ethylpiperazin-1-yl)propionitrile, -2-(4-ethylpiperazin-1-yl)ethyl oxazine-1-yl) ethane-1-ol, 1-methylpiperidin-4-yl, -2,2'-((2-(4-ethylpiperazin-1-yl)ethyl)azanediyl)bis(ethane-1-ol), methyl (2-(4-ethylpiperazin-1-yl)ethyl)carbamate, -3-(4-ethylpiperazin-1-yl)pentane-1,5-diol, -(1-methylpiperidin-4-yl)methyl and -2-(3-methylimidazolidin-1-yl)ethyl; R8 is H or a member selected from the group consisting of methyl, -CF3 and -CH2OH.

[0262] According to another preferred embodiment, the present invention relates to compounds of formula (I), wherein A is A2b

[0263]

[0264] It is represented by formula (Ibb)

[0265]

[0266] where R 3’ are -(1-methylazetidin-3-yl)-carboxamide and -(1-methylpiperidin-4-yl)-carboxamide.

[0267] According to another preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A is A3

[0268]

[0269] It is represented by formula (Ic)

[0270]

[0271] R1 is an aryl group optionally substituted by one or more halogen atoms;

[0272] R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0273] R5 is H or -(C1-C6)alkyl;

[0274] R7 is selected from the group consisting of heterocycloalkyl substituted with one or more -(C1-C6)alkyl and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl;

[0275] R8 is H or -(C1-C6)alkyl.

[0276] According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (Ic) listed in Table 3 below and pharmaceutically acceptable salts thereof.

[0277] Table 3: List of preferred compounds of formula (Ic)

[0278]

[0279]

[0280] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ic), wherein A is A3a

[0281]

[0282] It is represented by formula (Ica)

[0283]

[0284] R4 is -C(O)NR5R7;

[0285] R5 is H or methyl;

[0286] R7 is selected from the group consisting of 1-ethyl-4-methylpiperazine and 1-ethyl-4-methylpiperidine;

[0287] R8 is H or methyl.

[0288] In a further preferred embodiment, the present invention relates to compounds of formula (I), wherein R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted by one or more -(C1-C6)alkyl; heteroaryl substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted by one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is substituted with one or more -(C1-C6)alkyl; heterocycloalkyl substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one or more groups selected from -O H, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo.

[0289] In another preferred embodiment, the present invention relates to compounds of formula (I), wherein R7 is selected from the group consisting of:

[0290] -(C1-C6)alkylene-NR A R B ;

[0291] -heterocycloalkyl substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is substituted with one or more -(C1-C6)alkyl groups;

[0292] --(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is substituted by one or more -(C1-C6)alkyl;

[0293] and

[0294] --(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C -CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl.

[0295] The compounds of the present invention, including all compounds listed above, can be prepared from readily available starting materials using the following general methods and operations or by using a slightly modified method readily available to those of ordinary skill in the art. Although specific embodiments of the present invention are shown or described herein, it will be appreciated by those skilled in the art 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 temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used, unless otherwise indicated. Although the optimum reaction conditions may vary with the specific reactants or solvents used, such conditions can be easily determined by those skilled in the art through conventional optimization operations.

[0296] Therefore, the methods described below should not be construed as limiting the scope of synthetic methodologies that can be used to prepare the compounds of the present invention.

[0297] In some cases, a step is required to mask or protect sensitive or reactive moieties, which can be accomplished using commonly known protecting groups (PG) according to general principles of chemistry (Protective group in organic syntheses, 3rd edition, TW Greene, PGM Wuts).

[0298] It has surprisingly been found that the compounds of formula (I) of the present invention effectively inhibit the receptor ALK5. Advantageously, inhibition of ALK5 may lead to effective treatment of diseases or disorders in which the ALK5 receptor is involved.

[0299] In this regard, it has now been found, as shown in the present experimental part, that the compounds of formula (I) according to the invention have a half maximal inhibitory concentration (IC) of less than or equal to 10 nM for ALK5. 50 ) represents the inhibitory drug efficacy.

[0300] Preferably, the compounds of the present invention have an IC between 5 and 10 nM for ALK5. 50 .

[0301] Even more preferably, the compounds of the present invention have an IC of less than 1 nM for ALK5. 50 .

[0302] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. Accordingly, the present invention relates to the use of a compound of formula (I) in the preparation of a medicament, preferably for preventing and / or treating a disease, disorder or condition associated with the ALK5 signaling pathway.

[0303] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in preventing and / or treating a disease, disorder or condition associated with the ALK5 signaling pathway.

[0304] In one embodiment, the present invention relates to compounds of formula (I) useful for preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0305] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, and includes, but is not limited to, fibrosis of various organs or tissues such as the heart, kidney, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract.

[0306] Preferably, the compound of formula (I) of the present invention or a pharmaceutical composition comprising the compound of formula (I) can be used to treat and / or prevent fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0307] More preferably, the compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be used to treat idiopathic pulmonary fibrosis (IPF).

[0308] As used herein, a "safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent refers to an amount of the compound that is sufficient to treat the patient's condition but low enough to avoid serious side effects, and it can be routinely determined by a skilled artisan.

[0309] The compound of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at varying intervals over a given period of time. The typical daily dose may vary depending on the route of administration chosen.

[0310] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) in admixture with at least one or more pharmaceutically acceptable carriers or excipients.

[0311] In one embodiment, the present invention relates to pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, ed. XVII, Mack Pub., NY, USA.

[0312] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be accomplished according to the patient's needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternal and by infusion) and by inhalation.

[0313] Preferably, the compounds of the invention are administered orally or by inhalation.

[0314] More preferably, the compounds of the invention are administered by inhalation.

[0315] In a 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.

[0316] In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is a tablet.

[0317] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavorings, lubricants, etc.

[0318] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions and suspensions. Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorings and reagents for emulsifying and / or suspending the compound of the present invention.

[0319] In another embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable preparation such as an inhalable powder, a metered dose aerosol containing a propellant or an inhalable formulation without a propellant.

[0320] For administration as dry powder, single or multidose inhalers known from the prior art can be used. In this case, the powder can be filled in gelatin, plastic or other capsules, cores or blister packs or in a reservoir.

[0321] A diluent or carrier which is chemically inert to the compound of the invention, such as lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compound of the invention.

[0322] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compound of the invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers or optionally other excipients.

[0323] Propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by means of spray or ultrasonic nebulizers or by soft mist nebulizers known in the art.

[0324] The compounds of the present invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0325] The dosage of the compounds of the present invention will depend on a variety of factors including, among others, the specific disease to be treated, the severity of the symptoms, the route of administration, and the like.

[0326] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in the form of a single-dose or multi-dose dry powder inhaler or a metered-dose inhaler.

[0327] All preferred groups or embodiments described above for the compounds of the formula (I) can be combined with one another and apply mutatis mutandis.

[0328] The compounds of the present invention, including all compounds listed above, can be prepared from readily available starting materials using the following general methods and operations or by using a slightly modified method readily available to those of ordinary skill in the art. Although specific embodiments of the present invention are shown or described herein, it will be appreciated by those skilled in the art 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 temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used, unless otherwise indicated. Although the optimum reaction conditions may vary with the specific reactants or solvents used, such conditions can be easily determined by those skilled in the art through conventional optimization operations.

[0329] Therefore, the methods described below and reported in the following schemes should not be construed as limiting the scope of synthetic methodologies that can be used to prepare the compounds of the present invention.

[0330] Compounds of formula (I), including all or at least one of the compounds listed above, can generally be prepared according to the procedures detailed in the schemes shown below using generally known methods.

[0331] In a first embodiment of the present invention, compounds of formula (I) can be prepared as described in Scheme 1.

[0332] Solution 1

[0333]

[0334] Scheme 1 provides a possible synthetic route for the preparation of compounds of formula (I), wherein A, R1 and R8 are as defined above.

[0335] Compounds of formula (III) can be prepared by reacting commercially available compound (II) in a cross-coupling reaction (such as Suzuki cross-coupling) in the presence of a Pd catalyst. Typical Suzuki conditions for inserting the R8 group include reacting compound (II) with a suitable boronic acid in the presence of a Pd catalyst (such as Pd(dppf)Cl2 DCM) in a mixture of solvents (such as 1,4-dioxane and water) at a suitable temperature, such as, for example, 100°C.

[0336] Compounds of formula (III) are reacted under cross-coupling conditions (such as Suzuki cross-coupling) in the presence of a Pd catalyst to provide compounds (IV). Typical Suzuki conditions for inserting the R1 group include reacting compound (III) with a suitable boronic acid in the presence of a suitable base (such as KF) and a Pd catalyst (such as PdCl2(PPh3)2) in a mixture of solvents (such as MeCN and water) at a suitable temperature, such as, for example, 95°C.

[0337] Finally, by reacting a compound of formula (IV) with a suitable halide under standard Buchwald-Hartwig amination conditions, a compound of formula (I) can be obtained. Typical Buchwald-Hartwig conditions include: the presence of a suitable base (such as cesium carbonate), a suitable ligand reagent (such as Xantphos) and a suitable catalyst (such as Pd(OAc)2), in a suitable solvent (such as 1,4-dioxane), and at a suitable temperature, such as, for example, 100°C.

[0338] Alternatively, the nitrogen of the compound of formula (III) is protected as di-tert-butyloxycarbonyl (Boc) using di-tert-butyl dicarbonate (Boc anhydride, Boc O) in the presence of a base (such as triethylamine) in a suitable solvent (such as THF) at a suitable temperature, such as, for example, 70° C., to provide a compound of formula (V). Using, for example, a cross-coupling reaction (such as Suzuki cross-coupling) in the presence of a Pd catalyst, R1 can be introduced to provide a compound of formula (VI). Typical Suzuki conditions include reacting compound (V) with a suitable boronic acid in the presence of a Pd catalyst (such as Pd(dppf)Cl DCM) and a suitable base (such as sodium carbonate) in a mixture of a solvent (such as 1,4-dioxane and water) at a suitable temperature, such as, for example, 100° C.

[0339] The Boc protecting group is removed under acidic conditions, such as, for example, TFA in DCM, at room temperature to afford compounds of formula (IV).

[0340] Finally, compound (IV) is reacted under standard Buchwald-Hartwig amination conditions as described above to provide compound (I).

[0341] Alternatively, insertion of group A on a compound of formula (III) can be achieved by reaction with a suitable halide under standard Buchwald-Hartwig amination conditions to give a compound of formula (VII). Typical Buchwald-Hartwig conditions include the presence of a suitable base (such as sodium tert-butoxide), a suitable ligand reagent (such as Xantphos) and a suitable catalyst (such as Pd2(dba)3), in a suitable solvent (such as 1,4-dioxane), and at a suitable temperature, such as, for example, 105°C.

[0342] Finally, by reacting compound (VII) in a cross-coupling reaction (such as Suzuki cross-coupling) in the presence of a Pd catalyst, the introduction of R1 can be achieved to provide compound (I). Typical Suzuki conditions include reacting compound (VII) with a suitable boronic acid in the presence of a Pd catalyst (such as Pd(PPh3)4 or Pd(dppf)Cl2DCM) in the presence of a base (such as potassium carbonate) in a mixture of a solvent (such as 1,2-dimethoxyethane and water) at an appropriate temperature, such as, for example, 90°C.

[0343] In another embodiment, compounds of formula (I) can be prepared as described in Scheme 2.

[0344] Option 2

[0345]

[0346] Compounds of formula (IX) can be prepared by reacting compound (VIII) in a cross-coupling reaction (such as a Suzuki cross-coupling) in the presence of a Pd catalyst. Typical Suzuki conditions for inserting R1 include reacting compound (VIII) with a suitable boronic acid in the presence of a Pd catalyst (such as Pd(OAc)2), a ligand reagent (such as dppf), in the presence of a base (such as cesium carbonate), in a mixture of a solvent (such as 1,4-dioxane and water) at a suitable temperature, such as, for example, 60°C.

[0347] Compound (IX) is reacted under Buchwald-Hartwig cross-coupling conditions to provide compound (I). Typical Buchwald-Hartwig conditions for inserting group A include: the presence of a suitable base (such as cesium carbonate), a suitable ligand reagent (such as Xantphos) and a suitable catalyst (such as Pd (OAc) 2), in a suitable solvent (such as 1,4-dioxane), and at a suitable temperature, such as 110 ° C.

[0348] In another embodiment, compounds of formula (I) can be prepared as described in Scheme 3.

[0349] Option 3

[0350]

[0351] As described above, compounds of formula (IX) can be prepared by inserting the R1 group by reacting compound (VIII) in a cross-coupling reaction such as a Suzuki cross-coupling in the presence of a Pd catalyst.

[0352] Compounds of formula (XI) can be prepared by reacting a compound of formula (IX) with Teoc-NH2 (X, 2-(trimethylsilyl)ethyl carbamate) under Buchwald-Hartwig cross-coupling conditions. Typical Buchwald-Hartwig conditions include: 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 a suitable solvent (such as 1,4-dioxane) and at a suitable temperature, such as 100°C. Cleavage of Teoc (2-(trimethylsilyl)ethoxycarbonyl) using cesium fluoride in DMF provides compound (IV).

[0353] Finally, compound (IV) is reacted under Buchwald-Hartwig cross-coupling conditions to provide compound (I). Typical Buchwald-Hartwig conditions for inserting group A include reacting compound (IV) with a suitable halide in the presence of a Pd catalyst as described above.

[0354] Compounds of formula (III) can be prepared from compounds (VIII) by nucleophilic aromatic substitution with a nucleophile such as ammonium hydroxide in a suitable solvent such as in 1,4-dioxane at a suitable temperature such as 90°C.

[0355] Compounds of formula (IV) can be synthesized by reacting compound (III) under Suzuki cross-coupling conditions. Typical Suzuki conditions for inserting R1 include reacting compound (III) with a suitable boronic acid in the presence of a Pd catalyst as described above.

[0356] Finally, compound (IV) is reacted under Buchwald-Hartwig cross-coupling conditions as described above to provide compound (I).

[0357] In one embodiment of the present invention, compounds of formula (I) can be prepared as described in Scheme 4.

[0358] Option 4

[0359]

[0360] Scheme 4 provides a possible synthetic route for the preparation of compounds of formula (I) wherein R8 is -(C1-C6)alkylene-OH, such as -CH2OH.

[0361] Compounds of formula (XIII) can be obtained from commercially available compounds (XII) by nucleophilic aromatic substitution (SNAr) with 2,4-dimethoxybenzylamine (dmb) in a suitable solvent such as MeCN in the presence of a suitable base such as N,N-diisopropylethylamine, typically at room temperature.

[0362] In the presence of a Pd catalyst, using, for example, a cross-coupling reaction, such as a Suzuki cross-coupling, R1 can be introduced to provide a compound of formula (XIV). Typical Suzuki conditions include reacting compound (XIII) with a suitable boronic acid in the presence of a suitable base (such as N,N-diisopropylethylamine) and a Pd catalyst (such as Pd(PPh3)4) in a suitable solvent (such as 1,4-dioxane) at a suitable temperature, such as, for example, 110°C.

[0363] Reduction of compound (XIV) with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as THF, at a suitable temperature, such as between 0°C and room temperature, provides compound (XV).

[0364] N-deprotection of compound (XV) is carried out under acidic conditions such as, for example, TFA in DCM at room temperature to afford compounds of formula (XVI).

[0365] Protection of compound (XVI) under standard literature conditions, such as by reaction with tert-butyl(chloro)dimethylsilane in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, the reaction being carried out at room temperature in a suitable solvent such as DCM, provides compound (XVII).

[0366] Compound (XVII) is reacted under Buchwald-Hartwig cross-coupling conditions to provide compound (XVIII). Typical Buchwald-Hartwig conditions for inserting group A include reacting compound (XVII) with a suitable halide in the presence of a Pd catalyst as described above.

[0367] Finally, deprotection of compound (XVIII) is carried out under standard literature conditions, such as by reaction with tetrabutylammonium fluoride in a suitable solvent such as THF at an appropriate temperature such as room temperature, to provide compound (I).

[0368] In one embodiment of the present invention, compounds of formula (I) can be prepared as described in Scheme 5.

[0369] Option 5

[0370]

[0371] Scheme 5 provides a possible synthetic route for preparing compounds of formula (I), wherein R8 is selected from -(C1-C6)haloalkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl and -cycloalkyl-C(O)O-(C1-C6)alkyl.

[0372] Compounds of formula (XXIII) can be obtained by two different routes. When R8 is -(C1-C6)haloalkyl, such as CF3 (route A), compounds (XX) can be prepared starting from commercially available pyridazine (XIX) according to the general procedures reported in the literature (Baran and co-workers, Nature 2012, 95-99) using trifluoromethanesulfinate (e.g. zinc) and an oxidizing agent such as tert-butyl hydroperoxide (TBHP) in a suitable solvent (such as a mixture of dichloromethane and water) at a suitable temperature, typically 60°C, under Minisci-type reaction conditions.

[0373] Compound (XX) can be converted to compound (XXIII) by a cross-coupling reaction, such as a Suzuki cross-coupling reaction, in the presence of a typical Pd catalyst. Typical Suzuki conditions include reacting compound (XX) with a suitable boronic acid in the presence of a suitable base (such as potassium carbonate) and a Pd catalyst (such as Pd(dppf)Cl 2 ) in a suitable solvent (such as 1,4-dioxane and water) at a suitable temperature, such as, for example, 110° C.

[0374] When R8 is -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl or -cycloalkyl-C(O)O-(C1-C6)alkyl, compound (XXIII) can be obtained starting from commercially available compound (XIX) according to route B. Therefore, under similar conditions as reported for compound (XXIII), compound (XIX) is converted into compound (XXI) by Suzuki cross-coupling reaction. Then, R8 residue can be introduced by Minisci-type reaction to provide compound (XXIII), the Minisci-type reaction comprising: redox active ester (RAE, such as N-hydroxyphthalimide ester NHPI), a suitable photocatalyst, such as 4CzIPN, in a suitable solvent (such as DMSO), under appropriate LED light (usually blue) irradiation, as described in the literature (Dhar and colleagues, J.Org.Chem.2018, 83, 3000-3012). Compound (XXIII) is reacted under Buchwald-Hartwig cross-coupling conditions to provide compound (I). Typical Buchwald-Hartwig conditions for inserting group A include reacting compound (XXIII) with a suitable halide in the presence of a Pd catalyst as described above.

[0375] Preparation of intermediates and examples

[0376] Chemical names of the compounds were generated using Structure To Name Enterprise 10.0 Cambridge software.

[0377] All reagents whose synthesis is not described in the experimental part are either commercially available, are known compounds, or can be formed from known compounds by methods known to those skilled in the art.

[0378] In the procedures that follow, some starting materials are identified by an "Intermediate" or "Example" number and indicated above the step number. This is provided solely to assist the skilled chemist.

[0379] By "similar" or "analogous" procedure is meant that such procedure may contain minor changes, for example, reaction temperatures, amounts of reagents / solvents, reaction times, workup conditions, or chromatographic purification conditions.

[0380] Abbreviation-Meaning

[0381] Boc = tert-butyloxycarbonyl

[0382] cHex = cyclohexane

[0383] Cs2CO3=cesium carbonate

[0384] DIC=N,N′-diisopropylcarbodiimide

[0385] DCM = dichloromethane

[0386] DIPEA=N,N-diisopropylethylamine

[0387] DMAP = 4-(dimethylamino)pyridine

[0388] DMF = dimethylformamide

[0389] DMSO = dimethyl sulfoxide

[0390] DPPA = diphenylphosphoryl azide

[0391] dppf=1,1-ferrocenediyl-bis(diphenylphosphine)

[0392] EtOAc = ethyl acetate

[0393] HCOOH = Formic acid

[0394] h = hours

[0395] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0396] HBr = hydrobromic acid

[0397] HCl = hydrochloric acid

[0398] H2O = water

[0399] KF = Potassium Fluoride

[0400] K3PO4 = Tripotassium phosphate

[0401] LC-MS = Liquid Chromatography / Mass Spectrometry

[0402] MeCN = acetonitrile

[0403] MeOH = methanol

[0404] MTBE = tert-butyl methyl ether

[0405] NaI = Sodium Iodide

[0406] NaOH = Sodium Hydroxide

[0407] Na2SO4=Sodium sulfate

[0408] NaHCO3 = Sodium bicarbonate

[0409] NaHSO4 = Sodium bisulfate

[0410] Na2CO3=sodium carbonate

[0411] NH3 = ammonia

[0412] NH4Cl = ammonium chloride

[0413] Pd / C = Palladium on Carbon

[0414] PdCl2(PPh3)2=Bis(triphenylphosphine)palladium(II) dichloride

[0415] Pd2(dba)3=tris(dibenzylideneacetone)dipalladium(0)

[0416] Pd(dppf)Cl2 DCM=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, complex with dichloromethane

[0417] Pd(OAc)2=palladium(II) acetate

[0418] Pd(PPh3)4=tetrakis(triphenylphosphine)palladium(0)

[0419] PL-HCO3 = polymer-supported bicarbonate

[0420] PPh3=triphenylphosphine

[0421] RT = Room temperature

[0422] SCX = Strong Cation Exchange

[0423] SOCl2 = thionyl chloride

[0424] ss = saturated solution

[0425] t-BuOOH = tert-butyl hydroperoxide

[0426] T3P=propylphosphonic anhydride

[0427] TEA = triethylamine

[0428] Teoc = 2-(trimethylsilyl)ethyl carbamate

[0429] TFA = trifluoroacetic acid

[0430] TCFH=Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate

[0431] THF = Tetrahydrofuran

[0432] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0433] General experimental details and methods

[0434] Analytical methods

[0435] Instruments, materials, and methods used for analysis

[0436] 1H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), or on an Agilent VNMRS-500, or on a Bruker Avance 400 spectrometer equipped with: a self-shielded Z-gradient coil 5 mm 1H / nX broadband probe for reverse detection, a deuterium digital lock channel unit, and an orthogonal digital detection unit with emitter offset frequency shift. Chemical shifts are reported as delta 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 abbreviations (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br.s = broad singlet, nd = not determined, dd = doublet of doublets, ddd = doublet of a doublet of doublets, quin = quintet, td = triplet of doublets, tt = triplet of triplets, qd = quadruplet of doublets).

[0437] LC / UV / MS analysis method

[0438] Estimated LC / MS retention times are subject to an experimental error of ±0.5 minutes. LCMS can be recorded under the following conditions: Diode array DAD chromatographic traces, mass chromatograms, and mass spectra can be acquired on a UPLC / PDA / MS Acquity™ system coupled to a Micromass ZQ™ or Waters SQD single quadrupole mass spectrometer (operating in positive and / or negative electron spray ES ionization mode) and / or a Fractionlynx system used in analytical mode coupled to a ZQ™ single quadrupole (operating in positive and / or negative ES ionization mode). Quality control methods for runs performed at low pH or at high pH:

[0439] Method 1, low pH conditions: Column: Acquity CSH C18 2.1x50mm 1.7um, column temperature: 40°C; mobile phase solvent A: milliQ water + 0.1% HCOOH, mobile phase solvent B: MeCN + 0.1% HCOOH. Flow rate: 1 mL / min.

[0440] The gradient was t = 0 min 97% A 3% B, t = 1.5 min 0.1% A 99.9% B, t = 1.9 min 0.1% A 99.9% B and t = 2 min 97% A 3% B. The UV detection range was 210-350 nm and the ES+ / ES- range was 100-1500 AMU.

[0441] Method 2, high pH conditions: Column: Acquity Kinetex 1.7 μm EVO C18 100A, 2.1 x 50 mm, column temperature: 40°C; mobile phase A: 10 mM NH₄HCO₃ aqueous solution adjusted to pH 10 with ammonia, mobile phase B: MeCN. Flow rate: 1 mL / min. Gradient: t = 0 min: 97% A 3% B, t = 1.5 min: 0.1% A 99.9% B, t = 1.9 min: 0.1% A 99.9% B, and t = 2 min: 97% A 3% B. UV detection range: 210–350 nm, ES+ / ES- range: 100–1500 AMU.

[0442] Preparation of intermediates

[0443] Intermediate 1: tert-Butyl N-[(tert-Butoxy)carbonyl]-N-(6-chloropyridazin-4-yl)carbamate

[0444] 6-Chloropyridazine-4-amine (2.0 g, 15.44 mmol) was dissolved in THF (80 mL), TEA (3.12 g, 30.88 mmol) and DMAP (0.09 g, 0.77 mmol) were added, followed by di-tert-butyl dicarbonate (11.79 g, 54.03 mmol). The mixture was refluxed for 5 hours. THF was then evaporated and the residue was partitioned between EtOAc and saturated NH4Cl solution. The organic phase was dried and evaporated, and the crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 30% EtOAc) to provide intermediate 1 (3.96 g, 12.01 mmol, 78% yield) as a white solid.

[0445] LC-MS (ESI): m / z (M+1): 330.1 (Method 1)

[0446] Intermediate 2: tert-Butyl N-[(tert-Butoxy)carbonyl]-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]carbamate

[0447] Intermediate 1 (1.0 g, 3.03 mmol), (5-chloro-2-fluorophenyl)boronic acid (0.58 g, 3.34 mmol) and Na2CO32M (4.55 mL, 9.1 mmol) were degassed with N2 in 1,4-dioxane (12 mL) for 5 minutes, followed by the addition of Pd(dppf)Cl2DCM (248 mg, 0.30 mmol). The resulting mixture was heated at 100 ° C for 1 h. The reaction was complete, so the mixture was evaporated and the residue was partitioned between EtOAc and water, the organic phase was separated, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 30% EtOAc) to provide intermediate 2 (1.1 g, 2.6 mmol, 86% yield).

[0448] LC-MS (ESI): m / z (M+1): 330.1 (Method 1)

[0449] Intermediate 3: 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine

[0450] Method A

[0451] Intermediate 2 (1.1 g, 2.6 mmol) was dissolved in DCM (10 mL) and TFA (3.0 mL, 39.18 mmol), and the reaction solution was stirred for 5 hours, then another 2 mL of TFA was added and the reaction was stirred at room temperature overnight. The next day, the volatiles were removed under vacuum, the residue was dissolved in MeOH and loaded onto an SCX column, washed with MeOH and eluted with 1N NH3 in MeOH; the basic fractions were collected to provide Intermediate 3 (530 mg, 2.37 mmol, 91% yield) as a white solid.

[0452] Method B

[0453] A mixture of 6-chloropyridazin-4-amine (3.0 g, 23.16 mmol), (5-chloro-2-fluorophenyl)boronic acid (5.25 g, 30.1 mmol), and KF (3.42 g, 57.89 mmol) in MeCN (30 mL) / water (23.3 mL) was degassed with N₂ for 2 minutes, then PdCl₂(PPh₃)₂ (1.63 g, 2.32 mmol) was added, and the mixture was warmed at 95°C. After 7 hours, conversion was not complete, so more boronic acid (2 g), catalyst (300 mg), and KF (700 mg) were added and stirred at the same temperature for 24 hours. After cooling, the mixture was evaporated to dryness, and the residue was dissolved in a large amount of MeOH, and some insoluble material was filtered off. The methanol solution was concentrated under vacuum, dissolved in hot EtOAc, and allowed to reach room temperature. The insoluble material was discarded, and the solution was evaporated to dryness to produce a residue that was crystallized from hot EtOAc. After cooling, the solid was filtered to provide the first batch of the title compound (2.2 g). The mother liquor was evaporated and purified by flash chromatography on a Biotage NH silica gel column (from DCM to 3% MeOH) to produce another 500 mg. The two batches were recombined to provide intermediate 3 (2.7 g, 12.07 mmol, 52% yield).

[0454] LC-MS (ESI): m / z (M+1): 224 (Method 2)

[0455] Intermediate 4: 4-Bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester

[0456] 4- bromo -1H- pyrrolo [2,3-b] pyridine -3- methyl formate (1.5g, 5.88mmol) is suspended in THF (20mL) and cooled with an ice bath under N2, then 60% sodium hydride dispersion in oil (0.28g, 11.76mmol) is added and stirred at the same temperature for 30min, followed by dropwise addition of 2- (chloromethoxy) ethyl -trimethylsilane (1.35mL, 7.64mmol). The reaction mixture is allowed to reach room temperature and stirred for 3 hours. Water and EtOAc are added, the product is extracted several times with EtOAc, the organic phase is collected, dried and evaporated. The crude material is purified by flash chromatography on a Biotage silica gel column (from DCM to 5% MeOH) to provide intermediate 4 (1.05g, 2.72mmol, 46% yield) as a white wax.

[0457] LC-MS (ESI): m / z (M+1): 387.0 (Method 1)

[0458] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.15 (d, J = 5.0 Hz, 1H), 8.13 (s, 1H), 7.48 (d, J = 5.0 Hz, 1H), 3.92 (s, 3H), 5.70 (s, 2H), 3.56 (dd, J = 8.9, 7.8 Hz, 2H), 0.88-1.01 (m, 2H), -0.09--0.01 (m, 9H).

[0459] Intermediate 5: 4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester

[0460] To an ice-cooled suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (1.0 g, 4.75 mmol) in dry THF (35 mL), 60% sodium hydride dispersion in oil (0.28 g, 7.12 mmol) was added and the mixture was stirred for 30 min, followed by addition of 2-(chloromethoxy)ethyl-trimethylsilane (1.09 mL, 6.17 mmol). The reaction mixture was allowed to reach room temperature and stirred at room temperature for 3 hours. The mixture was quenched with saturated NH4Cl solution, diluted with EtOAc, and washed with brine (1x). The organic phase was dried and concentrated under vacuum and retained as a solid (yellow) at room temperature overnight. The next day, the color of the solid was white and UPLC inspection showed complete conversion to produce the reported positional isomers. The residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 10% EtOAc) to provide intermediate 5 (820 mg, 2.41 mmol, 51% yield).

[0461] LC-MS (ESI): m / z (M+1): 341.1 (Method 1)

[0462] 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 (d, J = 5.1 Hz, 1H), 7.40 (s, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.14 (s, 2H), 3.97 (s, 3H), 3.52-3.58 (m, 2H), 0.85-0.92 (m, 2H), -0.11--0.05 (m, 9H).

[0463] Intermediate 6: Lithium 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0464] Lithium hydroxide hydrate (116 mg, 2.77 mmol) was added to a solution of methyl 4-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carboxylate (Intermediate 4, 1.0 g, 2.52 mmol) in a mixture of THF (12 mL) / MeOH (2 mL) / water (2 mL) and stirred overnight at 50° C. The next day, the volatiles were removed under vacuum to provide Intermediate 6 (1 g, recovery assumed quantitative), which was used as is in the next step.

[0465] LC-MS (ESI): m / z (M+1): 373.0 (Method 1)

[0466] Intermediate 7: 4-Bromo-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0467] Intermediate 6 (300 mg, 0.80 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (125 mg, 0.87 mmol) were mixed in MeCN (8 mL), 1-methylimidazole (0.22 mL, 2.78 mmol) was added, followed by TCFH (268 mg, 0.95 mmol). The resulting solution was stirred at room temperature for 3 hours and then stirred at 60 ° C overnight. The next day, the solvent was removed by evaporation, the residue was redissolved with DCM, the solid was filtered off, and the liquid was concentrated and purified by flash chromatography on a Biotage NH silica gel column (from DCM to 35% EtOAc) to provide intermediate 7 (170 mg, 0.34 mmol, 43% yield).

[0468] LC-MS (ESI): m / z (M+1): 518.3 (Method 2)

[0469] Intermediate 8: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0470] 6-(5-Chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 70 mg, 0.31 mmol), Intermediate 7 (171 mg, 0.34 mmol), Xantphos (27 mg, 0.05 mmol) and K 3 PO 4 (135 mg, 0.63 mmol) were mixed in 1,4-dioxane (4 mL). The mixture was degassed with N 2 for 3 min, then Pd 2 (dba) 3 (29 mg, 0.03 mmol) was added and the resulting mixture was heated at 100 ° C overnight. The solid was filtered off and the residue was concentrated and purified by reverse phase flash chromatography on a Biotage C18 column (from H 2 O + 0.1% NH 4 OH to MeCN) to provide Intermediate 8 (36 mg, 0.06 mmol, 18% yield), which was used as is in the next step.

[0471] LC-MS (ESI): m / z (M+1): 639.3 (Method 2)

[0472] Intermediate 9: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester

[0473] 4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (Intermediate 5, 508 mg, 1.48 mmol), Cs2CO3 (880 mg, 2.68 mmol), Xantphos (93 mg, 0.16 mmol) and Intermediate 3 (300 mg, 1.34 mmol) were mixed in 1,4-dioxane (4 mL) and degassed with N2 for 5 min, followed by the addition of Pd(OAc)2 (15 mg, 0.07 mmol). The resulting reaction mixture was irradiated with microwaves at 110 ° C for 90 min. The solid was filtered, washed with EtOAc, the volatiles were removed under vacuum, and the residue was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 45% EtOAc) to provide Intermediate 9 (220 mg, 0.42 mmol, 31% yield) as a yellow foam.

[0474] LC-MS (ESI): m / z (M): 528.2 (Method 1)

[0475] Intermediate 10: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0476] Intermediate 9 (30 mg, 0.06 mmol) was dissolved in a mixture of THF (1.5 mL) / MeOH (0.50 mL) / H 2 O (0.50 mL), and then lithium hydroxide hydrate (2.62 mg, 0.06 mmol) was added and stirred at 50° C. for 2 hours. The volatiles were removed under vacuum to provide intermediate 10 (29 mg, 0.06 mmol, 98% yield) as a yellow solid.

[0477] LC-MS (ESI): m / z (M+1): 373.0 (Method 1)

[0478] Intermediate 11: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0479] 1-(2-Aminoethyl)-4-methylpiperazine (8 mg, 0.06 mmol) was added to a solution of intermediate 10 (29 mg, 0.06 mmol), HATU (25 mg, 0.07 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF (2.5 mL). The mixture was stirred at 50 ° C for 2 hours, then an additional 1 equivalent of HATU was added and stirred at 50 ° C overnight. The mixture was loaded on an SCX, washed with MeOH and eluted with a solution of 1N NH3 in MeOH. The basic fraction was collected, dried and purified by flash chromatography on a Biotage NH silica gel column (from 30% cyclohexane to 10% MeOH in EtOAc) to provide intermediate 11 (25 mg, 0.04 mmol, 70% yield).

[0480] LC-MS (ESI): m / z (M+1): 639.2 (Method 1)

[0481] Intermediate 12: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0482] Intermediate 12 was prepared following the procedure used for the synthesis of Intermediate 11 starting from Intermediate 10 (29 mg, 0.06 mmol) and 2-(1-methylpiperidin-4-yl)ethan-1-amine (8 mg, 0.06 mmol) to provide the title compound (22 mg, 0.03 mmol, 62% yield).

[0483] LC-MS (ESI): m / z (M+1): 638.3 (Method 1)

[0484] Intermediate 13: Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate

[0485] A suspension of intermediate 3 (320 mg, 1.43 mmol), methyl 4-chloroquinoline-7-carboxylate (380 mg, 1.72 mmol) and Cs2CO3 (938 mg, 2.86 mmol) in 1,4-dioxane (16 mL) was prepared and degassed with N2 for 2 minutes, then Pd(OAc)2 (16 mg, 0.07 mmol) and Xantphos (83 mg, 0.14 mmol) were added and the resulting mixture was irradiated with microwaves (110°C for 3 hours). The mixture was heated at 400°C for 1 hour. Filtered over a pad of Celite®, washed with EtOAc / MeOH, and the organic phase was evaporated under vacuum.The crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 5% MeOH) to afford intermediate 13 (360 mg, 0.88 mmol, 62% yield).

[0486] LC-MS (ESI): m / z (M+1): 409.1 (Method 2)

[0487] Intermediate 14: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate

[0488] Intermediate 14 was prepared following the procedure for the synthesis of Intermediate 6 starting from Intermediate 13 (125 mg, 0.31 mmol) to afford the title compound (125 mg, 0.31 mmol, quantitative yield) as a yellow solid.

[0489] LC-MS (ESI): m / z (M+1): 395.2 (Method 1)

[0490] Intermediate 15: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylic acid

[0491] Lithium hydroxide hydrate (78 mg, 1.82 mmol) was added to a stirred mixture of intermediate 13 (500 mg, 1.02 mmol) in THF (6 mL) and H O (2 mL) at room temperature. The reaction was warmed at 70° C. for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue was treated with H O and NaHSO was added until pH 6. The solvent was removed under reduced pressure to provide intermediate 15 (500 mg, recovery assumed quantitative), which was used in the next step without further purification.

[0492] LC-MS (ESI): m / z (M+1): 395.2 (Method 1)

[0493] Intermediate 16: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)formamido]ethyl}piperazine-1-carboxylate

[0494] A mixture of intermediate 14 (65 mg, 0.16 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (45 mg, 0.19 mmol), DIPEA (0.11 mL, 0.65 mmol) and HATU (80 mg, 0.21 mmol) in dry DMF (3 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc, then washed with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to produce a yellow oil, which was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O + 0.1% NH4OH to 55% MeCN) to provide intermediate 16 (48 mg, 0.08 mmol, 49% yield) as a yellow solid.

[0495] LC-MS (ESI): m / z (M+1): 606.4 (Method 1)

[0496] Intermediate 17: 4-Chloro-7-[2-(morpholin-4-yl)ethoxy]quinoline

[0497] A mixture of 4-chloro-7-hydroxyquinoline (175 mg, 0.97 mmol), 4-(2-hydroxyethyl)morpholine (153 mg, 1.17 mmol) and PPh3 (383 mg, 1.46 mmol) in dry THF (12 mL) was stirred under nitrogen for 2 minutes, then a solution of diisopropyl azodicarboxylate (0.23 mL, 1.17 mmol) in dry THF (3 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and brine. The aqueous phase was separated and extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in MeOH and loaded onto an SCX column, washed with MeOH and eluted with 1N NH3 in MeOH; the basic fractions were collected to provide intermediate 17 (376 mg, recovery assumed quantitative) as a light red solid, which was not subjected to any further purification.

[0498] LC-MS (ESI): m / z (M+1): 293.2 (Method 1)

[0499] Intermediate 18: tert-Butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperazine-1-carboxylate

[0500] The title compound was prepared following the procedure used for the synthesis of Intermediate 17 starting from 4-chloro-7-hydroxyquinoline (300 mg, 1.67 mmol) and 1-Boc-4-(2-hydroxyethyl)piperazine (423 mg, 1.84 mmol) to provide the title compound (700 mg, recovery assumed quantitative).

[0501] LC-MS (ESI): m / z (M+1): 392.3 (Method 1)

[0502] Intermediate 19: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazine-1-carboxylate

[0503] Intermediate 19 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 18 (159 mg, 0.41 mmol) and Intermediate 3 (70 mg, 0.32 mmol) to provide the title compound (30 mg, 0.05 mmol, 17% yield).

[0504] LC-MS (ESI): m / z (M+1): 579.3 (Method 2)

[0505] Intermediate 20: 4-Chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline

[0506] To a stirred mixture of 4-chloro-7-hydroxyquinoline (150 mg, 0.840 mmol), 3-(4-methylpiperazin-1-yl)propan-1-ol (199 mg, 1.26 mmol) and PPh (329 mg, 1.25 mmol) in THF (5 mL) at 0 ° C. and under an N atmosphere, diisopropyl azodicarboxylate (0.25 mL, 1.27 mmol) was added portionwise, and the resulting reaction mixture was heated to 55 ° C. and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc and concentrated NH4Cl solution. The organic phase was washed with water, brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a BiotageNH silica gel column (from DCM to 3% MeOH) to provide intermediate 20 (172 mg, 0.54 mmol, 64% yield) as an orange oil.

[0507] LC-MS (ESI): m / z (M+1): 320.1 (Method 1)

[0508] Intermediate 21: 4-Chloro-7-[2-(piperazin-1-yl)ethoxy]quinoline

[0509] Intermediate 18 (534 mg, 1.36 mmol) was dissolved in DCM (3.36 mL) and TFA (1.57 mL, 20.44 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX column, washed with MeOH, and eluted with a solution of 4N NH in MeOH; the basic fraction was collected to provide intermediate 21 (340 mg, 1.16 mmol, 86% yield) as a yellow solid.

[0510] LC-MS (ESI): m / z (M+1): 292.1 (Method 1)

[0511] Intermediate 22: 4-Chloro-7-[2-(4-ethylpiperazin-1-yl)ethoxy]quinoline

[0512] To a stirred solution of intermediate 21 (164 mg, 0.56 mmol) in MeOH (3 mL) at 0°C under N2, acetic acid (0.32 mL, 5.62 mmol) and acetaldehyde (0.38 mL, 6.74 mmol) were added. After 5 min, sodium cyanoborohydride (174 mg, 2.81 mmol) was added portionwise, the ice bath was removed, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was then dissolved in DCM and concentrated NaHCO3 solution. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 4% MeOH) to provide intermediate 22 (74 mg, 0.23 mmol, 41% yield).

[0513] LC-MS (ESI): m / z (M+1): 320.1 (Method 1)

[0514] Intermediate 23: 4-Chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline

[0515] The title compound was prepared following the procedure for the synthesis of Intermediate 17 starting from 4-chloro-7-hydroxyquinoline (300 mg, 1.67 mmol) and 1-(2-hydroxyethyl)-4-methylpiperazine (265 mg, 1.84 mmol) to provide the title compound (200 mg, 0.65 mmol, 39% yield).

[0516] LC-MS (ESI): m / z (M+1): 306.1 (Method 1)

[0517] Intermediate 24: tert-Butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate

[0518] Intermediate 24 was prepared following the procedure for the synthesis of Intermediate 17 starting from 4-chloro-7-hydroxyquinoline (250 mg, 1.39 mmol) and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (383 mg, 1.67 mmol) to provide the title compound (320 mg, 0.82 mmol, 59% yield).

[0519] LC-MS (ESI): m / z (M+1): 391.3 (Method 1)

[0520] Intermediate 25: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate

[0521] Intermediate 25 was prepared following the procedure used for the synthesis of Intermediate 13 starting from tert-butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 24, 273 mg, 0.70 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 120 mg, 0.54 mmol) to afford the title compound (130 mg, 0.22 mmol, 42% yield).

[0522] LC-MS (ESI): m / z (M+1): 578.5 (Method 1)

[0523] Intermediate 26: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperidin-4-yl)ethoxy]quinolin-4-amine

[0524] Intermediate 26 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 25, 130 mg, 0.22 mmol) to provide the title compound (106 mg, 0.22 mmol, 98% yield).

[0525] LC-MS (ESI): m / z (M+1): 478.1 (Method 1)

[0526] Intermediate 27: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-methoxyquinolin-4-amine

[0527] Intermediate 27 was prepared following the procedure used for the synthesis of Intermediate 13 starting from 4-chloro-7-methoxyquinoline (484 mg, 2.5 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 480 mg, 2.08 mmol) to provide the title compound (350 mg, 0.92 mmol, 44% yield).

[0528] LC-MS (ESI): m / z (M+1): 381.1 (Method 2)

[0529] Intermediate 28: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol

[0530] A 48% solution of HBr in water (4 mL, 0.78 mmol) was added to intermediate 27 (300 mg, 0.78 mmol). The vial was sealed and the mixture was warmed at 120° C. for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue was treated with water, and the solid was filtered and dried under vacuum to provide intermediate 28 (300 mg, 0.82 mmol, recovery assumed quantitative).

[0531] LC-MS (ESI): m / z (M+1): 367.0 (Method 2)

[0532] Intermediate 29: N-(4-Bromopyridin-2-yl)prop-2-enamide

[0533] A mixture of 4-bromo-2-pyridinamine (1.0 g, 5.78 mmol) and TEA (2.42 mL, 17.34 mmol) in dry DCM (30 mL) was stirred at 0 ° C under nitrogen, and 3-chloropropionyl chloride (807 mg, 6.36 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. Water was added and the organic solution was separated and washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated to produce a red oil, which was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 25% EtOAc) to provide intermediate 29 (990 mg, 4.36 mmol, 75% yield) as a white solid.

[0534] LC-MS (ESI): m / z (M+1): 228.9 (Method 1)

[0535] Intermediate 30: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate

[0536] Intermediate 29 (150 mg, 0.66 mmol) was dissolved in THF (5 mL), tert-butyl 1-piperazinecarboxylate (2701 mg, 1.45 mmol) was added and the reaction solution was stirred at 65° C. for 16 hours. The volatiles were removed under vacuum and the residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to EtOAc) to provide intermediate 30 (125 mg, 0.30 mmol, 46% yield) as a foam.

[0537] LC-MS (ESI): m / z (M+1): 415.2 (Method 1)

[0538] Intermediate 31: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate

[0539] Intermediate 30 (126 mg, 0.30 mmol), Cs2CO3 (200 mg, 0.61 mmol), Xantphos (21 mg, 0.04 mmol) and intermediate 3 (68 mg, 0.30 mmol) were mixed in 1,4-dioxane (4 mL) and degassed with N2 for 5 min, then Pd(OAc)2 (3.44 mg, 0.02 mmol) was added. The resulting reaction mixture was heated at 100 ° C for 12 hours. The solid was filtered, the volatiles were removed under vacuum, and the residue was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O + 0.1% HCOOH to 50% MeCN + 0.1% HCOOH) to provide intermediate 31 (70 mg, 0.13 mmol, 41% yield).

[0540] LC-MS (ESI): m / z (M+1): 556.4 (Method 1)

[0541] Intermediate 32: N-(4-Bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide

[0542] Intermediate 32 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (150 mg, 0.66 mmol) and 1-methylpiperazine (330 mg, 3.30 mmol) to provide the title compound (220 mg, 0.67 mmol, quantitative yield).

[0543] LC-MS (ESI): m / z (M+1): 327.2 (Method 1)

[0544] Intermediate 33: 4-Chloro-6-(5-chloro-2-fluorophenyl)-3-methylpyridazine

[0545] 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 dppf (110 mg, 0.190 mmol) were mixed in 1,4-dioxane (15 mL) / water (5 mL). The mixture was degassed with N2 for 5 min, then Pd(OAc)2 (44 mg, 0.190 mmol) was added and the resulting dark mixture was heated at 60 °C for 1 h. EtOAc and water were added, the product was extracted several times with EtOAc, and the organic phase was collected, dried and evaporated. The residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 15% EtOAc) to provide intermediate 33 (665 mg, 2.59 mmol, 67% yield) as a white solid.

[0546] LC-MS (ESI): m / z (M+1): 257.1 (Method 1)

[0547] Intermediate 34: N-(4-Nitropyridin-2-yl)prop-2-enamide

[0548] To ice-cooled 4-nitropyridine-2-amine (300mg, 2.16mmol) in dry DCM (12mL) solution, TEA (0.9mL, 6.47mmol) and 2-acryloyl chloride (293mg, 3.23mmol) were added. The solution became an orange suspension, which was stirred at 0 ° C for 30min. Water was added, each phase was separated, and the organic phase was dried and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 50% EtOAc) to provide intermediate 34 (150mg, 0.78mmol, 36% yield) as a yellow solid.

[0549] LC-MS (ESI): m / z (M+1): 194.1 (Method 1)

[0550] Intermediate 35: 3-(4-Methylpiperazin-1-yl)-N-(4-nitropyridin-2-yl)propionamide

[0551] Intermediate 35 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 34 (150 mg, 0.78 mmol) and 1-methylpiperazine (172 mg, 1.71 mmol) to provide the title compound (220 mg, 0.75 mmol, 97% yield).

[0552] LC-MS (ESI): m / z (M+1): 294.1 (Method 1)

[0553] Intermediate 36: N-(4-aminopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide

[0554] To a mixture of intermediate 35 (220 mg, 0.75 mmol) and ammonium formate (236 mg, 3.75 mmol) in ethanol (9 mL) was added 10% Pd / C (40 mg, 0.04 mmol), and the mixture was refluxed for 1 h. The mixture was cooled to room temperature and washed with water. The filtrate was concentrated and the residue was suspended in DCM and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum to afford intermediate 36 (120 mg, 0.46 mmol, 61% yield) as an off-white solid.

[0555] LC-MS (ESI): m / z (M+1): 264.1 (Method 2)

[0556] Intermediate 37: N-(4-Bromopyridin-2-yl)-3-(morpholin-4-yl)propanamide

[0557] Intermediate 37 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (60 mg, 0.26 mmol) and morpholine (50 mg, 0.58 mmol) to provide the title compound (64 mg, 0.2 mmol, 77% yield).

[0558] LC-MS (ESI): m / z (M+1): 314.1 (Method 1)

[0559] Intermediate 38 :3-(4-acetylpiperazin-1-yl)-N-(4-bromopyridin-2-yl)propionamide

[0560] Intermediate 38 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (300 mg, 1.1 mmol) and 1-acetylpiperazine (420 mg, 3.29 mmol) to provide the title compound (400 mg, 1.1 mmol, quantitative yield).

[0561] LC-MS (ESI): m / z (M+1): 357.0 (Method 1)

[0562] Intermediate 39: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-3-oxopiperazin-1-yl)propanamide

[0563] Intermediate 39 was prepared following the procedure for the synthesis of Intermediate 30 starting from Intermediate 29 (250 mg, 1 mmol) and 1-methylpiperazin-2-one (252 mg, 2.2 mmol) to provide the title compound (330 mg, 0.97 mmol, 96% yield).

[0564] LC-MS (ESI): m / z (M+1): 341.0 (Method 1)

[0565] Intermediate 40: N-(4-Bromopyridin-2-yl)-3-[methyl(oxetan-3-yl)amino]propanamide

[0566] Intermediate 40 was prepared following the procedure for the synthesis of Intermediate 30 starting from Intermediate 29 (150 mg, 0.66 mmol) and N-methyl-3-aminooxetane (173 mg, 1.98 mmol) to provide the title compound (205 mg, 0.65 mmol, 99% yield).

[0567] LC-MS (ESI): m / z (M+1): 314.1 (Method 1)

[0568] Intermediate 41: N-(4-Bromopyridin-2-yl)-4-chlorobutanamide

[0569] Intermediate 41 was prepared following the procedure for the synthesis of Intermediate 29 starting from 4-bromo-2-pyridinamine (150 mg, 0.87 mmol) and 4-chlorobutyryl chloride (0.11 mL, 0.95 mmol) to afford the title compound (183 mg, 0.66 mmol, 76% yield) as a white solid.

[0570] LC-MS (ESI): m / z (M+1): 279.1 (Method 1)

[0571] Intermediate 42: N-(4-Bromopyridin-2-yl)-4-(morpholin-4-yl)butanamide

[0572] A mixture of intermediate 41 (183 mg, 0.65 mmol), morpholine (0.19 mL, 2.22 mmol), TEA (0.16 mL, 1.13 mmol) and NaI (catalytic amount) in dry toluene (10 mL) was stirred at reflux overnight. The mixture was evaporated to dryness, and the crude material was then partitioned between EtOAc and brine, and the aqueous phase was extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated to provide intermediate 42 (100 mg, 0.30 mmol, 47% yield).

[0573] LC-MS (ESI): m / z (M+1): 328.1 (Method 1)

[0574] Intermediate 43: N-(4-bromopyridin-2-yl)-3-(4-methyl-2-oxopiperazin-1-yl)propanamide

[0575] To a solution of intermediate 29 (140 mg, 0.62 mmol) in THF (7 mL) / DMF (0.80 mL) was added sodium hydroxide (210 mg, 5.25 mmol) at room temperature, followed by 4-methyl-2-piperazinone (196 mg, 1.72 mmol). The reaction mixture was stirred at room temperature overnight. The reactant was diluted with water and extracted 3 times with EtOAc. The organic layer was dried and evaporated under vacuum, and the residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 70% EtOAc) to provide intermediate 43 (96 mg, 0.28 mmol, 71% yield) as a white solid.

[0576] LC-MS (ESI): m / z (M+1): 342.9 (Method 1)

[0577] Intermediate 44: N-(4-Bromopyridin-2-yl)cyclopropanecarboxamide

[0578] 4- bromo-2-pyridinamine (500mg, 2.89mmol) is dissolved in DCM (15mL) and pyridine (0.7mL, 8.67mmol), the mixture is stirred at 0 DEG C under N2 atmosphere, and then cyclopropanecarbonyl chloride (0.31mL, 3.47mmol) is added dropwise. The reaction mixture is stirred for 1h at the same temperature. Water is added and the two phases are separated, the organic phase is dried and evaporated. The residue is purified by flash chromatography on a Biotage silica gel column (from DCM to 30% EtOAc) to provide intermediate 44 (220mg, 0.91mmol, 32% yield) as a white solid.

[0579] LC-MS (ESI): m / z (M+1): 241.2 (Method 1)

[0580] Intermediate 45: N-(4-Bromopyridin-2-yl)-1-methylpiperidine-4-carboxamide

[0581] Intermediate 45 was prepared following the procedure for the synthesis of Intermediate 7 starting from 4-bromo-2-pyridinamine (150 mg, 0.87 mmol) and 1-methylpiperidine-4-carboxylic acid to afford the title compound as a white solid (118 mg, 0.40 mmol, 46% yield).

[0582] LC-MS (ESI): m / z (M+1): 300.0 (Method 1)

[0583] Intermediate 46: N-(4-Nitropyridin-2-yl)cyclopropanecarboxamide

[0584] To the solution of ice-cooled 2-amino-4-nitropyridine (0.26mL, 2.16mmol) in dry pyridine (2.5mL) is added cyclopropanecarbonyl chloride (0.29mL, 3.23mmol). The solution is stirred at room temperature overnight. Water is added, each phase is separated, and the organic phase is dried and evaporated under vacuum. The crude material is purified by flash chromatography on Biotage NH silica gel column (from cyclohexane to 40% EtOAc) to provide intermediate 46 (125mg, 0.60mmol, 28% yield).

[0585] LC-MS (ESI): m / z (M+1): 208.1 (Method 1)

[0586] Intermediate 47: N-(4-Aminopyridin-2-yl)cyclopropanecarboxamide

[0587] To a mixture of intermediate 46 (125 mg, 0.60 mmol) and ammonium formate (190 mg, 3.02 mmol) in ethanol (5 mL) was added 10% Pd / C (32 mg, 0.03 mmol), and the mixture was stirred at reflux for 30 minutes. The mixture was cooled to room temperature and washed with water. The filtrate was concentrated and the residue was suspended in DCM and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum to afford intermediate 47 (57 mg, 0.32 mmol, 53% yield) as an off-white solid.

[0588] LC-MS (ESI): m / z (M+1): 178.1 (Method 1)

[0589] Intermediate 48: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)carbamate

[0590] At room temperature under N2, DPPA (369 mg, 1.34 mmol) was added dropwise to a stirred mixture of intermediate 15 (300 mg, 0.74 mmol) and TEA (196 mg, 1.94 mmol) in tert-butanol (4 mL). The reactants were warmed at 95 ° C for 4 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on a Biotage silica gel column (from DCM to 3% MeOH) to provide intermediate 48 (60 mg, 0.13 mmol, 17% yield).

[0591] LC-MS (ESI): m / z (M+1): 466.1 (Method 2)

[0592] Intermediate 49: N4-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]quinoline-4,7-diamine

[0593] A 4N solution of HCl in dioxane (1.0 mL, 32.91 mmol) was added to a stirred solution of intermediate 48 (60 mg, 0.13 mmol) in MeOH at room temperature. After 3 hours, the solvent was removed under vacuum. The residue was treated with water and extracted with EtOAc. The aqueous phase was treated with NH4OH and extracted with DCM. The organic layer was separated, dried and evaporated under vacuum to provide intermediate 49 (35 mg, 0.1 mmol, 74% yield).

[0594] LC-MS (ESI): m / z (M+1): 366.1 (Method 2)

[0595] Intermediate 50: 5-{[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl]amino}pyridine-2-carbonitrile

[0596] A mixture of 5-amino-2-pyridinecarbonitrile (10 g, 83.95 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.1 g, 83.95 mmol) and triethyl orthoformate (80.0 mL, 480.97 mmol) was stirred at reflux (145 ° C, external temperature) for 5 hours. The mixture was allowed to reach room temperature and filtered. The solid was washed with EtOH and dried under vacuum to provide intermediate 50 (16.32 g, 60 mmol, 71% yield) as a dark yellow solid, which was used as is.

[0597] LC-MS (ESI): m / z (M+1): 274.2 (Method 1)

[0598] Intermediate 51: 8-Oxo-5,8-dihydro-1,5-naphthyridine-2-carbonitrile

[0599] In a flask equipped with a condenser, intermediate 50 (4 g, 14.35 mmol) was added portionwise to Dowtherm A (90.0 mL, 14.35 mmol) at 220 ° C under stirring and N2 atmosphere, and the resulting reaction mixture was stirred at the same temperature for 10 min. The mixture was allowed to reach room temperature, then Et2O (80 mL) was added and the mixture thus obtained was filtered. The solid was washed with MeOH and filtered. The solid was discarded, the solution was concentrated under vacuum, and the crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 3% MeOH) to provide intermediate 51 (331 mg, 1.93 mmol, 13% yield).

[0600] LC-MS (ESI): m / z (M+1): 172.0 (Method 1)

[0601] Intermediate 52: 8-Bromo-1,5-naphthyridine-2-carbonitrile

[0602] To a stirred solution of intermediate 51 (425 mg, 2.46 mmol) in DMF (4.52 mL) was added tribromophosphine (0.3 mL, 3.21 mmol) dropwise at 0°C under N2, the ice bath was removed, and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled at 0°C, and MeOH (2 mL) was slowly added, followed by a 1N aqueous solution of NaOH. The pH of the mixture was then brought to approximately 8-9 by the addition of concentrated NaHCO3 solution. The mixture was concentrated under vacuum to remove MeOH, and then extracted twice with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 60% EtOAc) to provide intermediate 52 (415 mg, 1.77 mmol, 72% yield) as a white solid.

[0603] LC-MS (ESI): m / z (M+1): 236.0 (Method 1)

[0604] Intermediate 53: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1,7-naphthyridine-6-carbonitrile

[0605] In a suitable vial, to a mixture of intermediate 3 (340 mg, 1.54 mmol), intermediate 52 (407 mg, 1.74 mmol), Xantphos (142 mg, 0.24 mmol), Pd2(dba)3 (16 mg, 0.18 mmol) and sodium tert-butoxide (309 mg, 3.2 mmol) was added 1,4-dioxane (8.8 mL), the bottle was sealed and subjected to a microwave cycle at 140 ° C for 45 min. The reaction mixture was concentrated, triturated with MeOH and filtered, and the solid was discarded; the methanol solution was concentrated. The crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 12% MeOH) to provide intermediate 53 (203 mg, 0.54 mmol, 35% yield) as a yellow solid.

[0606] LC-MS (ESI): m / z (M+1): 377.1 (Method 1)

[0607] Intermediate 54: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1,7-naphthyridine-6-carboxylic acid

[0608] To a solution of intermediate 53 (375 mg, 1 mmol) in MeOH (8 mL) was added 1N aqueous NaOH solution (8 mL, 8 mmol) at room temperature, and the resulting reaction mixture was stirred at 70 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and 6N aqueous HCl was added until the pH was about 2-3. The mixture was filtered. The solid was dried under vacuum. The material was washed with DCM, the mixture was filtered and the solid was dried under vacuum to provide intermediate 54 (278 mg, 0.70 mmol, 71% yield) as a light yellow solid, which was used as is.

[0609] LC-MS (ESI): m / z (M+1): 396.2 (Method 1)

[0610] Intermediate 55: Methyl 4-bromoquinoline-6-carboxylate

[0611] 4-Bromoquinoline-6-carboxylic acid (150 mg, 0.60 mmol) was suspended in MeOH (5 mL) and THF (5 mL), which was then cooled with an ice bath and a 2 M solution of (trimethylsilyl)diazomethane in EtO (2 mL, 1.19 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and the volatiles were then removed under vacuum to provide intermediate 55 (170 mg, 0.64 mmol, quantitative yield), which was used as is.

[0612] LC-MS (ESI): m / z (M+1): 268.0 (Method 1)

[0613] Intermediate 56: Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate

[0614] Intermediate 56 was prepared following the procedure for the synthesis of Intermediate 31 starting from Intermediate 55 (171 mg, 0.64 mmol) and Intermediate 3 (120 mg, 0.54 mmol) to afford the title compound (90 mg, 0.22 mmol, 41% yield) as a yellow solid.

[0615] LC-MS (ESI): m / z (M+1): 409.2 (Method 1)

[0616] Intermediate 57: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate

[0617] Intermediate 57 was prepared following the procedure used for the synthesis of Intermediate 6 starting from Intermediate 56 (50 mg, 0.12 mmol) to provide the title compound (50 mg, 0.12 mmol, quantitative yield).

[0618] LC-MS (ESI): m / z (M+1): 395.3 (Method 1)

[0619] Intermediate 58: tert-Butyl N-[3-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)propyl]-N-methylcarbamate

[0620] Intermediate 58 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (300 mg, 1.32 mmol) and 3-(N-Boc-N-methylamino)propylamine (622 mg, 3.3 mmol) to provide the title compound (420 mg, 1.0 mmol, 77% yield).

[0621] LC-MS (ESI): m / z (M+1): 417.1 (Method 1)

[0622] Intermediate 59: tert-Butyl N-[3-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)propyl]-N-methylcarbamate

[0623] Di-tert-Butyl dicarbonate (137 mg, 0.63 mmol) was added to a solution of intermediate 58 (200 mg, 0.48 mmol) and TEA (0.1 mL, 0.72 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 4 hours, and then the volatiles were removed under vacuum, and the residue was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 45% EtOAc) to provide intermediate 59 (210 mg, 0.41 mmol, 85% yield) as a white foam.

[0624] LC-MS (ESI): m / z (M+1): 517.2 (Method 1)

[0625] Intermediate 60: tert-Butyl N-(3-{[(tert-Butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl})amino}propyl)-N-methylcarbamate

[0626] Intermediate 60 was prepared following the procedure used for the synthesis of Intermediate 31 starting from Intermediate 59 (209 mg, 0.41 mmol) and Intermediate 3 (85 mg, 0.37 mmol) to provide the title compound (70 mg, 0.11 mmol, 29% yield).

[0627] LC-MS (ESI): m / z (M+1): 659.4 (Method 1)

[0628] Intermediate 61: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-{[3-(methylamino)propyl]amino}propionamide

[0629] Intermediate 61 was prepared following the procedure used for the synthesis of Intermediate 21 from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl})amino}propyl)-N-methylcarbamate (Intermediate 60, 70 mg, 0.1 mmol) to afford the title compound (60 mg, yield assumed quantitative).

[0630] LC-MS (ESI): m / z (M+1): 458.1 (Method 1)

[0631] Intermediate 62: N-(4-Bromopyridin-2-yl)-3-(4-methylsulfonylpiperazin-1-yl)propanamide

[0632] Intermediate 62 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 1-methylsulfonylpiperazine (289 mg, 1.76 mmol) to provide the title compound (190 mg, 0.49 mmol, 55% yield).

[0633] LC-MS (ESI): m / z (M+1): 393.0 (Method 1)

[0634] Intermediate 63: 6-[2-Fluoro-5-(propan-2-yl)phenyl]pyridazin-4-amine

[0635] A mixture of 6-chloropyridazin-4-amine (200 mg, 1.54 mmol), Pd(dppf)Cl2 DCM (109 mg, 0.15 mmol) and (2-fluoro-5-isopropylphenyl)boronic acid (421 mg, 2.32 mmol) in MeCN (8 mL) and water (3 mL) was degassed with N2 for 2 minutes, then KF (228 mg, 3.86 mmol) was added and the mixture was irradiated with microwaves (110 ° C, 3 hours). After cooling, the mixture was treated with water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on a Biotage NH silica gel column (100% EtOAc) to provide intermediate 63 (290 mg, 1.25 mmol, 81% yield).

[0636] LC-MS (ESI): m / z (M+1): 232 (Method 1)

[0637] Intermediate 64: 6-(5-chloro-2-fluorophenyl)-N-[2-(4-methylpiperazine-1-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]pyridazin-4-amine

[0638] Intermediate 64 was prepared following the procedure used for the synthesis of Intermediate 11 starting from Intermediate 10 (70 mg, 0.13 mmol) and 1-methylpiperazine (16 mg, 0.16 mmol) to provide the title compound (46 mg, 0.08 mmol, 57% yield).

[0639] LC-MS (ESI): m / z (M+1): 596.3 (Method 1)

[0640] Intermediate 66: 2-Hydroxy-1-(4-methylpiperazin-1-yl)ethan-1-one

[0641] In a suitable flask, 1-methylpiperazine (2.9 mL, 26.15 mmol) was added to a mixture of 2-hydroxyethyl ester (3.09 mL, 32.66 mmol) in 1,4-dioxane (5 mL). The flask was sealed and the reaction mixture was stirred at 120 ° C overnight. The mixture was allowed to reach room temperature and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 4% MeOH) to provide intermediate 66 (642 mg, 4.06 mmol, 12% yield) as a thick colorless oil.

[0642] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.16 (s, 2H), 3.66-3.75 (m, 2H), 3.25-3.34 (m, 2H), 2.41 (q, J=5.06 Hz, 4H), 2.32 (s, 3H).

[0643] Intermediate 67: 2-[(4-chloroquinolin-7-yl)oxy]-1-(4-methylpiperazin-1-yl)ethan-1-one

[0644] Intermediate 67 was prepared following the procedure for the synthesis of Intermediate 20 starting from 4-chloro-7-hydroxyquinoline (300 mg, 1.67 mmol) and Intermediate 66 (396 mg, 2.5 mmol) to provide the title compound (402 mg, 1.26 mmol, 75% yield).

[0645] LC-MS (ESI): m / z (M+1): 320.1 (Method 1)

[0646] Intermediate 68: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0647] Intermediate 68 was prepared following the procedure for the synthesis of Intermediate 11 starting from Intermediate 10 (70 mg, 0.13 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (24 mg, 0.15 mmol) to provide the title compound (60 mg, 0.09 mmol, 72% yield).

[0648] LC-MS (ESI): m / z (M+1): 653.4 (Method 1)

[0649] Intermediate 69:4-Chloro-7-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}quinoline

[0650] In a vial, to a solution of intermediate 21 (100 mg, 0.34 mmol) in THF (2 mL) was added DIPEA (0.18 mL, 1.03 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.07 mL, 0.52 mmol) at room temperature. The bottle was sealed and shaken at 50 ° C overnight. The solvent was removed under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX, washed with MeOH and eluted with a solution of 1N NH3 in MeOH. The basic fraction was collected and evaporated to provide intermediate 69 (83 mg, 0.22 mmol, 65% yield) as a white solid, which was used as is.

[0651] LC-MS (ESI): m / z (M+1): 374.1 (Method 1)

[0652] Intermediate 70: tert-Butyl N-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-N-methylcarbamate

[0653] Intermediate 70 was prepared following the procedure used for the synthesis of Intermediate 20 starting from 4-chloro-7-hydroxyquinoline (300 mg, 1.67 mmol) and 1,1-dimethylethyl (2-hydroxyethyl)methylcarbamate (450 mg, 2.57 mmol) to afford the title compound (653 mg, recovery assumed quantitative).

[0654] LC-MS (ESI): m / z (M+1): 337.2 (Method 1)

[0655] Intermediate 71: {2-[(4-chloroquinolin-7-yl)oxy]ethyl}(methyl)amine

[0656] Intermediate 71 was prepared following the procedure for the synthesis of Intermediate 21 starting from Intermediate 70 (653 mg, 1.93 mmol) to provide the title compound (365 mg, 1.54 mmol, 79% yield).

[0657] LC-MS (ESI): m / z (M+1): 237.1 (Method 1)

[0658] Intermediate 72: N-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-N-methyloxetan-3-amine

[0659] Intermediate 72 was prepared following the procedure for the synthesis of Intermediate 22 starting from Intermediate 71 (180 mg, 0.76 mmol) and 3-oxetanone (165 mg, 2.29 mmol) to provide the title compound (168 mg, 0.57 mmol, 75% yield).

[0660] LC-MS (ESI): m / z (M+1): 293.1 (Method 1)

[0661] Intermediate 73: tert-Butyl N-(3-acetamidopropyl)carbamate

[0662] TEA (0.96 mL, 6.89 mmol) and acetyl acetate (0.59 mL, 6.31 mmol) were added to a solution of tert-butyl N-(3-aminopropyl)carbamate (1.0 g, 5.74 mmol) in DCM (28.7 mL). The mixture was stirred for 1 h, then the volatiles were removed under vacuum, and the residue was partitioned between EtOAc and saturated NH4Cl solution, the phases were separated, and the organic phase was washed with saturated NaHCO3 solution and then evaporated to provide tert-butyl N-(3-acetamidopropyl)carbamate (1.1 g, 5.09 mmol, 89% yield).

[0663] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.24 (br. s., 1H), 4.91 (br. s., 1H), 3.30 (q, J = 6.31 Hz, 2H), 3.13-3.24 (m, 2H), 2.01 (s, 3H), 1.63 (quintet, J = 6.22 Hz, 2H), 1.43-1.46 (s, 9H).

[0664] Intermediate 74: N-(3-Azoniapropyl)acetamide chloride

[0665] 4N HCl in 1,4-dioxane (11.44 mL, 45.77 mmol) was added dropwise to an ice-cold solution of Intermediate 73 (1.1 g, 5.09 mmol) in 1,4-dioxane (8 mL). The mixture was stirred at room temperature for 72 hours, and then the volatiles were removed under vacuum to provide Intermediate 74 (990 mg, recovery assumed quantitative).

[0666] 1 H NMR (400MHz, DMSO-d6) δppm 7.87-8.14 (m, 4H), 3.09 (q, J = 6.60Hz, 2H), 2.71-2.84 (m, 2H), 1.82 (s, 3H), 1.63-1.73 (m, 2H).

[0667] Intermediate 75: N-(4-Bromopyridin-2-yl)-3-[(3-acetamidopropyl)amino]propionamide

[0668] Intermediate 75 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (250 mg, 1.10 mmol) and Intermediate 74 (168 mg, 1.10 mmol) to provide the title compound (150 mg, 0.44 mmol, 40% yield).

[0669] LC-MS (ESI): m / z (M+1): 345.0 (Method 1)

[0670] Intermediate 76: tert-Butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-acetamidopropyl)carbamate

[0671] Intermediate 76 was prepared following the procedure used for the synthesis of Intermediate 59 starting from Intermediate 75 (150 mg, 0.44 mmol) to provide the title compound (100 mg, 0.23 mmol, 52% yield).

[0672] LC-MS (ESI): m / z (M+1): 444.2 (Method 1)

[0673] Intermediate 77: tert-Butyl N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-N-(3-acetamidopropyl)carbamate

[0674] Intermediate 77 was prepared following the procedure used for the synthesis of Intermediate 31 starting from Intermediate 76 (130 mg, 0.29 mmol) and Intermediate 3 (65 mg, 0.29 mmol) to provide the title compound (60 mg, 0.10 mmol, 35% yield).

[0675] LC-MS (ESI): m / z (M+1): 588.2 (Method 2)

[0676] Intermediate 78: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(3-acetamidopropyl)amino]propionamide

[0677] Intermediate 78 was prepared following the procedure used for the synthesis of Intermediate 21 starting from Intermediate 77 (60 mg, 0.1 mmol) to provide the title compound (40 mg, 0.08 mmol, 80% yield).

[0678] LC-MS (ESI): m / z (M+1): 486.0 (Method 2)

[0679] Intermediate 79: tert-Butyl N-(3-methylsulfonylaminopropyl)carbamate

[0680] Tert-butyl N-(3-aminopropyl)carbamate (1.0 g, 5.74 mmol) was dissolved in THF (20 mL) and cooled with an ice bath, TEA (1.6 mL, 11.48 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (0.58 mL, 7.46 mmol). A precipitate was observed. The mixture was allowed to reach room temperature and stirred for 2 hours, water and EtOAc were added, the phases were separated, the organic phase was washed with saturated NH4Cl solution, then with saturated NaHCO3 solution, dried and evaporated to provide intermediate 79 (1.1 g, 4.36 mmol, 76% yield).

[0681] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.31 (br. s., 1H), 4.74 (br. s., 1H), 3.28 (q, J = 6.38 Hz, 2H), 3.15-3.22 (m, 2H), 2.94-2.99 (m, 3H), 1.73 (quintet, J = 6.11 Hz, 2H), 1.41-1.49 (m, 9H).

[0682] Intermediate 80: N-(3-Azoniapropyl)methanesulfonamide chloride

[0683] Intermediate 80 was prepared following the procedure used for the synthesis of Intermediate 74 starting from Intermediate 79 (1.1 g, 4.36 mmol) to provide the title compound (910 mg, recovery assumed quantitative).

[0684] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (br. s., 3H), 7.16 (t, J = 6.05 Hz, 1H), 2.97-3.08 (m, 2H), 2.91 (s, 3H), 2.76-2.88 (m, 2H), 1.77 (quintet, J = 7.21 Hz, 2H)

[0685] Intermediate 81: N-(4-Bromopyridin-2-yl)-3-[(3-methanesulfonylaminopropyl)amino]propionamide

[0686] Intermediate 81 was prepared following the procedure used for the synthesis of Intermediate 30 starting from Intermediate 29 (250 mg, 1.10 mmol) and Intermediate 80 (312 mg, 1.65 mmol) to provide the title compound (400 mg, 1.05 mmol, 95% yield).

[0687] LC-MS (ESI): m / z (M+1): 381.0 (Method 1)

[0688] Intermediate 82: tert-Butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-methanesulfonylaminopropyl)carbamate

[0689] Intermediate 82 was prepared following the procedure for the synthesis of Intermediate 59 starting from Intermediate 81 (400 mg, 1.05 mmol) to provide the title compound (310 mg, 0.65 mmol, 61% yield).

[0690] LC-MS (ESI): m / z (M+1): 481.0 (Method 1)

[0691] Intermediate 83: tert-Butyl N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-N-(3-methanesulfonylaminopropyl)carbamate

[0692] Intermediate 83 was prepared following the procedure for the synthesis of Intermediate 31 starting from Intermediate 82 (260 mg, 0.54 mmol) and Intermediate 3 (110 mg, 0.49 mmol) to provide the title compound (130 mg, 0.21 mmol, 42% yield).

[0693] LC-MS (ESI): m / z (M+1): 622.2 (Method 2)

[0694] Intermediate 84: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(3-methanesulfonylaminopropyl)amino]propanamide

[0695] Intermediate 84 was prepared following the procedure used for the synthesis of Intermediate 21 starting from Intermediate 83 (130 mg, 0.21 mmol) to provide the title compound (80 mg, 0.15 mmol, 73% yield).

[0696] LC-MS (ESI): m / z (M+1): 522.2 (Method 2)

[0697] Intermediate 85:4-Bromo-N-[3-(4-methylpiperazin-1-yl)propyl]pyridin-2-amine

[0698] KCO (707 mg, 5.11 mmol) was added to a mixture of 3-(4-methylpiperazin-1-yl)propan-1-amine (0.44 mL, 2.56 mmol) and 4-bromo-2-fluoropyridine (300 mg, 1.7 mmol) in DMSO (3 mL). The resulting mixture was stirred at 90 ° C overnight. The next day, the mixture was allowed to reach room temperature, the solid was filtered off and discarded, and the crude material was purified by reverse phase flash chromatography on a Biotage C18 column (from H O + 0.1% NH OH to 90% MeCN) to provide intermediate 85 (320 mg, 1.02 mmol, 60% yield).

[0699] LC-MS (ESI): m / z (M+1): 315.2 (Method 2)

[0700] Intermediate 86: tert-Butyl N-(4-bromopyridin-2-yl)-N-[3-(4-methylpiperazin-1-yl)propyl]carbamate

[0701] Under N2, a 1N solution of bis(trimethylsilyl)lithium amide in THF (1.23mL, 1.23mmol) was added dropwise to an ice-cooled solution of intermediate 85 (320mg, 1.02mmol) in THF (6mL). After stirring at the same temperature for 10min, di-tert-butyl dicarbonate (268mg, 1.23mmol) was added and the reactants were allowed to reach room temperature and stirred for 5 hours. Conversion did not end, so another 1N solution of bis(trimethylsilyl)lithium amide in THF (1.23mL) was added, followed by di-tert-butyl dicarbonate (267mg) after 5min. The mixture was stirred at room temperature overnight. The next day, conversion did not end, so another 1N solution of bis(trimethylsilyl)lithium amide in THF (2.46mL) was added, followed by di-tert-butyl dicarbonate (540mg) after 5min. The reaction mixture was stirred at room temperature for 24 hours. Water and EtOAc were added, the product was extracted with EtOAc (3 times), the organic layer was collected, dried and evaporated. The crude material was purified by flash chromatography on a Biotage NH silica gel column (from cyclohexane to 5% MeOH in EtOAc) to provide intermediate 86 (210 mg, 0.51 mmol, 50% yield).

[0702] Intermediate 87: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-N-[3-(4-methylpiperazin-1-yl)propyl]carbamate

[0703] Intermediate 87 was prepared following the procedure used for the synthesis of Intermediate 13 starting from Intermediate 86 (203 mg, 0.49 mmol) and Intermediate 3 (10 mg, 0.45 mmol) to provide the title compound (58 mg, 0.10 mmol, 23% yield).

[0704] LC-MS (ESI): m / z (M+1): 556.3 (Method 2)

[0705] Intermediate 88 :N-(4-bromopyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propionamide

[0706] Intermediate 88 was prepared following the procedure for the synthesis of Intermediate 30 starting from Intermediate 29 (300 mg, 1.1 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (200 mg, 1.19 mmol) to provide the title compound (220 mg, 0.56 mmol, 63%).

[0707] LC-MS (ESI): m / z (M+1): 397.0 (Method 1)

[0708] Intermediate 89: 2-(Trimethylsilyl)ethyl carbamate

[0709] 1,1'-carbonyldiimidazole (9.9g, 60.9mmol) is added to a stirred suspension of 2-(trimethylsilyl)ethanol (6.0g, 50.7mmol) in dry toluene (50mL). The reactant is stirred at room temperature for 5 hours, then an ammonium hydroxide solution (28% NH4OH solution in water, 10mL) is added. The mixture is stirred vigorously overnight. Each phase is separated, the organic phase is washed with salt water, then filtered through a phase separator and concentrated under vacuum. The residue is dissolved in EtOAc, washed with salt water (5x), then filtered and evaporated to provide intermediate 89 (7.5g, 46.5mmol, 92% yield) as a colorless oil, which solidifies after cooling.

[0710] 1 H 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).

[0711] Intermediate 90: 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine

[0712] Method A

[0713] Step 1: 4,6-dichloro-3-methylpyridazine (400 mg, 2.45 mmol) was added to a stirred solution of ammonium hydroxide solution (28% NH4OH in water, 3 mL) in 1,4-dioxane (3 mL) at room temperature. The vial was sealed and the reactants were heated at 90 ° C for 40 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Biotage NH silica gel column (EtOAc) to provide 6-chloro-3-methylpyridazine-4-amine (210 mg).

[0714] Step 2: A mixture of PdCl2(PPh3)2DCM (50 mg, 0.07 mmol), KF (115 mg, 1.95 mmol), (5-chloro-2-fluorophenyl)boronic acid (170 mg, 0.97 mmol) in MeCN (8 mL) and H2O (2 mL) was degassed with N2 for 2 minutes, followed by addition of 6-chloro-3-methylpyridazin-4-amine (110 mg, 0.77 mmol), and microwave irradiation of the mixture (110 ° C, 1 h 15 min). After cooling, the mixture was treated with water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 3% MeOH) to provide 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (100 mg, 0.42 mmol, 55% yield).

[0715] Method B

[0716] In a suitable vial, 4-chloro-6-(5-chloro-2-fluorophenyl)-3-methylpyridazine (Intermediate 33 (500 mg, 1.94 mmol), 2-trimethylsilylethyl carbamate (Intermediate 89, 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), bubbled with N2 for 2 min, then Pd2(dba)3 (184 mg, 0.20 mmol) was added and the vial was sealed and microwaved at 100°C for 5 h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 15% The product was purified by 4% EtOAc) to provide 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. It was allowed to reach room temperature and loaded onto an SCX column (20 g), washed with MeOH and eluted with a solution of 1N NH3 in MeOH. The basic fraction was collected and evaporated, and the residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 3% MeOH) to provide intermediate 90 (170 mg, 0.71 mmol, 37% yield).

[0717] LC-MS (ESI): m / z (M+1): 228.0 (Method 1)

[0718] Intermediate 91: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester

[0719] Intermediate 91 was prepared following the procedure used for the synthesis of Intermediate 9 starting from Intermediate 5 (284 mg, 0.83 mmol) and Intermediate 90 (210 mg, 0.75 mmol) to provide the title compound (100 mg, 0.18 mmol, 25% yield).

[0720] LC-MS (ESI): m / z (M+1): 542.2 (Method 1)

[0721] Intermediate 92: Lithium 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0722] Intermediate 92 was prepared following the procedure used for the synthesis of Intermediate 10 starting from Intermediate 91 (100 mg, 0.18 mmol) to provide the title compound (90 mg, 0.17 mmol, 94% yield).

[0723] LC-MS (ESI): m / z (M+1): 528.1 (Method 1)

[0724] Intermediate 93: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-yl

[0725] Intermediate 93 was prepared following the procedure for the synthesis of Intermediate 11 starting from Intermediate 92 (45 mg, 0.08 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (16 mg, 0.11 mmol) to provide the title compound (40 mg, 0.06 mmol, 73% yield).

[0726] LC-MS (ESI): m / z (M+1): 653.3 (Method 2)

[0727] Intermediate 94: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0728] Intermediate 94 was prepared following the procedure used for the synthesis of Intermediate 11 starting from Intermediate 92 (45 mg, 0.08 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (17 mg, 0.11 mmol) to provide the title compound (60 mg, recovery assumed quantitative).

[0729] LC-MS (ESI): m / z (M+1): 667.4 (Method 1)

[0730] Intermediates of comparative compounds

[0731] Intermediate 95: tert-Butyl N-[(tert-Butoxy)carbonyl]-N-(4-chloropyrimidin-2-yl)carbamate

[0732] A mixture of 4-chloro-2-pyrimidinamine (200 mg, 1.54 mmol) and DMAP (38 mg, 0.31 mmol), TEA (0.04 mL, 0.31 mmol) and di-tert-butyl dicarbonate (674 mg, 3.09 mmol) in DCM (8 mL) was stirred at room temperature for 3 hours. The volatiles were removed under vacuum and the residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 20% EtOAc) to provide intermediate 95 (500 mg, 1.52 mmol, 98% yield) as a white wax.

[0733] LC-MS (ESI): m / z (M+1): 330.3 (Method 1)

[0734] Intermediate 96: tert-Butyl N-[(tert-Butoxy)carbonyl]-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyrimidin-2-yl)carbamate

[0735] Intermediate 96 was prepared following the procedure for the synthesis of Intermediate 31 starting from Intermediate 95 (113 mg, 0.34 mmol) and Intermediate 3 (70 mg, 0.31 mmol) to afford the title compound as a white solid (30 mg, 0.06 mmol, 18% yield).

[0736] LC-MS (ESI): m / z (M+1): 517.4 (Method 1)

[0737] Intermediate 97: 2-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine

[0738] 2-chloro-1H-imidazo[4,5-b]pyridine (200mg, 1.3mmol) was suspended in THF (8mL) under N2 and DIPEA (0.68mL, 3.91mmol) was added, followed by 2-(chloromethoxy)ethyl-trimethylsilane (0.3mL, 1.69mmol). The reaction mixture was stirred at reflux for 4 hours. It was then allowed to reach room temperature, water and EtOAc were added, the product was extracted several times with EtOAc, the organic phase was collected, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 100% EtOAc) to provide intermediate 97 (180mg, 0.63mmol 49% yield) as an oil.

[0739] LC-MS (ESI): m / z (M+1): 284.2 (Method 1)

[0740] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.40 (dd, J = 4.8, 1.3 Hz, 1H), 7.99 (dd, J = 8.0, 1.4 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 5.71 (s, 2H), 3.61-3.72 (m, 2H), 0.91-1.00 (m, 2H), -0.05 (s, 9H).

[0741] Intermediate 98: 6-(5-chloro-2-fluorophenyl)-N-(3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-2-yl)pyridazin-4-amine

[0742] Intermediate 98 was prepared following the procedure for the synthesis of Intermediate 31 starting from Intermediate 97 (113 mg, 0.40 mmol) and Intermediate 3 (70 mg, 0.31 mmol) to afford the title compound (35 mg, 0.07 mmol, 24% yield) as a yellow solid.

[0743] LC-MS (ESI): m / z (M+1): 471.4 (Method 1)

[0744] Intermediate 99: tert-Butyl N-{4-[(6-chloropyridazin-4-yl)amino]pyridin-2-yl}carbamate

[0745] A mixture of 6-chloropyridazine-4-amine (600 mg, 4.63 mmol), tert-butyl 4-bromopyridin-2-ylcarbamate (1.52 g, 5.56 mmol) and sodium tert-butoxide (0.94 g, 9.73 mmol) in dry 1,4-dioxane (16 mL) was degassed with N2 for 2 minutes, followed by the addition of Xantphos (400 mg, 0.69 mmol) and Pd2(dba)3 (0.42 mg, 0.46 mmol). The resulting mixture was microwaved at 105 ° C for 1 h. Conversion was complete, so the mixture was suspended in MeOH and the insoluble solid was filtered off. The solution was evaporated and purified by flash chromatography on a Biotage NH silica gel column (from DCM to 3% MeOH) to provide intermediate 99 (256 mg, 0.8 mmol, 17% yield).

[0746] LC-MS (ESI): m / z (M+1): 322.2 (Method 1)

[0747] Intermediate 100: Methyl 3-{5-[(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)amino]pyridazin-3-yl}-2-fluorobenzoate

[0748] K2CO3 (77 mg, 0.56 mmol) was added to a stirred mixture of intermediate 99 (70 mg, 0.21 mmol), Pd(PPh3)4 (32.3 mg, 0.030 mmol) and (2-fluoro-3-methoxycarbonylphenyl)boronic acid (83 mg, 0.42 mmol) in 1,2-dimethoxyethane (4 mL) / H2O (0.500 mL). The mixture was degassed with N2. The vial was sealed and warmed at 90°C for 3 hours. After cooling, the solvent was removed under reduced pressure. The residue was treated with H2O and extracted with EtOAc. The organic layer was separated, dried and evaporated. The residue was purified by flash chromatography on a Biotage silica gel column (from DCM to 3% MeOH) to provide intermediate 100 (25 mg, 0.06 mmol, 20% yield).

[0749] LC-MS (ESI): m / z (M+1): 440.1 (Method 2)

[0750] Intermediate 101: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide

[0751] A 48% solution of HBr in water (10.1 mL, 89.29 mmol) was added to N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-methoxyquinolin-4-amine (Intermediate 27, 850 mg, 2.23 mmol). The vial was sealed and the mixture was stirred at 120 ° C for 48 hours. After cooling, the aqueous solution was evaporated to complete dryness, the residue was suspended in DCM / MeOH and the white solid was collected by filtration to provide the first batch. The mother liquor was evaporated, the residue was triturated with DCM and filtered again to provide a second batch, which was mixed with the first batch to provide 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (785 mg, 1.75 mmol, y=79%).

[0752] LC-MS (ESI): m / z (M+1): 367.0 (Method 2)

[0753] Intermediate 102: Ethyl N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate

[0754] At 0 ° C under N2, ethyl chloroformate (470 mg, 4.33 mmol) was added dropwise to a stirred solution of 2- (1-methylpiperidin-4-yl) ethane-1-amine (560 mg, 3.94 mmol) and TEA (0.6 mL, 4.33 mmol) in dry THF (10 mL). After 20 minutes, the reactant was warmed and stirred at room temperature for 1 hour, and then the solvent was removed by reduced pressure. The residue was dissolved in DCM and the organic phase was washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 2% MeOH) to provide N- [2- (1-methylpiperidin-4-yl) ethyl] ethyl carbamate (450 mg, 2.1 mmol, y = 53%).

[0755] LC-MS (ESI): m / z (M+1): 215.1 (Method 2)

[0756] Intermediate 103 :Methyl[2-(1-methylpiperidin-4-yl)ethyl]amine

[0757] A solution of ethyl N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate (Intermediate 102, 440 mg, 2.05 mmol) in dry THF (10 mL) was added dropwise to a stirred solution of 2M LiAlH4 in THF (2.57 mL, 5.13 mmol) at room temperature under N2. The reaction was stirred at reflux for 3 hours. The mixture was allowed to reach room temperature and then cooled at 0-5°C before adding 0.2 ml of a solution of water in THF, followed by 0.3 ml of a 15% NaOH solution and 0.2 ml of a solution of water in THF. The mixture was warmed and stirred at room temperature for 30 min before it was allowed to stand for 1 h. Filtered over a pad of Celite®. The solvent was removed by reduced pressure to provide methyl[2-(1-methylpiperidin-4-yl)ethyl]amine (300 mg, 1.92 mmol, y = 93%), which was used in the next step without further purification.

[0758] LC-MS (ESI): m / z (M+1): 157.1 (Method 1)

[0759] Intermediate 104: tert-Butyl N-[3-(Methanesulfonyloxy)propyl]-N-methylcarbamate

[0760] Intermediate 104 was prepared following the procedure used for the synthesis of Intermediate 79 starting from tert-butyl (3-hydroxypropyl)(methyl)carbamate (1 g, 6.28 mmol) to provide the title compound (1.32 g, 4.94 mmol, y = 93%).

[0761] LC-MS (ESI): m / z (M+1): 268.1 (Method 1)

[0762] Intermediate 105: tert-Butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate

[0763] In a vial, to a solution of tert-butyl N-[3-(methylsulfonyloxy)propyl]-N-methylcarbamate (intermediate 104, 650 mg, 2.43 mmol) in MeCN (5 mL) was added 3-amino-1-propanol (0.93 mL, 12.16 mmol), the bottle was sealed and stirred at 70 ° C for 9 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and the organic solution was washed with saturated NaHCO solution, water, dried over Na SO and filtered. The solvent was removed under reduced pressure to provide tert-butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate (487 mg, 1.98 mmol, y=81%) as a colorless thick oil, which was used as is.

[0764] LC-MS (ESI): m / z (M+1): 247.5 (Method 1)

[0765] Intermediate 106 : tert-Butyl N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)-N-(3-hydroxypropyl)carbamate

[0766] Intermediate 106 was prepared following the procedure used for the synthesis of Intermediate 59 starting from tert-butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate (Intermediate 105, 485 mg, 1.97 mmol) to provide the title compound (780 mg, recovery assumed quantitative).

[0767] LC-MS (ESI): m / z (M+1): 347.3 (Method 1)

[0768] Intermediate 107: tert-Butyl N-(3-bromopropyl)-N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)carbamate

[0769] To a stirred solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)-N-(3-hydroxypropyl)carbamate (intermediate 106, 380 mg, 1.1 mmol) and PPh3(433 mg, 1.65 mmol) in DCM (15 mL) was added portionwise CBr4(546 mg, 1.65 mmol) in DCM (3 mL) at 0 ° C and under N2 atmosphere. The resulting reaction mixture was stirred at 0 ° C for 1 hour. The mixture was concentrated under reduced pressure, and the crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 30% EtOAc) to provide tert-butyl N-(3-bromopropyl)-N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)carbamate (196 mg, 0.48 mmol, y=44% yield) as a colorless thick oil.

[0770] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.38-3.48 (m, 2H), 3.34 (t, J = 6.93 Hz, 2H), 3.22 (d, J = 7.04 Hz, 4H), 2.87 (s, 3H), 2.06-2.20 (m, 2H), 1.71-1.85 (m, 2H), 1.43-1.54 (m, 18H).

[0771] Intermediate 108: tert-Butyl N-(3-{[(tert-Butoxy)carbonyl]({3-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]propyl})amino}propyl)-N-methylcarbamate

[0772] To a mixture of 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol (Intermediate 28, 320 mg, 0.87 mmol) and KCO (274 mg, 1.98 mmol) in DMF (8 mL) was added tert-butyl N-(3-bromopropyl)-N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)carbamate (Intermediate 107, 321 mg, 0.78 mmol) in a vial at room temperature. The vial was sealed and stirred at 50°C for 3 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was further diluted with EtOAc, washed twice with water, and the organic phase was dried over NaSO, filtered, and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica gel column (DCM to 3% MeOH) to afford tert-butyl N-(3-{[(tert-butoxy)carbonyl]({3-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]propyl})amino}propyl)-N-methylcarbamate as a light yellow foam (149 mg, 0.21 mmol, y = 27%).

[0773] LC-MS (ESI): m / z (M+1): 695.3 (Method 1)

[0774] Intermediate 109: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(3-{[3-(methylamino)propyl]amino}propoxy)quinolin-4-amine

[0775] Intermediate 109 was prepared following the procedure used for the synthesis of Intermediate 21 from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({3-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]propyl})amino}propyl)-N-methylcarbamate (Intermediate 108, 149 mg, 0.21 mmol) to afford the title compound (121 mg, recovery assumed quantitative).

[0776] LC-MS (ESI): m / z (M+1): 495.2 (Method 2)

[0777] Intermediate 110: cis-5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0778] To a mixture of cis-2-boc-hexahydropyrrolo[3,4-c]pyrrole (250 mg, 1.18 mmol) and K2CO3 (162.76 mg, 1.18 mmol) in MeCN (3.5 mL) in a vial was added 2-bromoethanol (0.08 mL, 1.18 mmol) at room temperature, the vial was sealed and stirred at 80°C overnight.

[0779] The reaction mixture was filtered, washed with EtOAC.The solution was evaporated under vacuum to afford cis-5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (320 mg, recovery assumed quantitative) which was used as is.

[0780] LC-MS (ESI): m / z (M+1): 256.8 (Method 2)

[0781] Intermediate 111: cis-5-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0782] Intermediate 111 was prepared following the procedure used for the synthesis of Intermediate 17 starting from 4-chloro-7-hydroxyquinoline (150 mg, 0.83 mmol) and cis-tert-butyl 5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (Intermediate 110, 320 mg, 1.18 mmol) to afford the title compound (700 mg, recovery assumed quantitative).

[0783] LC-MS (ESI): m / z (M+1): 418.2 (Method 1)

[0784] Intermediate 112: cis-5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0785] In a suitable microwave vial, to a mixture of cis-tert-butyl 5-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (Intermediate 111, 560 mg, 0.54 mmol), 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 120 mg, 0.54 mmol), CsCO (356 mg, 1.09 mmol), Xantphos (45 mg, 0.08 mmol) and Pd(dba) (54 mg, 0.06 mmol) was added 1,4-dioxane (4 mL). The vial was sealed and microwave cycled at 130°C for 50 min. The solid was filtered, washed with EtOAc, the filtrate was evaporated under vacuum, and the crude material was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O + 0.1% NH4OH to 70% MeCN) to afford cis 5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (90 mg, 0.15 mmol, 28% yield).

[0786] LC-MS (ESI): m / z (M+1): 605.3 (Method 2)

[0787] Intermediate 113: cis-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{octahydropyrrolo[3,4-c]pyrrol-2-yl}ethoxy)quinolin-4-amine

[0788] Intermediate 113 was prepared following the procedure used for the synthesis of Intermediate 21 starting from cis 5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (Intermediate 112, 90 mg, 0.15 mmol) to provide the title compound (45 mg, 0.09 mmol, y = 60%).

[0789] LC-MS (ESI): m / z (M+1): 505.2 (Method 2)

[0790] Intermediate 114: 4-Chloro-7-(2-chloroethoxy)quinoline

[0791] To a mixture of 4-chloro-7-hydroxyquinoline (200 mg, 1.11 mmol) and KCO (308 mg, 2.23 mmol) in DMF (3.5 mL) was added 1-bromo-2-chloroethane (0.37 mL, 4.45 mmol) in a vial at room temperature. The vial was sealed and stirred at 60°C for 3 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was diluted with water, extracted with EtOAc, and the organic phase was washed with water, dried over NaSO, and filtered. The solvent was removed under reduced pressure to provide 4-chloro-7-(2-chloroethoxy)quinoline (229 mg, 0.95 mmol, y=85%) as a pale yellow solid, which was used as is.

[0792] LC-MS (ESI): m / z (M+1): 242.0 (Method 1)

[0793] Intermediate 115: tert-Butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]carbamate

[0794] In tubular flask, to 4- chloro- 7- (2- chloroethoxy) quinoline (intermediate 114,183mg, 0.76mmol) in 1,2- dimethoxyethane (8mL) solution, add N- (3- aminopropyl) t-butyl carbamate (1.32g, 7.58mmol), then add NaI (114mg, 0.76mmol), the bottle is sealed and stirred at 85 DEG C for 24 hours.Reactant mixture is concentrated under reduced pressure, and residue is purified by flash chromatography on Biotage NH silica gel column (from cyclohexane to 70% EtOAc).Suitable fraction is purified again by flash chromatography on Biotage silica gel column (from DCM to 15% MeOH) to provide N- [3- ({ 2- [(4- chloroquinoline -7- bases) epoxide] ethyl} amino) propyl group] t-butyl carbamate (222mg, 0.58mmol, 77% yield) as light orange oil.

[0795] LC-MS (ESI): m / z (M+1): 380.1 (Method 1)

[0796] Intermediate 116: (3-Aminopropyl)({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amine

[0797] Intermediate 116 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]carbamate (Intermediate 115, 222 mg, 0.58 mmol) to provide the title compound (132 mg, 0.47 mmol, 81% yield).

[0798] LC-MS (ESI): m / z (M+1): 280.0 (Method 2)

[0799] Intermediate 117: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)carbamate

[0800] Intermediate 117 was prepared following the procedure used for the synthesis of Intermediate 59 starting from (3-aminopropyl)({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amine (Intermediate 116, 133 mg, 0.48 mmol) to afford the title compound (255 mg, recovery assumed quantitative).

[0801] LC-MS (ESI): m / z (M+1): 480.2 (Method 1)

[0802] Intermediate 118: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}propyl)carbamate

[0803] Intermediate 118 was prepared following the procedure used for the synthesis of Intermediate 112 starting from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)carbamate (Intermediate 117, 50 mg, 0.10 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 28 mg, 0.12 mmol) to provide the title compound (24 mg, 0.04 mmol, y = 34%).

[0804] LC-MS (ESI): m / z (M+1): 667.3 (Method 1)

[0805] Intermediate 119: 7-{2-[(3-aminopropyl)amino]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine

[0806] Intermediate 119 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}propyl)carbamate (Intermediate 118, 24 mg, 0.04 mmol) to afford the title compound (21 mg, recovery assumed quantitative).

[0807] LC-MS (ESI): m / z (M+1): 467.2 (Method 2)

[0808] Intermediate 120: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1,3-diazinan-1-yl)ethoxy]quinolin-4-amine

[0809] To a solution of 7-{2-[(3-aminopropyl)amino]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine (Intermediate 119, 21 mg, 0.04 mmol) in MeOH (0.8 mL) was added a 37% w / w solution of formaldehyde in water (0.02 mL, 0.22 mmol) in a vial at room temperature. The vial was sealed and stirred at 50° C. for 1.5 h. The mixture was concentrated under reduced pressure to afford N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1,3-diazinan-1-yl)ethoxy]quinolin-4-amine (22 mg, recovery assumed quantitative) as a thick yellow oil, which was used as is.

[0810] LC-MS (ESI): m / z (M+1): 479.3 (Method 2)

[0811] Intermediate 121: 1-{2-[(tert-Butyldiphenylsilyl)oxy]ethyl}piperazine

[0812] A solution of tert-butyl-chloro-diphenylsilane (2.53 g, 9.22 mmol) in DCM (10 mL) was added dropwise to a stirred solution of 2-(1-piperazinyl)ethanol (1.0 g, 7.68 mmol), pyridine (0.93 mL, 11.52 mmol) and DMAP (93.8 mg, 0.77 mmol) in DCM (20 mL) at 5 ° C. The reaction was warmed and stirred at room temperature for 10 hours. The mixture was washed with water, and the organic layer was separated, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography on a BiotageNH silica gel column (from DCM to 3% MeOH) to provide 1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine (2.2 g, 5.97 mmol, y = 77%)

[0813] LC-MS (ESI): m / z (M+1): 368.7 (Method 2)

[0814] Intermediate 122: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine-1-carboxylate

[0815] 1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine (intermediate 121, 413 mg, 1.12 mmol) in THF (5.47 mL) was added dropwise to a stirred mixture of triphosgene (334.8 mg, 1.13 mmol) in MTBE (5.47 mL) at 0°C under N2. After 1 hour, the solvent was evaporated. The solid was treated with MTBE and filtered. The recovered solid was quickly added to a mixture of 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (intermediate 101, 200 mg, 0.45 mmol) and K2CO3 (317 mg, 2.29 mmol) in dry DMF (4.1 mL). The mixture was stirred at room temperature overnight. The reactant was poured into ice-cold water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 5% MeOH / 0.5% H2O) to afford 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine-1-carboxylate (120 mg, 0.16 mmol, y = 35%)

[0816] LC-MS (ESI): m / z (M+1): 761.5 (Method 2)

[0817] Intermediate 123 :tert-Butyl N-{3-[(2,2,2-trifluoroethyl)amino]propyl}carbamate

[0818] Intermediate 123 was prepared following the procedure used for the synthesis of Intermediate 69 starting from tert-butyl N-(3-aminopropyl)carbamate (500 mg, 2.87 mmol) to afford the title compound (840 mg, recovery assumed quantitative).

[0819] LC-MS (ESI): m / z (M+1): 257.1 (Method 2)

[0820] Intermediate 124 :tert-Butyl N-{3-[N-(2,2,2-trifluoroethyl)acetylamino]propyl}carbamate

[0821] Intermediate 124 was prepared following the procedure for the synthesis of Intermediate 73 starting from tert-butyl N-{3-[(2,2,2-trifluoroethyl)amino]propyl}carbamate (Intermediate 123, 2.87 mmol) to provide the title compound (810 mg, 2.71 mmol, y = 94%).

[0822] LC-MS (ESI): m / z (M+1): 299.1 (Method 2)

[0823] Intermediate 125: (3-Aminopropyl)(2,2,2-trifluoroethyl)amine dihydrochloride

[0824] TFA (0.83 mL, 10.86 mmol) was added to a solution of tert-butyl N-{3-[N-(2,2,2-trifluoroethyl)acetamido]propyl}carbamate (intermediate 124, 450 mg, 1.5 mmol) in DCM (4 mL) and stirred at room temperature overnight. Volatiles were removed under vacuum to provide a sticky solid. The residue was dissolved in EtOH (5 mL), 6N HCl (3.0 mL, 18.02 mmol) was added, and the resulting mixture was refluxed for 36 hours. The volatiles were removed under vacuum, and the residue was dried to provide (3-aminopropyl)(2,2,2-trifluoroethyl)amine dihydrochloride (230 mg, 1 mmol, y = 67%).

[0825] LC-MS (ESI): m / z (M+1): 157.4 (Method 2)

[0826] Intermediate 126: N-(4-Bromopyridin-2-yl)-3-({3-[(2,2,2-trifluoroethyl)amino]propyl}amino)propanamide

[0827] Intermediate 126 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 228 mg, 1 mmol), (3-aminopropyl)(2,2,2-trifluoroethyl)amine dihydrochloride (Intermediate 125, 230 mg, 1 mmol) and TEA (0.7 mL, 5 mmol) to afford the title compound (230 mg, 0.6 mmol, 60% yield).

[0828] LC-MS (ESI): m / z (M+1): 383.1 (Method 1)

[0829] Intermediate 127: tert-Butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)carbamate

[0830] Intermediate 127 was prepared following the procedure for the synthesis of Intermediate 59 starting from N-(4-bromopyridin-2-yl)-3-({3-[(2,2,2-trifluoroethyl)amino]propyl}amino)propanamide (Intermediate 126, 200 mg, 0.52 mmol) to provide the title compound (150 mg, 0.26 mmol, 50% yield).

[0831] LC-MS (ESI): m / z (M+1): 585.2 (Method 1)

[0832] Intermediate 128: tert-Butyl N-(3-{[(tert-Butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)-N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}carbamate

[0833] Intermediate 128 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)carbamate (Intermediate 127, 150 mg, 0.26 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 58 mg, 0.26 mmol) to afford the title compound (55 mg, 0.08 mmol, 29% yield).

[0834] LC-MS (ESI): m / z (M+1): 726.2 (Method 1)

[0835] Intermediate 129: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-({3-[(2,2,2-trifluoroethyl)amino]propyl}amino)propanamide

[0836] Intermediate 129 was prepared following the procedure used for the synthesis of Intermediate 21 from tert-butyl N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)-N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}carbamate (Intermediate 128, 55 mg, 0.08 mmol) to afford the title compound (40 mg, recovery assumed quantitative).

[0837] LC-MS (ESI): m / z (M+1): 526.3 (Method 2)

[0838] Intermediate 130: 7-(2-bromoethoxy)-4-chloroquinoline

[0839] Intermediate 130 was prepared following the procedure for the synthesis of Intermediate 114 starting from 4-chloro-7-hydroxyquinoline (200 mg, 1.11 mmol) and 1,2-dibromoethane (0.59 mL, 6.85 mmol) to provide the title compound (158 mg, 0.55, y=50%).

[0840] LC-MS (ESI): m / z (M+1): 288.0 (Method 1)

[0841] Intermediate 131: tert-Butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]-N-methylcarbamate

[0842] To a suspension of 7-(2-bromoethoxy)-4-chloroquinoline (Intermediate 130, 136 mg, 0.47 mmol) and KCO (138 mg, 1 mmol) in MeCN (4 mL) in a vial was added tert-butyl N-(3-aminopropyl)-n-methylcarbamate (449 mg, 2.38 mmol). The vial was sealed and stirred at 70°C for 5 hours. The reaction mixture was diluted with MeCN and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed twice with water and brine, dried over NaSO, filtered, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica gel column (DCM to 4% MeOH) to afford tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]-N-methylcarbamate (152 mg, 0.39 mmol, y = 81%) as a colorless oil.

[0843] LC-MS (ESI): m / z (M+1): 394.2 (Method 1)

[0844] Intermediate 132: tert-Butyl N-(3-{[(tert-Butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate

[0845] To a stirred solution of tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]-N-methylcarbamate (Intermediate 131, 152 mg, 0.38 mmol) in DCM (2 mL) was added portionwise a solution of di-tert-butyl dicarbonate (103 mg, 0.47 mmol) in DCM (1 mL) at room temperature and the resulting mixture was allowed to stand overnight. The mixture was diluted with DCM, the solution was washed with saturated NaHCO solution, dried over NaSO, filtered, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 50% EtOAc) to afford tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate (180 mg, 0.36 mmol, y = 95%) as a colorless thick oil.

[0846] LC-MS (ESI): m / z (M+1): 495.7 (Method 2)

[0847] Intermediate 133: tert-Butyl N-(3-{[(tert-Butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate

[0848] Intermediate 133 was prepared following the procedure used for the synthesis of Intermediate 112 starting from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate (Intermediate 132, 150 mg, 0.30 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 82 mg, 0.37 mmol) to provide the title compound (89 mg, 0.13 mmol, y = 43%).

[0849] LC-MS (ESI): m / z (M+1): 681.5 (Method 2)

[0850] Intermediate 134: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{[3-(methylamino)propyl]amino}ethoxy)quinolin-4-amine

[0851] Intermediate 134 was prepared starting from tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate (Intermediate 133, 89 mg, 0.13 mmol) following the procedure used for the synthesis of Intermediate 21 to afford the title compound (62 mg, recovery assumed quantitative).

[0852] LC-MS (ESI): m / z (M+1): 481.2 (Method 2)

[0853] Intermediate 135: tert-Butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate

[0854] To an ice-cooled solution of tert-butyl 4-(2-hydroxyethyl)-1-piperidincarboxylate (1g, 4.36mmol) in DCM (10.9mL), TEA (1.22mL, 8.72mmol) and 4-methylbenzenesulfonyl chloride (1.08mL, 5.67mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated NaHCO solution (3x), filtered through a phase separator and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 40% EtOAc) to provide tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate (1.60g, 4.19mmol, y=96%) as a colorless oil.

[0855] LC-MS (ESI): m / z (M+1): 384.2 (Method 2)

[0856] Intermediate 136: Benzyl 4-(2-{1-[(tert-Butoxy)carbonyl]piperidin-4-yl}ethyl)piperazine-1-carboxylate

[0857] A mixture of tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 135, 1.16 g, 2.72 mmol) and benzyl piperazine-1-carboxylate (500 mg, 2.27 mmol) was dissolved in dry MeCN (22.7 mL), TEA (3.16 mL, 22.7 mmol) was added and the reaction was stirred overnight at 80° C. The volatiles were removed under vacuum, and the crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 10% MeOH) to provide benzyl 4-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}ethyl)piperazine-1-carboxylate (580 mg, 1.34 mmol, y=59%).

[0858] LC-MS (ESI): m / z (M+1): 432.3 (Method 2)

[0859] Intermediate 137: Benzyl 4-[2-(piperidin-4-yl)ethyl]piperazine-1-carboxylate

[0860] Intermediate 137 was prepared following the procedure used for the synthesis of Intermediate 21 starting from benzyl 4-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}ethyl)piperazine-1-carboxylate (Intermediate 136, 289 mg, 0.67 mmol) to provide the title compound (130 mg, 0.39 mmol, y = 59%).

[0861] 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.45 (m, 5H), 5.14 (s, 2H), 3.47-3.56 (m, 4H), 3.02-3.20 (m, 2H), 2.63 (td, J = 12.27, 2.53 Hz, 2H), 2.30-2.50 (m, 6H), 1.64-1.77 (m, 2H), 1.33-1.60 (m, 3H), 1.10-1.32 (m, 2H)

[0862] Intermediate 138: Benzyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate

[0863] Intermediate 138 was prepared following the procedure used for the synthesis of Intermediate 22 starting from benzyl 4-[2-(piperidin-4-yl)ethyl]piperazine-1-carboxylate (Intermediate 137, 250 mg, 0.75 mmol) and 37% w / w formaldehyde in water (0.41 mL, 9.65 mmol) to afford the title compound (258 mg, 0.75 mmol, recovery assumed quantitative).

[0864] 1 H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.51 (m, 5H), 5.14 (s, 2H), 3.46-3.56 (m, 4H), 2.71-2.91 (m, 2H), 2.30-2.43 (m, 6H), 2.25 (s, 3H), 1.80-1.96 (m, 2H), 1.63-1.70 (m, 2H), 1.38-1.47 (m, 2H), 1.20-1.33 (m, 3H)

[0865] Intermediate 139: 1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine

[0866] Ammonium formate (282.9 mg, 4.49 mmol) was added to a stirred mixture of benzyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate (Intermediate 138, 310 mg, 0.90 mmol) and 5% Pd on carbon (191 mg, 0.09 mmol) in isopropanol (10 mL) at room temperature under N2. The reaction was warmed at 80°C for 1 hour. After cooling, the mixture was stirred at 40°C for 1 hour. The mixture was filtered over a pad of 4-nitropropene and the organic solvent was removed under reduced pressure. The residue was treated with water and NaHCO 3 was added until pH 8. The water was evaporated. The residue was treated with DCM / MeOH and the solid was discarded. The organic solvent was removed under reduced pressure to provide 1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine (170 mg, 0.80 mmol, y=90%), which was used without further purification.

[0867] 1 H NMR(400MHz,DMSO-d6)δppm 2.71(d,J=3.08Hz,1H),2.62-2.70(m,5H),2.22(dd,J=8.72,6.39Hz,5H),2.11(s,3H),1.78(td,J=1 1.20, 2.35Hz, 2H), 1.54-1.63 (m, 2H), 1.27-1.37 (m, 2H), 1.15 (d, J = 2.75Hz, 1H), 1.04-1.14 (m, 2H).

[0868] Intermediate 140: N-(4-Bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide

[0869] A solution of N-(4-bromopyridin-2-yl)-4-chlorobutanamide (Intermediate 41, 100 mg, 0.35 mmol), TEA (0.15 mL, 1.05 mmol) and 1-methylpiperazine (0.38 mL, 3.49 mmol) in THF (5.5 mL) was stirred at 70° C. for 24 hours. The volatiles were removed under vacuum, and the crude material was purified by reverse phase flash chromatography on a Biotage C18 column (from H 2 O + 0.1% NH 4 OH to 50% MeCN) to provide N-(4-bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide (100 mg, 0.29 mmol, y=84%) as a light yellow oil.

[0870] LC-MS (ESI): m / z (M+1): 343.1 (Method 1)

[0871] Intermediate 141: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]carbamate

[0872] A mixture of 2-(Boc-amino)ethyl bromide (54 mg, 0.24 mmol), N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine (Example 9, 110 mg, 0.23 mmol) and KCO (48 mg, 0.34 mmol) in dry DMF (3 mL) was stirred at 55 ° C for 24 hours. The mixture was treated with saturated NH4Cl solution and then diluted with brine. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated to give an orange oil, which was purified by flash chromatography on a Biotage silica gel column (from DCM to 2% MeOH) to afford tert-butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]carbamate (100 mg, 0.16 mmol, y = 70%) as a red oil.

[0873] LC-MS (ESI): m / z (M+1): 622.9 (Method 2)

[0874] Intermediate 142: tert-Butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate

[0875] 1-Methylpiperazine (163 mg, 1.63 mmol) and a catalytic amount of NaI were added to a stirred solution of KCO (346 mg, 2.5 mmol) and tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 135, 480 mg, 1.25 mmol) in dry MeCN (16 mL) at room temperature. The reaction was stirred at 70 ° C for 10 hours. After cooling, the mixture was poured into cold water and extracted with EtOAc. The organic layer was separated, dried over NaSO, filtered, and evaporated. The residue was purified by flash chromatography on a Biotage silica gel column (from DCM to 5% MeOH) to provide tert-butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate (290 mg, 0.93 mmol, y = 74%).

[0876] LC-MS (ESI): m / z (M+1): 312.3 (Method 1)

[0877] Intermediate 143: 1-Methyl-4-[2-(piperidin-4-yl)ethyl]piperazine

[0878] Intermediate 143 was prepared following the procedure used for the synthesis of Intermediate 49 starting from tert-butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate (Intermediate 142, 290 mg, 0.93 mmol) to provide the title compound (190 mg, 0.9 mmol, y = 96%).

[0879] LC-MS (ESI): m / z (M+1): 212.2 (Method 1)

[0880] Intermediate 144: tert-Butyl 4-[(4-chloroquinolin-7-yl)oxy]piperidine-1-carboxylate

[0881] The title compound was prepared according to the procedure used for the synthesis of Intermediate 17 starting from 4-chloro-7-hydroxyquinoline (250 mg, 1.39 mmol) and tert-butyl 4-hydroxy-1-piperidincarboxylate (308 mg, 1.53 mmol) to provide the title compound (430 mg, 1.19 mmol, y = 85%).

[0882] LC-MS (ESI): m / z (M+1): 363.3 (Method 1)

[0883] Intermediate 145: tert-Butyl 4-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]piperidine-1-carboxylate

[0884] Intermediate 145 was prepared following the procedure used for the synthesis of Intermediate 9 starting from tert-butyl 4-[(4-chloroquinolin-7-yl)oxy]piperidine-1-carboxylate (Intermediate 144, 316 mg, 0.67 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 150 mg, 0.67 mmol) to afford the title compound (230 mg, 0.42 mmol, 62% yield).

[0885] LC-MS (ESI): m / z (M+1): 550.3 (Method 1)

[0886] Intermediate 146: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(piperidin-4-yloxy)quinolin-4-amine

[0887] Intermediate 146 was prepared following the procedure used for the synthesis of Intermediate 49 starting from tert-butyl 4-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]piperidine-1-carboxylate (Intermediate 145, 230 mg, 0.42 mmol) to provide the title compound (129 mg, 0.29 mmol, y = 69%).

[0888] LC-MS (ESI): m / z (M+1): 450.2 (Method 2)

[0889] Intermediate 147: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate

[0890] Intermediate 147 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate (Intermediate 30, 96 mg, 0.23 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 50 mg, 0.21 mmol) to afford the title compound (90 mg, 0.16 mmol, 75% yield).

[0891] LC-MS (ESI): m / z (M+1): 5760.3 (Method 2)

[0892] Intermediate 148: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate

[0893] In room temperature by N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazine-4-yl] amino}pyridin-2-yl)-3-(piperazine-1-yl) propionamide (embodiment 74,54mg, 0.11mmol) solution in DMF (0.57mL) is processed with N-(2-bromoethyl) tert-butyl carbamate (77mg, 0.34mmol) and TEA (0.09mL, 0.69mmol).The mixture is stirred at room temperature for 60 hours.The reactant is quenched with saturated NaHCO solution and diluted with saline.The mixture is extracted with EtOAc (x3), filtered using phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage NH silica gel (from DCM to 2% MeOH) and then by flash chromatography on Biotage silica gel (from EtOAc to 50% MeOH) to afford tert-butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate (49 mg, 0.08 mmol, 69% yield) as an off-white solid.

[0894] LC-MS (ESI): m / z (M+1): 613.5 (Method 2)

[0895] Intermediate 149: N-(4-Bromopyridin-2-yl)-3-[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]propanamide

[0896] Intermediate 149 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 233 mg, 1.03 mmol), (3-ethoxyazetidin-3-yl)methanol hydrochloride (206 mg, 1.23 mmol) and TEA (0.29 mL, 2.05 mmol) to afford the title compound (325 mg, 0.91 mmol, 88% yield).

[0897] LC-MS (ESI): m / z (M+1): 358.1 (Method 1)

[0898] Intermediate 150: N-[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-methoxyquinolin-4-amine

[0899] Intermediate 150 was prepared following the procedure used for the synthesis of Intermediate 13 starting from 4-chloro-7-methoxyquinoline (139 mg, 0.72 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 150 mg, 0.6 mmol) to afford the title compound (170 mg, 0.43 mmol, 72% yield).

[0900] LC-MS (ESI): m / z (M+1): 395.1 (Method 1)

[0901] Intermediate 151: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-ol hydrobromide

[0902] Intermediate 151 was prepared following the procedure used for the synthesis of Intermediate 101 starting from N-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-methoxyquinolin-4-amine (Intermediate 150, 140 mg, 0.35 mmol) to afford the title compound (170 mg, recovery assumed quantitative).

[0903] LC-MS (ESI): m / z (M+1): 381.1 (Method 2)

[0904] Intermediate 152: N-(4-Bromopyridin-2-yl)-3-[4-(2-methylsulfonylethyl)piperazin-1-yl]propionamide

[0905] Intermediate 152 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), 1-(2-methylsulfonylethyl)piperazine dihydrochloride (350 mg, 1.5 mmol) and TEA (0.49 mL, 4 mmol) to afford the title compound (316 mg, 0.65 mmol, 86% yield).

[0906] LC-MS (ESI): m / z (M+1): 421.0 (Method 2)

[0907] Intermediate 153: N-(4-Bromopyridin-2-yl)-2,2,2-trichloroacetamide

[0908] At 0 ° C, a solution of 4-bromo-2-pyridinamine (780mg, 4.51mmol) and TEA (0.69mL, 4.96mmol) in THF (23.1mL) was treated with 2,2,2-trichloroacetyl chloride (0.48mL, 4.28mmol). The mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature for 4 hours. The mixture was cooled to 0 ° C and carefully quenched with water, and then quenched with saturated NaHCO3 solution. The mixture was extracted with EtOAc, dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage NH silica gel (from cyclohexane to 100% EtOAc) to provide N- (4-bromopyridin-2-yl) -2,2,2-trichloroacetamide (1.10g, 3.45mmol, 77% yield) as a white solid.

[0909] LC-MS (ESI): m / z (M+1): 318.8 (Method 1)

[0910] Intermediate 154: N-(4-Bromopyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0911] A mixture of N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (intermediate 153, 200 mg, 0.63 mmol), commercially available 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (147 mg, 0.69 mmol) in DMSO (4.2 mL) and Na2CO3 (233 mg, 2.2 mmol) was stirred at 100 ° C for 2.5 hours. The mixture was treated with saturated NaHCO3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage NH silica gel (from DCM to 5% MeOH) to provide N-(4-bromopyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxamide (90 mg, 0.265 mmol, 42% yield) as a colorless oil.

[0912] LC-MS (ESI): m / z (M+1): 341.1 (Method 2)

[0913] Intermediate 155: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamate

[0914] Intermediate 155 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-bromopyridin-2-ylcarbamate (125 mg, 0.46 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 100 mg, 0.42 mmol) to afford the title compound (89 mg, 0.21 mmol, 50% yield).

[0915] LC-MS (ESI): m / z (M+1): 430.2 (Method 1)

[0916] Intermediate 156 :N4-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]pyridine-2,4-diamine

[0917] Intermediate 156 was prepared according to the procedure used for the synthesis of Intermediate 21 starting from tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamate (Intermediate 155, 89 mg, 0.21 mmol) to provide the title compound (42 mg, 0.13 mmol, y = 62%).

[0918] LC-MS (ESI): m / z (M+1): 330.1 (Method 1)

[0919] Intermediate 157:1,5-Dimethyl 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)pentanedioate

[0920] To a solution of N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine (Example 9, 150 mg, 0.31 mmol) in MeOH (1.8 mL) in a vial was added (E)-dimethyl pent-2-enedioate (0.32 mL, 2.26 mmol), the vial was sealed and stirred overnight at 70° C. The mixture was concentrated under reduced pressure, and the crude material was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 2% MeOH) to afford 1,5-dimethyl 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)pentanedioate (85 mg, 0.13 mmol, y=42%) as a light yellow solid.

[0921] LC-MS (ESI): m / z (M+1): 637.8 (Method 2)

[0922] Intermediate 158: 4-Chloro-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline

[0923] Intermediate 158 was prepared following the procedure for the synthesis of Intermediate 20 starting from 4-chloro-6-methoxyquinolin-7-ol (500 mg, 2.39 mmol) and 1-(2-hydroxyethyl)-4-methylpiperazine (447 mg, 3.1 mmol) to provide the title compound (198 mg, 0.58 mmol, 25% yield).

[0924] LC-MS (ESI): m / z (M+1): 336.2 (Method 1)

[0925] Intermediate 159: N-(4-Bromopyridin-2-yl)-2-chloroacetamide

[0926] 2-Chloroacetyl chloride (0.25mL, 3.18mmol) was added dropwise to a solution of 4-bromo-2-pyridinamine (500mg, 2.89mmol) and TEA (1.21mL, 8.67mmol) in dry DCM (14.45mL) at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine. The organic phase was filtered through a phase separator and evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 10% EtOAc) to provide N-(4-bromopyridin-2-yl)-2-chloroacetamide (470mg, 1.88mmol, y=65%) as an off-white solid.

[0927] LC-MS (ESI): m / z (M+1): 249.0 (Method 2)

[0928] Intermediate 160: tert-Butyl 4-{[(4-chloroquinolin-7-yl)oxy]methyl}piperidine-1-carboxylate

[0929] Intermediate 160 was prepared following the procedure for the synthesis of Intermediate 17 starting from 4-chloro-6-methoxyquinolin-7-ol (150 mg, 0.83 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (198 mg, 0.92 mmol) to afford the title compound (280 mg, 0.74 mmol, 89% yield).

[0930] LC-MS (ESI): m / z (M+1): 377.2 (Method 1)

[0931] Intermediate 161: tert-Butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]methyl}piperidine-1-carboxylate

[0932] Intermediate 161 was prepared following the procedure used for the synthesis of Intermediate 9 starting from tert-butyl 4-{[(4-chloroquinolin-7-yl)oxy]methyl}piperidine-1-carboxylate (Intermediate 161, 241 mg, 0.64 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 130 mg, 0.58 mmol) to afford the title compound (310 mg, 0.55 mmol, 95% yield).

[0933] LC-MS (ESI): m / z (M+1): 564.3 (Method 1)

[0934] Intermediate 162: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(piperidin-4-yl)methoxy]quinolin-4-amine

[0935] Intermediate 162 was prepared according to the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]methyl}piperidine-1-carboxylate (Intermediate 161, 282 mg, 0.42 mmol) to provide the title compound (190 mg, 0.41 mmol. y = 96%).

[0936] LC-MS (ESI): m / z (M+1): 464.2 (Method 2)

[0937] Intermediate 163: tert-Butyl N-[2-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)ethyl]-N-methylcarbamate

[0938] Intermediate 163 was prepared following the procedure used for the synthesis of Intermediate 131 starting from 7-(2-bromoethoxy)-4-chloroquinoline (Intermediate 130, 100 mg, 0.35 mmol) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (305 mg, 1.75 mmol) to afford the title compound (140 mg, recovery assumed quantitative).

[0939] LC-MS (ESI): m / z (M+1): 380.2 (Method 1)

[0940] Intermediate 164: tert-Butyl N-(2-{[(tert-Butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate

[0941] Intermediate 164 was prepared following the procedure used for the synthesis of Intermediate 132 starting from tert-butyl N-[2-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)ethyl]-N-methylcarbamate (Intermediate 163, 140 mg, 0.37 mmol) to afford the title compound (18 mg, recovery assumed quantitative).

[0942] LC-MS (ESI): m / z (M+1): 681.5 (Method 2)

[0943] Intermediate 165: tert-Butyl N-(2-{[(tert-Butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate

[0944] Intermediate 165 was prepared following the procedure used for the synthesis of Intermediate 112 starting from tert-butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate (Intermediate 164, 176 mg, 0.31 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 67 mg, 0.30 mmol) to provide the title compound (135 mg, 0.20 mmol, y = 68%).

[0945] LC-MS (ESI): m / z (M+1): 667.5 (Method 2)

[0946] Intermediate 166: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{[2-(methylamino)ethyl]amino}ethoxy)quinolin-4-amine

[0947] Intermediate 166 was prepared following the procedure used for the synthesis of Intermediate 21 from tert-butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate (Intermediate 165, 135 mg, 0.20 mmol) to afford the title compound (100 mg, recovery assumed quantitative).

[0948] LC-MS (ESI): m / z (M+1): 467.3 (Method 2)

[0949] Intermediate 167 :2-Methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1,2-dicarboxylate 1-tert-butyl ester

[0950] Intermediate 167 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.65 mmol) and 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (288 mg, 1.18 mmol) to afford the title compound (248 mg, 0.53 mmol, 80% yield).

[0951] LC-MS (ESI): m / z (M+1): 471.1 (Method 1)

[0952] Intermediate 168: 2-Methyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1,2-dicarboxylate

[0953] Intermediate 168 was prepared following the procedure used for the synthesis of Intermediate 31 starting from 1-tert-butyl 2-methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1,2-dicarboxylate (Intermediate 167, 109 mg, 0.23 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 50 mg, 0.21 mmol) to afford the title compound (110 mg, 0.17 mmol, 83% yield).

[0954] LC-MS (ESI): m / z (M+1): 628.4 (Method 2)

[0955] Intermediate 169 : tert-Butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)ethyl]-N-methylcarbamate

[0956] Intermediate 169 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (288 mg, 1.65 mmol) to afford the title compound (240 mg, 0.6 mmol, 90% yield).

[0957] LC-MS (ESI): m / z (M+1): 403.1 (Method 1)

[0958] Intermediate 170: tert-Butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)ethyl]-N-methylcarbamate

[0959] Intermediate 170 was prepared according to the procedure used for the synthesis of Intermediate 59 starting from tert-butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)ethyl]-N-methylcarbamate (Intermediate 169, 240 mg, 0.60 mmol) to provide the title compound (238 mg, 0.47 mmol, y = 79%).

[0960] LC-MS (ESI): m / z (M+1): 503.2 (Method 1)

[0961] Intermediate 171: tert-Butyl N-(2-{[(tert-Butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl})amino}ethyl)-N-methylcarbamate

[0962] Intermediate 171 was prepared following the procedure used for the synthesis of Intermediate 31 from tert-butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)ethyl]-N-methylcarbamate (Intermediate 170, 130 mg, 0.26 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 56 mg, 0.24 mmol) to afford the title compound (114 mg, 0.17 mmol, 73% yield).

[0963] LC-MS (ESI): m / z (M+1): 658.4 (Method 1)

[0964] Intermediate 172: 1-tert-Butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate

[0965] Intermediate 172 was prepared following the procedure for the synthesis of Intermediate 22 starting from methyl 4-boc-piperazine-2-carboxylate (150 mg, 0.61 mmol) and 37% w / w solution of formaldehyde in water (0.23 mL, 3.07 mmol) to provide the title compound (124 mg, 0.48 mmol, y = 78%).

[0966] LC-MS (ESI): m / z (M+1): 293.1 (Method 1)

[0967] Intermediate 173: 1-Methylpiperazine-2-carboxylic acid methyl ester hydrochloride

[0968] A solution of 1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (Intermediate 172 (124 mg, 0.48 mmol) in 4M HCl in dioxane (1.2 mL, 4.8 mmol) and MeOH (1.2 mL) was stirred at room temperature for 2 hours. The volatiles were removed under vacuum to provide methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 160 mg, 0.82 mmol, recovery assumed quantitative), which was used in the next step without further purification.

[0969] LC-MS (ESI): m / z (M+1): 159.1 (Method 2)

[0970] Intermediate 174: 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid methyl ester

[0971] Intermediate 174 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 83 mg, 0.37 mmol), methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 0.47 mmol) and TEA (0.1 mL, 0.73 mmol) to afford the title compound (135 mg, 0.35 mmol, 96% yield).

[0972] LC-MS (ESI): m / z (M+1): 383.1 (Method 1)

[0973] Intermediate 175 :N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide

[0974] N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 200 mg, 0.79 mmol) was added to a stirred solution of 1-methyl-1,4-diazepane (181 mg, 1.59 mmol) in dry DMF (3 mL) at room temperature. After 3 hours, the mixture was treated with H2O and extracted with EtOAc. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and evaporated to provide N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepane-1-yl)acetamide (180 mg, 0.55 mmol, 69% yield).

[0975] LC-MS (ESI): m / z (M+1): 327.4 (Method 2)

[0976] Intermediate 176: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate

[0977] A mixture of N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 150 mg, 0.60 mmol), tert-butyl 1-piperazinecarboxylate (224 mg, 1.2 mmol) and KCO (249 mg, 1.8 mmol) in dry DMF (6 mL) was stirred at room temperature under nitrogen for 18 hours. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed several times with brine, dried over NaSO and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 45% EtOAc) to provide tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (150 mg, 0.38 mmol, y = 62%) as a white sticky solid.

[0978] LC-MS (ESI): m / z (M+1): 399.2 (Method 1)

[0979] Intermediate 177: N-(4-Bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide

[0980] Intermediate 177 was prepared following the procedure for the synthesis of Intermediate 21 starting from tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (Intermediate 176, 140 mg, 0.35 mmol) to provide the title compound (104 mg, 0.35 mmol, y = 99%).

[0981] LC-MS (ESI): m / z (M+1): 299.1 (Method 2)

[0982] Intermediate 178: Methyl 2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)acetate

[0983] To a solution of N-(4-bromopyridin-2-yl)-2-(piperazine-1-yl)acetamide (intermediate 177, 104 mg, 0.35 mmol) in DMF (3.5 mL) was added KCO (96 mg, 0.700 mmol) followed by methyl 2-bromoacetate (0.04 mL, 0.38 mmol). The mixture was stirred at room temperature for 1.5 hours. The mixture was poured into a saturated aqueous NaHCO solution and extracted with EtOAc. The organic phase was separated, filtered through a hydrophobic phase separator, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica gel column (from DCM to 15% MeOH). The appropriate fractions were evaporated under reduced pressure to provide methyl 2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-yl)acetate (190 mg, recovery assumed quantitative) as a white solid.

[0984] LC-MS (ESI): m / z (M+1): 371.1 (Method 1)

[0985] Intermediate 179: (2E / Z)-4-[Benzyl({2-[(triphenylmethyl)amino]ethyl})amino]but-2-enoic acid ethyl ester

[0986] To a solution of N-benzyl-N'-tritylethane-1,2-diamine (1.4 g, 3.57 mmol) in MeCN (10 mL) was added KCO (0.99 g, 7.13 mmol) and ethyl (2E / Z)-4-bromo-2-butenoate (0.49 mL, 3.57 mmol). The mixture was heated at 50°C for 90 min. EtOAc and water were added, and the product was extracted with EtOAc (2x). The organic phase was collected, dried, and evaporated. The crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 10% EtOAc) to provide ethyl (E / Z)-4-[benzyl-[2-(tritylamino)ethyl]amino]but-2-enoate (1.57 g, 3.11 mmol, y = 87%) as a white wax.

[0987] LC-MS (ESI): m / z (M+1): 505.1 (Method 1)

[0988] Intermediate 180: Methyl 2-(4-benzylpiperazin-2-yl)acetate

[0989] A 4M solution of HCl in dioxane (3.89 mL, 15.6 mmol) was added to a solution of (2E / Z)-ethyl 4-[benzyl({2-[(triphenylmethyl)amino]ethyl})amino]but-2-enoate (Intermediate 179, 1.57 g, 3.11 mmol) in MeOH (6 mL), and the mixture was refluxed for 1 hour. The volatiles were removed under vacuum, and the residual material was loaded into an SCX, washed with MeOH and eluted with 1N NH3 in MeOH. The basic fraction was evaporated to provide methyl 2-(4-benzylpiperazin-2-yl)acetate (560 mg, 2.25 mmol, y = 72%), which was used as is in the next step.

[0990] LC-MS (ESI): m / z (M+1): 248.7 (Method 2)

[0991] Intermediate 181: tert-Butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[0992] Di-tert-Butyl dicarbonate (591 mg, 2.71 mmol) was added to a solution of methyl 2-(4-benzylpiperazin-2-yl)acetate (Intermediate 180, 560 mg, 2.26 mmol) in DCM (6 mL). The solution was stirred at room temperature for 1 hour. The volatiles were removed under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 15% EtOAc) to provide tert-butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (410 mg, 1.2 mmol, y = 52%) as a colorless oil.

[0993] LC-MS (ESI): m / z (M+1): 349.2 (Method 1)

[0994] Intermediate 182: tert-Butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[0995] A solution of tert-butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 181, 410 mg, 1.18 mmol) in MeOH (8 mL) was sparged with N2, and then 10% Pd / C (118 mg, 1.18 mmol) was added and the resulting suspension was stirred at room temperature under H2 atmosphere overnight. The next day, the catalyst was added to Filtered over a pad of Celite®, rinsed with MeOH, and the solvent was dried under vacuum to afford tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (280 mg, 1.08 mmol, y = 92%) as a colorless oil.

[0996] LC-MS (ESI): m / z (M+1): 259.1 (Method 1)

[0997] Intermediate 183: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[0998] Intermediate 183 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 182, 278 mg, 1.07 mmol) to afford the title compound (320 mg, 0.53 mmol, 75% yield).

[0999] LC-MS (ESI): m / z (M+1): 487.1 (Method 1)

[1000] Intermediate 184:tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[1001] Intermediate 184 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 183, 157 mg, 0.32 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 70 mg, 0.29 mmol) to afford the title compound (106 mg, 0.16 mmol, 56% yield).

[1002] LC-MS (ESI): m / z (M+1): 642.3 (Method 2)

[1003] Intermediate 185: Methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate

[1004] Intermediate 185 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 183, 100 mg, 0.20 mmol) to afford the title compound (100 mg, recovery assumed quantitative).

[1005] LC-MS (ESI): m / z (M+1): 387.1 (Method 2)

[1006] Intermediate 186: Methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazin-2-yl)acetate

[1007] Intermediate 186 was prepared as described for Intermediate 22 starting from methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate (Intermediate 185, 100 mg, 0.20 mmol) and a 37% w / w solution of formaldehyde in water (0.03 mL, 0.39 mmol) to afford the title compound (100 mg, 0.25 mmol, 97% yield).

[1008] LC-MS (ESI): m / z (M+1): 399.1 (Method 1)

[1009] Intermediate 187: 2-Methyl 1-tert-butyl 4-methylpiperazine-1,2-dicarboxylate

[1010] Intermediate 187 was prepared following the procedure for the synthesis of Intermediate 22 starting from 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (200 mg, 0.82 mmol) and 37% w / w solution of formaldehyde in water (0.31 mL, 4.09 mmol) to afford the title compound (173 mg, 0.7 mmol, 82% yield).

[1011] LC-MS (ESI): m / z (M+1): 259.2 (Method 2)

[1012] Intermediate 188: Methyl 4-methylpiperazine-2-carboxylate hydrochloride

[1013] Intermediate 188 was prepared following the procedure used for the synthesis of Intermediate 173 starting from 1-tert-butyl 2-methyl 4-methylpiperazine-1,2-dicarboxylate (Intermediate 187, 170 mg, 0.66 mmol) to afford the title compound (170 mg, recovery assumed quantitative).

[1014] LC-MS (ESI): m / z (M+1): 159.1 (Method 2)

[1015] Intermediate 189: 1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazine-2-carboxylic acid methyl ester

[1016] Intermediate 189 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 110 mg, 0.48 mmol), methyl 4-methylpiperazine-2-carboxylate hydrochloride (Intermediate 188, 123 mg, 0.63 mmol) and TEA (0.14 mL, 0.97 mmol) to afford the title compound (82 mg, 0.21 mmol, 44% yield).

[1017] LC-MS (ESI): m / z (M+1): 385.1 (Method 1)

[1018] Intermediate 190: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[1019] Intermediate 190 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 110 mg, 0.48 mmol), commercially available methyl N-4-Boc-2-piperazineacetate (150 mg, 0.58 mmol) and TEA (0.07 mL, 0.48 mmol) to afford the title compound (180 mg, 0.37 mmol, 78% yield).

[1020] LC-MS (ESI): m / z (M+1): 485.0 (Method 2)

[1021] Intermediate 191: Methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate

[1022] Intermediate 191 was prepared as described for Intermediate 173 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 190, 180 mg, 0.37 mmol) to afford the title compound (133 mg, 0.34 mmol, 93% yield).

[1023] LC-MS (ESI): m / z (M+1): 384.8 (Method 2)

[1024] Intermediate 192: Methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazin-2-yl)acetate

[1025] Intermediate 192 was prepared as described for Intermediate 22 starting from methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate (Intermediate 191, 130 mg, 0.34 mmol) and a 37% w / w solution of formaldehyde in water (0.04 mL, 0.5 mmol) to afford the title compound (135 mg, 0.34 mmol, 99% yield).

[1026] LC-MS (ESI): m / z (M+1): 399.6 (Method 2)

[1027] Intermediate 193: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate

[1028] Intermediate 193 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 190, 101 mg, 0.21 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 45 mg, 0.19 mmol) to afford the title compound (79 mg, 0.12 mmol, 65% yield).

[1029] LC-MS (ESI): m / z (M+1): 642.2 (Method 2)

[1030] Intermediate 194: N-(4-Bromopyridin-2-yl)-3-piperazin-1-ylpropionamide

[1031] Intermediate 194 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate (Intermediate 30, 650 mg, 1.41 mmol) to provide the title compound (488 mg, recovery assumed quantitative).

[1032] LC-MS (ESI): m / z (M+1): 315.0 (Method 2)

[1033] Intermediate 195: tert-Butyl N-[2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate

[1034] Intermediate 195 was prepared following the procedure for the synthesis of Intermediate 22 starting from 1N-(4-bromopyridin-2-yl)-3-piperazin-1-ylpropionamide (Intermediate 194, 150 mg, 0.48 mmol) and N-boc-(methylamino)acetaldehyde (124 mg, 0.72 mmol) to provide the title compound (160 mg, 0.34 mmol, 71% yield).

[1035] LC-MS (ESI): m / z (M+1): 470.4 (Method 2)

[1036] Intermediate 196: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate

[1037] Intermediate 196 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl N-[2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 195, 129 mg, 0.27 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 60 mg, 0.25 mmol) to afford the title compound (103 mg, 0.16 mmol, 66% yield).

[1038] LC-MS (ESI): m / z (M+1): 627.1 (Method 2)

[1039] Intermediate 197 : tert-Butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate

[1040] Intermediate 197 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 156 mg, 0.53 mmol) and N-Boc-(methylamino)acetaldehyde (138 mg, 0.8 mmol) to provide the title compound (176 mg, 0.38 mmol, 72% yield).

[1041] LC-MS (ESI): m / z (M+1): 456.7 (Method 2)

[1042] Intermediate 198: tert-Butyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate

[1043] Intermediate 198 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 197, 169 mg, 0.37 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 80 mg, 0.34 mmol) to afford the title compound (110 mg, 0.18 mmol, 53% yield).

[1044] LC-MS (ESI): m / z (M+1): 627.1 (Method 2)

[1045] Intermediate 199:tert-Butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate

[1046] Intermediate 199 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 234 mg, 0.78 mmol) and tert-butyl N-(2-oxoethyl)carbamate (372 mg, 2.34 mmol) to afford the title compound (179 mg, 0.4 mmol, 52% yield).

[1047] LC-MS (ESI): m / z (M+1): 442.3 (Method 2)

[1048] Intermediate 200: tert-Butyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate

[1049] Intermediate 200 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate (Intermediate 199, 174 mg, 0.39 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 85 mg, 0.36 mmol) to afford the title compound (65 mg, 0.11 mmol, 30% yield).

[1050] LC-MS (ESI): m / z (M+1): 599.5 (Method 2)

[1051] Intermediate 201: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)prop-2-enamide

[1052] A solution of N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 16, 140 mg, 0.29 mmol) in MeOH (2.43 mL) and H2O (0.80 mL) was added. To the 4- (4- { [6- (5- chloro-2-fluorophenyl) -3- methylpyridazine -4- bases] amino} pyridin-2-yl) propane-2-ene amides (21mg, 0.05mmol, 19% yield) of 5 ...

[1053] LC-MS (ESI): m / z (M+1): 384.7 (Method 2)

[1054] Intermediate 202: tert-Butyl (1S,4S)-5-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1055] Intermediate 202 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.89 mmol), commercially available tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (209 mg, 1.05 mmol) and TEA (0.12 mL, 0.99 mmol) to afford the title compound (380 mg, 0.89 mmol, quantitative yield).

[1056] LC-MS (ESI): m / z (M+1): 425.3 (Method 2)

[1057] Intermediate 203: N-(4-Bromopyridin-2-yl)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide

[1058] Intermediate 203 was prepared according to the procedure used for the synthesis of Intermediate 173 starting from tert-butyl (1S,4S)-5-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 202, 380 mg, 0.89 mmol) to provide the title compound (260 mg, 0.80 mmol, y = 89%).

[1059] LC-MS (ESI): m / z (M+1): 325.3 (Method 2)

[1060] Intermediate 204:N-(4-Bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]propanamide

[1061] Intermediate 204 was prepared following the procedure for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide (Intermediate 203, 260 mg, 0.80 mmol) and 37% w / w solution of formaldehyde in water (0.30 mL, 4 mmol) to provide the title compound (215 mg, 0.63 mmol, y = 79%).

[1062] LC-MS (ESI): m / z (M+1): 340.9 (Method 2)

[1063] Intermediate 205: 8-tert-Butyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate 2-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)

[1064] DIPEA (0.15 mL, 0.87 mmol) was added to a stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (105 mg, 0.44 mmol) and 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (Intermediate 101, 150 mg, 0.29 mmol) in DCM (10 mL) and DMSO (1 mL) at room temperature. After 5 minutes, the mixture was cooled to 5°C and 4-nitrophenyl chloroformate (88 mg, 0.44 mmol) was added. After 30 minutes, the reaction was warmed to room temperature. After 4 hours, the mixture was diluted with DCM and washed with water and aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 3% MeOH / 0.3% H2O) to afford 8-tert-butyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate 2-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)ester (120 mg, 0.19 mmol, y = 65%).

[1065] LC-MS (ESI): m / z (M+1): 633.4 (Method 2)

[1066] Intermediate 206 :1-tert-Butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate

[1067] In a suitable vial, 4-Boc-piperazine-2-carboxylic acid methyl ester (300 mg, 1.23 mmol) and K CO (271 mg, 1.96 mmol) were stirred in MeCN (2 mL) and 2-iodopropane (0.16 mL, 1.6 mmol) was added. The vial was capped and heated at 85 ° C (external temperature) overnight. Additional K CO (271 mg, 1.96 mmol) and 2-iodopropane (0.16 mL, 1.6 mmol) were added again and heated at the same temperature for another 8 hours. The mixture was diluted with DCM and the solid was filtered out and washed with more DCM. The filtrate was evaporated under vacuum. The crude material was purified by flash chromatography on a Biotage silica gel column (from DCM to 5% MeOH) to afford 1-tert-butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate (292 mg, 1.02 mmol, y = 83%) as a light yellow oil.

[1068] LC-MS (ESI): m / z (M+1): 287.6 (Method 2)

[1069] Intermediate 207: 1-(Propan-2-yl)piperazine-2-carboxylic acid methyl ester dihydrochloride

[1070] Intermediate 207 was prepared following the procedure used for the synthesis of Intermediate 173 starting from 1-tert-butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate (Intermediate 206, 290 mg, 1.01 mmol) to afford the title compound (400 mg, recovery assumed quantitative).

[1071] LC-MS (ESI): m / z (M+1): 187.0 (Method 2)

[1072] Intermediate 208: 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-(propan-2-yl)piperazine-2-carboxylic acid methyl ester

[1073] Intermediate 208 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.89 mmol), methyl 1-(propan-2-yl)piperazine-2-carboxylate dihydrochloride (Intermediate 207, 1.06 mmol) and TEA (0.25 mL, 1.76 mmol) to provide the title compound (211 mg, 0.51 mmol, y = 58%).

[1074] LC-MS (ESI): m / z (M+1): 413.4 (Method 2)

[1075] Intermediate 209:tert-Butyl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate

[1076] Intermediate 209 was prepared following the procedure used for the synthesis of Intermediate 22 starting from tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (327 mg, 1.44 mmol) and 37% w / w solution of formaldehyde in water (0.27 mL, 3.6 mmol) to afford the title compound (244 mg, 1.02 mmol, 70% yield).

[1077] LC-MS (ESI): m / z (M+1): 241.2 (Method 1)

[1078] Intermediate 210 :2-Methyl-2,7-diazaspiro[3.5]nonane dihydrochloride

[1079] Intermediate 210 was prepared following the procedure used for the synthesis of Intermediate 173 starting from tert-butyl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (Intermediate 209, 244 mg, 1.01 mmol) to provide the title compound (202 mg, 0.95 mmol, y = 94%).

[1080] 1 H NMR (400MHz, methanol-d4) δppm 4.07 (s, 4H), 3.20 (t, J = 5.9Hz, 4H), 2.96 (s, 3H), 2.17-2.10 (m, 4H).

[1081] Intermediate 211: tert-Butyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate

[1082] Intermediate 211 was prepared following the procedure used for the synthesis of Intermediate 22 starting from tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.05 g, 4.63 mmol) and 37% w / w solution of formaldehyde in water (348 mL, 46.31 mmol) to provide the title compound (718 mg, 2.99 mmol, y = 64%).

[1083] LC-MS (ESI): m / z (M+1): 241.2 (Method 2)

[1084] Intermediate 212: 7-Methyl-2,7-diazaspiro[3.5]nonane dihydrochloride

[1085] Intermediate 212 was prepared following the procedure used for the synthesis of Intermediate 173 starting from tert-butyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate (Intermediate 211, 718 mg, 2.99 mmol) to provide the title compound (620 mg, 2.9 mmol, y = 97%).

[1086] 1 H NMR (500MHz, methanol-d4) δppm 3.82-4.10(m,4H),3.48(br.s,2H),3.05(br.s,2H),2.86(s,3H),2.32(br.s,2H),2.04(br.s,2H).

[1087] Intermediate 213: N-(4-Bromopyridin-2-yl)-2-(morpholin-4-yl)acetamide

[1088] Intermediate 213 was prepared following the procedure for the synthesis of Intermediate 176 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 250 mg, 1 mmol) and morpholine (0.13 mL, 1.5 mmol) to provide the title compound (200 mg, 0.67 mmol, y = 66%).

[1089] LC-MS (ESI): m / z (M+1): 302.1 (Method 1)

[1090] Intermediate 214 :N-(4-bromopyridin-2-yl)-3-(thiomorpholin-4-yl)propionamide

[1091] Intermediate 214 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol) and thiomorpholine (154 mg, 1.49 mmol) to provide the title compound (174 mg, 0.53 mmol, 80% yield).

[1092] LC-MS (ESI): m / z (M+1): 332.0 (Method 1)

[1093] Intermediate 215: 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride

[1094] 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (500 mg, 1.82 mmol) was loaded into an SCX and eluted with a 1N NH3 solution in MeOH. The fractions were concentrated under reduced pressure and then treated with HCl (4N solution in dioxane) (1.82 mL, 7.3 mmol). The mixture was concentrated under reduced pressure to provide 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (140 mg, 0.76 mmol, y = 41%) as a white solid.

[1095] LC-MS (ESI): m / z (M+1): 113.0 (Method 1)

[1096] Intermediate 216: N-(4-Bromopyridin-2-yl)-3-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}propionamide

[1097] Intermediate 216 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 60 mg, 0.26 mmol), 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (Intermediate 215, 59 mg, 0.32 mmol) and TEA (0.11 mL, 0.79 mmol) to afford the title compound (78 mg, 0.23 mmol, 87% yield).

[1098] LC-MS (ESI): m / z (M+1): 340.9 (Method 2)

[1099] Intermediate 217: (1R,4R)-2-(1H-imidazole-1-carbonyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane

[1100] To (1R, 4R) -2- methyl -2,5- diazabicyclo [2.2.1] heptane dihydrochloride (200mg, 1.08mmol) and 1,1 '- carbonyldiimidazole (192.73mg, 1.19mmol) in DCM (5.4mL) stirred suspension was added TEA (0.31mL, 2.22mmol), and the reactant was stirred at room temperature overnight. The mixture was diluted with water, saturated Na2CO3 solution was used to adjust pH to approximately 9. Each phase was separated, and the aqueous phase was extracted with DCM (2x). The combined organic layer was filtered through a phase separator and concentrated under vacuum to provide (1R, 4R) -2- (1H- imidazole -1- carbonyl) -5- methyl -2,5- diazabicyclo [2.2.1] heptane (225mg, 1.08mmol, quantitative yield) as a light yellow oil.

[1101] LC-MS (ESI): m / z (M+1): 207.0 (Method 2)

[1102] Intermediate 218: N-(4-Bromopyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide

[1103] Intermediate 218 was prepared following the procedure used for the synthesis of Intermediate 69 starting from N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 200 mg, 0.67 mmol) and TEA (0.14 mL, 1 mmol) at room temperature to provide the title compound (204 mg, 0.53 mmol, 80% yield).

[1104] LC-MS (ESI): m / z (M+1): 381.3 (Method 2)

[1105] Intermediate 219: N-(4-Bromopyridin-2-yl)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)propanamide

[1106] Intermediate 219 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol) and thiomorpholine-1,1-dioxide (135 mg, 3.5 mmol) in MeCN at reflux to afford the title compound (225 mg, 0.62 mmol, 94% yield).

[1107] LC-MS (ESI): m / z (M+1): 364.0 (Method 1)

[1108] Intermediate 220: 1-(azetidin-3-yl)pyrrolidine

[1109] 1-(Azetidin-3-yl)pyrrolidine dihydrochloride (150 mg, 0.75 mmol) was dissolved in MeOH and loaded onto an SCX (2 g, washed with MeOH and eluted with 1N NH in MeOH). The basic fractions were evaporated to afford 1-(azetidin-3-yl)pyrrolidine (49 mg, 0.39 mmol, 51% yield) as a light yellow oil.

[1110] LC-MS (ESI): m / z (M+1): 127.0 (Method 2)

[1111] Intermediate 221: tert-Butyl 7-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4,7-diazaspiro[2.5]octane-4-carboxylate

[1112] Intermediate 221 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (243 mg, 1.15 mmol) and TEA (0.24 mL, 1.76 mmol) in MeOH to afford the title compound (360 mg, 0.82 mmol, 93% yield).

[1113] LC-MS (ESI): m / z (M+1): 439.1 (Method 2)

[1114] Intermediate 222: N-(4-Bromopyridin-2-yl)-3-{4,7-diazaspiro[2.5]octan-7-yl}propanamide

[1115] Intermediate 222 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 7-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 221, 360 mg, 0.82 mmol) to provide the title compound (277 mg, quantitative yield).

[1116] LC-MS (ESI): m / z (M+1): 339.1 (Method 2)

[1117] Intermediate 223: N-(4-Bromopyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}propanamide

[1118] Intermediate 223 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-3-{4,7-diazaspiro[2.5]octan-7-yl}propanamide (Intermediate 222, 277 mg, 0.82 mmol) and 37% w / w solution of formaldehyde in water (0.09 mL, 1.22 mmol) to afford the title compound (256 mg, 0.72 mmol, 89% yield).

[1119] LC-MS (ESI): m / z (M+1): 353.0 (Method 2)

[1120] Intermediate 224: N-(4-Bromopyridin-2-yl)-3-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}propanamide

[1121] Intermediate 224 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol), 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (146 mg, 1.2 mmol) and TEA (0.32 mL, 2.31 mmol) in MeOH to afford the title compound (100 mg, 0.29 mmol, 47% yield).

[1122] LC-MS (ESI): m / z (M+1): 339.1 (Method 2)

[1123] Intermediate 225: N-(4-Bromopyridin-2-yl)-3-(4,4-difluoropiperidin-1-yl)propanamide

[1124] Intermediate 225 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), 4,4-difluoropiperidine hydrochloride (166 mg, 1.06 mmol) and TEA (0.24 mL, 1.76 mmol) in MeOH to afford the title compound (288 mg, 0.83 mmol, 94% yield).

[1125] LC-MS (ESI): m / z (M+1): 348.0 (Method 2)

[1126] Intermediate 226 :N-(4-bromopyridin-2-yl)-3-(4-hydroxypiperidin-1-yl)propionamide

[1127] Intermediate 226 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 100 mg, 0.44 mmol), 4-piperidinol (53 mg, 0.53 mmol) and TEA (0.12 mL, 0.88 mmol) in MeOH to afford the title compound (110 mg, 0.33 mmol, 76% yield).

[1128] LC-MS (ESI): m / z (M+1): 328.0 (Method 2)

[1129] Intermediate 227: N-(4-Bromopyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide

[1130] TEA (0.87 mL, 6.25 mmol) was added to a stirred solution of 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (386 mg, 2.08 mmol) in dry MeCN (8 mL) at room temperature under N2. After 10 minutes, the reaction was cooled with an ice bath, and N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 350 mg, 1.39 mmol) and a catalytic amount of potassium iodide were added. The reaction mixture was allowed to reach room temperature and stirred at this temperature for 2 hours. Water and EtOAc were added, the organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 45% EtOAc) to afford N-(4-bromopyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide (330 mg, 1.01 mmol, y = 73%).

[1131] LC-MS (ESI): m / z (M+1): 327.0 (Method 2)

[1132] Intermediate 228: tert-Butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate

[1133] A solution of N-(4-bromopyridin-2-yl)-2-chloroacetamide (intermediate 159, 250 mg, 1 mmol), 4-boc-4,7-diazaspiro[2.5]octane (255 mg, 1.2 mmol) and DIPEA (0.35 mL, 2 mmol) in dry DCM (10 mL) was stirred at room temperature for 48 hours. The conversion was almost complete, so the mixture was stirred at 40 ° C for 16 hours. The mixture was then washed with water and brine. The organic solvent was separated, dried over Na2SO4, and filtered. The solvent was evaporated to provide tert-butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (450 mg, recovery assumed quantitative) as a yellow crude product, which was not subjected to any further purification.

[1134] LC-MS (ESI): m / z (M+1): 425.1 (Method 1)

[1135] Intermediate 229: N-(4-Bromopyridin-2-yl)-2-{4,7-diazaspiro[2.5]octan-7-yl}acetamide

[1136] Intermediate 229 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 228, 450 mg, 1 mmol) to provide the title compound (322 mg, 0.99 mmol, y = 94%).

[1137] LC-MS (ESI): m / z (M+1): 325.0 (Method 2)

[1138] Intermediate 230: N-(4-Bromopyridin-2-yl)-2-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}acetamide

[1139] Intermediate 230 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-2-{4,7-diazaspiro[2.5]octan-7-yl}acetamide (Intermediate 229, 322 mg, 0.99 mmol) and 37% w / w solution of formaldehyde in water (0.11 mL, 1.48 mmol) to afford the title compound (218 mg, 0.64 mmol, 65% yield).

[1140] LC-MS (ESI): m / z (M+1): 330.0 (Method 1)

[1141] Intermediate 231: N-(4-Bromopyridin-2-yl)-3-(3,4-dimethylpiperazin-1-yl)propanamide

[1142] Intermediate 231 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), 1,2-dimethyl-piperazine (160 mg, 1.41 mmol) and TEA (0.18 mL, 1.32 mmol) to afford the title compound (297 mg, 0.87 mmol, 99% yield).

[1143] LC-MS (ESI): m / z (M+1): 341.0 (Method 2)

[1144] Intermediate 232: tert-Butyl 3-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[1145] Intermediate 232 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (262 mg, 1.32 mmol) and TEA (0.24 mL, 1.76 mmol) to afford the title compound (395 mg, recovery assumed quantitative).

[1146] LC-MS (ESI): m / z (M+1): 425.1 (Method 1)

[1147] Intermediate 233: N-(4-Bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptan-3-yl}propionamide

[1148] A 4M solution of HCl in dioxane (1.18 mL, 4.7 mmol) and MeOH (0.392 mL) were added to tert-butyl 3-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (intermediate 232, 200 mg, 0.47 mmol). The mixture was stirred at room temperature for 3 hours. Volatiles were removed under vacuum. The residue was treated with saturated NaHCO solution and extracted 3 times with DCM. The aqueous phase was further extracted with EtOAc (3x). The combined organic layer was filtered through a phase separator and evaporated under vacuum to provide N-(4-bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptane-3-yl}propionamide (140 mg, 0.43 mmol, 92% yield) as a white solid.

[1149] LC-MS (ESI): m / z (M+1): 325.0 (Method 1)

[1150] Intermediate 234: N-(4-Bromopyridin-2-yl)-3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}propionamide

[1151] Intermediate 234 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptan-3-yl}propionamide (Intermediate 233, 140 mg, 0.43 mmol) and 37% w / w solution of formaldehyde in water (0.05 mL, 0.65 mmol) to provide the title compound (121 mg, 0.36 mmol, 83% yield).

[1152] LC-MS (ESI): m / z (M+1): 339.0 (Method 2)

[1153] Intermediate 235: tert-Butyl 8-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate

[1154] Intermediate 235 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol), tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (196 mg, 0.86 mmol) and TEA (0.14 mL, 0.99 mmol) to afford the title compound (364 mg, recovery assumed quantitative).

[1155] LC-MS (ESI): m / z (M+1): 455.1 (Method 2)

[1156] Intermediate 236: N-(4-Bromopyridin-2-yl)-3-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide

[1157] Intermediate 236 was prepared following the procedure used for the synthesis of Intermediate 233 starting from tert-butyl 8-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (Intermediate 235, 364 mg, 0.66 mmol, recovery assumed quantitative in previous step) to afford the title compound (215 mg, 0.60 mmol, 92% yield).

[1158] LC-MS (ESI): m / z (M+1): 355.0 (Method 2)

[1159] Intermediate 237: N-(4-Bromopyridin-2-yl)-3-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide

[1160] Intermediate 237 was prepared following the procedure used for the synthesis of Intermediate 22 starting from N-(4-bromopyridin-2-yl)-3-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propionamide (Intermediate 236, 215 mg, 0.60 mmol) and 37% w / w solution of formaldehyde in water (0.07 mL, 0.91 mmol) to afford the title compound (106 mg, 0.29 mmol, 48% yield).

[1161] LC-MS (ESI): m / z (M+1): 368.6 (Method 2)

[1162] Intermediate 238: tert-Butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate

[1163] Intermediate 238 was prepared following the procedure used for the synthesis of Intermediate 22 starting from tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (3.16 g, 13.15 mmol) and 37% w / w solution of formaldehyde in water (4.95 mL, 65.77 mmol) to afford the title compound (1.37 g, 5.41 mmol, 41% yield).

[1164] LC-MS (ESI): m / z (M+1): 255.4 (Method 2)

[1165] Intermediate 239: 2-Methyl-2,8-diazaspiro[4.5]decane dihydrochloride

[1166] Intermediate 239 was prepared following the procedure used for the synthesis of Intermediate 173 starting from tert-butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (Intermediate 238, 1.37 g, 5.4 mmol) to provide the title compound (912 mg, 4 mmol, 74% yield).

[1167] 1 H NMR (500 MHz, methanol-d4) δ ppm 3.76 (ddd, J = 11.7, 7.8, 3.9 Hz, 1H), 3.69 (d, J = 12.1 Hz, 1H), 3.18-3.29 (m, 5H), 3.04 (d, J = 12.1 Hz, 1H), 2.97 (s, 3H), 2.15-2.26 (m, 1H), 1.87-2.10 (m, 5H).

[1168] Intermediate 240: N-(4-Bromopyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide

[1169] Intermediate 240 was prepared following the procedure used for the synthesis of Intermediate 154 starting from N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 153, 200 mg, 0.63 mmol) and 2-methyl-2,8-diazaspiro[4.5]decane dihydrochloride (Intermediate 239, 157 mg, 0.69 mmol) to afford the title compound (103 mg, 0.29 mmol, 46% yield).

[1170] LC-MS (ESI): m / z (M+1): 353.1 (Method 1)

[1171] Intermediate 241:N-{4-[(6-chloro-3-methylpyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide

[1172] N-(4-Bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 32, 752 mg, 2.3 mmol), Cs2CO3 (1.37 g, 4.18 mmol), Xantphos (145 mg, 0.25 mmol), 6-chloro-3-methylpyridazin-4-amine (300 mg, 2.09 mmol) were mixed in 4 mL of dioxane and degassed with N2 for 5 min, followed by the addition of Pd(OAc)2 (23.67 mg, 0.100 mmol). The resulting reaction mixture was heated at 100°C for 2 hours. The solid was filtered, washed with EtOAc, the volatiles were removed in vacuo, and the residue was purified by flash chromatography on a Biotage NH silica gel column (20% cyclohexane to 10% MeOH in EtOAc) to afford N-{4-[(6-chloro-3-methylpyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide (610 mg, 1.56 mmol, 75% yield) as a foam.

[1173] LC-MS (ESI): m / z (M+1): 390.9 (Method 2)

[1174] Intermediate 242: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate

[1175] Intermediate 242 was prepared following the procedure for the synthesis of Intermediate 176 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 600 mg, 2.4 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (722 mg, 3.6 mmol) to provide the title compound (740 mg, 1.79 mmol, y = 40%).

[1176] LC-MS (ESI): m / z (M+1): 414.3 (Method 2)

[1177] Intermediate 243: tert-Butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate

[1178] Intermediate 243 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate (Intermediate 242, 140 mg, 0.34 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 70 mg, 0.29 mmol) to afford the title compound as a yellow solid (80 mg, 0.14 mmol, 48% yield).

[1179] LC-MS (ESI): m / z (M+1): 570.2 (Method 1)

[1180] Intermediate 244: 1-(2-{[(tert-Butoxy)carbonyl](methyl)amino}ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[1181] At 0 DEG C, diisopropyl azodicarboxylate (1.73mL, 8.8mmol) is added dropwise to tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.5g, 8.56mmol), 1H-pyrazole-4-ethyl carboxylate (800mg, 5.61mmol) and PPh3(2.32g, 8.65mmol) in a stirred mixture in THF (20mL), and the reaction mixture is then heated to 55 DEG C and stirred at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure. The crude material is purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 45% EtOAc) to provide 1-(2-{[(tert-butoxy) carbonyl](methyl) amino}ethyl)-1H-pyrazole-4-ethyl carboxylate (1.42g, 4.77mmol, 84% yield) as a light yellow solid.

[1182] LC-MS (ESI): m / z (M+1): 298.2 (Method 1)

[1183] Intermediate 245: N-(2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methyl tert-Butyl carbamate

[1184] To a stirred solution of 4-bromopyridin-2-amine (585 mg, 3.38 mmol) in THF (13 mL) at -78°C under N2 was added 1.6 N n-butyllithium in hexanes (1.85 mL, 2.96 mmol) portionwise over 10 min, and the reaction mixture was then stirred at -78°C for 1 h. A solution of ethyl 1-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)-1H-pyrazole-4-carboxylate (Intermediate 244, 400 mg, 1.35 mmol) in THF (6 mL) was added portionwise over 10 min at -78°C. After 5 min, the cooling bath was removed, and the resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 95% EtOAc), and then it was further purified by flash chromatography on a Biotage silica gel column (cyclohexane to 90% EtOAc) to afford tert-butyl N-(2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate (94 mg, 0.22 mmol, 16% yield) as a light yellow oil.

[1185] LC-MS (ESI): m / z (M+1): 425.5 (Method 2)

[1186] Intermediate 246: tert-Butyl N-(2-{4-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate

[1187] Intermediate 246 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl N-(2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate (Intermediate 245, 94 mg, 0.22 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 64 mg, 0.27 mmol) to afford the title compound (71 mg, 0.12 mmol, 55% yield).

[1188] LC-MS (ESI): m / z (M+1): 581.3 (Method 1)

[1189] Intermediate 247: N-(4-Bromopyridin-2-yl)-2-(1-methylpiperidin-4-yl)acetamide

[1190] Intermediate 247 was prepared following the procedure for the synthesis of Intermediate 245 starting from ethyl 2-(1-methylpiperidin-4-yl)acetate (150 mg, 0.81 mmol) and 4-bromopyridin-2-amine (350 mg, 2.02 mmol) to afford the title compound (100 mg, 0.32 mmol, 40% yield).

[1191] LC-MS (ESI): m / z (M+1): 312.0 (Method 2)

[1192] Intermediate 248: tert-Butyl 4-{3-[(4-bromopyridin-2-yl)carbamoyl]propyl}-1,4-diazepane-1-carboxylate

[1193] Intermediate 248 was prepared following the procedure for the synthesis of Intermediate 140 starting from N-(4-bromopyridin-2-yl)-4-chlorobutanamide (Intermediate 41, 350 mg, 1.26 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (758 mg, 3.78 mmol) to provide the title compound (260 mg, 0.59 mmol, y = 47%).

[1194] LC-MS (ESI): m / z (M+1): 441.2 (Method 1)

[1195] Intermediate 249: tert-Butyl 4-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]propyl}-1,4-diazepane-1-carboxylate

[1196] Intermediate 249 was prepared starting from tert-butyl 4-{3-[(4-bromopyridin-2-yl)carbamoyl]propyl}-1,4-diazepane-1-carboxylate (Intermediate 248, 167 mg, 0.38 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 75 mg, 0.32 mmol) at 120°C following the procedure used for the synthesis of Intermediate 112 to provide the title compound (140 mg, 0.23 mmol, y = 74%).

[1197] LC-MS (ESI): m / z (M+1): 598.2 (Method 1)

[1198] Intermediate 250: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[1199] Intermediate 250 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 250 mg, 1.10 mmol) and commercially available tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (310 mg, 1.4 mmol) to afford the title compound (410 mg, 0.92 mmol, 84% yield).

[1200] LC-MS (ESI): m / z (M+1): 444.6 (Method 2)

[1201] Intermediate 251: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[1202] Intermediate 251 was prepared following the procedure used for the synthesis of Intermediate 31 starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate (Intermediate 250, 182 mg, 0.41 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 85 mg, 0.36 mmol) to afford the title compound (70 mg, 0.12 mmol, 33% yield).

[1203] LC-MS (ESI): m / z (M+1): 600.3 (Method 2)

[1204] Intermediate 252: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(hydroxymethyl)piperazin-1-yl]propanamide

[1205] Intermediate 252 was prepared according to the procedure used for the synthesis of Intermediate 21 starting from tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate (Intermediate 251, 70 mg, 0.12 mmol) to provide the title compound (40 mg, 0.08 mmol. y = 67%).

[1206] LC-MS (ESI): m / z (M+1): 500.2 (Method 2)

[1207] Intermediate 253: tert-Butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate

[1208] Intermediate 253 was prepared following the procedure used for the synthesis of Intermediate 9 starting from tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (Intermediate 176, 120 mg, 0.29 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 60 mg, 0.25 mmol) in 1,2-dimethoxyethane / toluene (3 / 1 ratio) at 120 °C for 1 hour and 45 minutes to provide the title compound (55 mg, 0.10 mmol, 39% yield).

[1209] LC-MS (ESI): m / z (M+1): 556.2 (Method 2)

[1210] Intermediate 254: 1-Methyl-4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]piperazine

[1211] A solution of 2-(4-methylpiperazin-1-yl)ethane-1-ol (765 mg, 5.31 mmol), PPh (2.5 g, 9.55 mmol) and 3-nitro-1H-pyrazole (600 mg, 5.31 mmol) in THF (21 mL) was treated with di-tert-butyl azodicarboxylate (2.07 g, 9.02 mmol) at room temperature. The mixture was stirred for 16 hours before it was concentrated under reduced pressure; the residual material was loaded into an SCX, washed with MeOH and eluted with 1N NH in MeOH. The basic fraction was evaporated to provide crude material, which was purified by flash chromatography on a Biotage silica gel column (from DCM to 30% MeOH) to provide 1-methyl-4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]piperazine (355 mg, 1.48 mmol, 28% yield) as a pale yellow oil.

[1212] LC-MS (ESI): m / z (M+1): 239.7 (Method 2)

[1213] Intermediate 255: 1-[2-(4-Methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine

[1214] A solution of 1-methyl-4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]piperazine (Intermediate 254, 58 mg, 0.24 mmol) in ethanol (0.40 mL) was treated with 10% w / w Pd / C (5.03 mg) and stirred at room temperature under H2 atmosphere for 5 hours. Filtration over a pad of Celite® and then concentration under reduced pressure provided 1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine (48 mg, 0.23 mmol, 97% yield) as a colorless oil.

[1215] LC-MS (ESI): m / z (M+1): 210.3 (Method 2)

[1216] Intermediate 256: 4-Chloro-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl}pyridin-2-amine

[1217] In a sealed container, Cs2CO3 (83 mg, 0.26 mmol), Xantphos (6 mg, 0.01 mmol), 1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine (Intermediate 255, 28 mg, 0.13 mmol), Pd2(dba)3 (6 mg, 0.01 mmol) and 2,4-dichloropyridine (18 mg, 0.12 mmol) were suspended in 1,2-dimethoxyethane (1.22 mL) under N2. The suspension was degassed by several vacuum / nitrogen cycles and then N2 was bubbled through the mixture at room temperature (10 minutes). The mixture was then immediately warmed to 100°C and stirred for 4 hours. The mixture was heated at 400°C for 1 hour. The mixture was filtered over a pad of 4-nitropropene and washed with EtOAc. The crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 100% EtOAc) to afford 4-chloro-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl}pyridin-2-amine (17 mg, 0.05 mmol, 44% yield) as a light yellow oil.

[1218] LC-MS (ESI): m / z (M+1): 321.4 (Method 2)

[1219] Intermediate 257: 1-tert-Butyl 3-methyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate

[1220] Step 1: To a stirred solution of DMSO (1.19 mL, 16.76 mmol) in DCM (20 mL) at -78 ° C and under N2, oxalyl chloride (0.72 mL, 8.38 mmol) was added portionwise, and the mixture was stirred at -78 ° C for 10 min. Then, a solution of 2-(1-methylpiperidin-4-yl)ethane-1-ol (1 g, 6.98 mmol) in DCM (5 mL) was added over 10 min, and the resulting reaction mixture was stirred at -78 ° C for 15 min. TEA (4.9 mL, 35.18 mmol) was then added portionwise over 10 min, and the reaction mixture was stirred at -78 ° C for 10 min. The cooling bath was removed, and the reaction mixture was allowed to reach room temperature and stirred at room temperature for 30 min. The reaction mixture was filtered, DCM was added until the total amount was 45 mL, and the solution containing the aldehyde derivative (6.98 mmol, recovery assumed quantitative) was used as is.

[1221] Step 2: To a stirred solution of 2-(1-methylpiperidin-4-yl)acetaldehyde (from Step 1, theoretical 6.98 mmol) in DCM (45 mL) was added portionwise 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (1.23 g, 5.05 mmol) at room temperature. After 10 min, sodium triacetoxyborohydride (2.25 g, 10.61 mmol) was added portionwise and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated NaHCO solution. The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure, and the crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 25% EtOAc) to afford 1-tert-butyl 3-methyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate (1.61 g, 4.36 mmol, 86% yield) as a light yellow oil.

[1222] LC-MS (ESI): m / z (M+1): 371.6 (Method 2)

[1223] Intermediate 258: Lithium 4-[(tert-Butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate

[1224] To a solution of 1-tert-butyl 3-methyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate (Intermediate 257, 1.61 g, 4.36 mmol) in THF (14 mL) and MeOH (4 mL) was added a solution of lithium hydroxide hydrate (205 mg, 4.89 mmol) in H O (5 mL), and the mixture was heated at 48° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to afford lithium 4-[(tert-butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate (1.56 g, 4.36 mmol, recovery assumed quantitative) as a white solid, which was used as is.

[1225] LC-MS (ESI): m / z (M-1): 354.3 (Method 1)

[1226] Intermediate 259: 1-tert-Butyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate 3-oxetan-3-yl ester

[1227] To a stirred mixture of lithium 4-[(tert-butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate (Intermediate 258, 550 mg, 1.52 mmol) in MeCN (13 mL) at room temperature were added HATU (814 mg, 2.14 mmol) followed by DIPEA (0.81 mL, 4.67 mmol). After 10 min, 3-oxetanol (0.33 mL, 5.04 mmol) was added portionwise to the solution, and the resulting reaction mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure, the residue was taken up with DCM and saturated NaHCO 3 solution, the aqueous phase was extracted with DCM, the organic phases were collected, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage NH silica gel column (cyclohexane to 25% EtOAc) to afford 1-tert-butyl 3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate as a colorless oil (371 mg, 0.90 mmol, 64% yield).

[1228] LC-MS (ESI): m / z (M-1): 413.3 (Method 2)

[1229] Intermediate 260: Methyl 4-chloro-7-hydroxyquinoline-6-carboxylate

[1230] Boron tribromide (5.96 mL, 5.96 mmol) was added dropwise to a stirred solution of 4-chloro-7-methoxyquinoline-6-formic acid methyl ester (500 mg, 1.99 mmol) in DCM (20 mL) at 0 ° C under N2. The reactant was stirred at 0 ° C for 1 hour and then stirred at room temperature for another 1 hour. The reactant was cooled with an ice bath and MeOH was added dropwise. The solvent was removed under reduced pressure, the residue was treated with a NaHCO3 aqueous solution, and extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to provide 4-chloro-7-hydroxyquinoline-6-formic acid methyl ester (320 mg, 1.35 mmol, 68% yield).

[1231] LC-MS (ESI): m / z (M-1): 238.1 (Method 1)

[1232] Intermediate 261: Methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate

[1233] Di-tert-butyl azodicarboxylate (581 mg, 2.52 mmol) was added portionwise to a stirred mixture of methyl 4-chloro-7-hydroxyquinoline-6-carboxylate (Intermediate 260, 300 mg, 1.26 mmol), 1-(2-hydroxyethyl)-4-methylpiperazine (225 mg, 1.56 mmol) and PPh (662 mg, 2.52 mmol) in dry DCM (50 mL) at room temperature under N. After 3 hours, the mixture was washed with H.sub.2O, and the organic layer was separated, dried over Na.sub.2SO.sub.4, filtered, and evaporated. The residue was treated with 0.1N HCl, the aqueous phase was washed with EtOAc, treated with NaHCO until pH 9, and extracted with DCM. The organic layer was separated, dried over Na 2 SO 4 and evaporated to afford methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate (350 mg, 0.96 mmol, 76% yield).

[1234] LC-MS (ESI): m / z (M-1): 365.5 (Method 2)

[1235] Intermediate 262: tert-Butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

[1236] Intermediate 262 was prepared following the procedure for the synthesis of Intermediate 22 starting from tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (300 mg, 1.39 mmol) and 37% w / w solution of formaldehyde in water (0.1 mL, 1.39 mmol) to afford the title compound (270 mg, 1.17 mmol, 85% yield).

[1237] LC-MS (ESI): m / z (M-1): 231.3 (Method 2)

[1238] Intermediate 263: (1-Methylpiperazin-2-yl)methanol dihydrochloride

[1239] A 3M solution of HCl in cyclopentyl methyl ether (1.56 mL, 4.69 mmol) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (Intermediate 262, 270 mg, 1.17 mmol) in MeOH (4 mL). The reaction mixture was stirred overnight and the volatiles were removed under vacuum to provide (1-methylpiperazin-2-yl)methanol dihydrochloride (250 mg, recovery assumed quantitative) as a white solid.

[1240] LC-MS (ESI): m / z (M-1): 131.3 (Method 2)

[1241] Intermediate 264: N-(4-Bromopyridin-2-yl)-3-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide

[1242] Intermediate 264 was prepared as described for Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and (1-methylpiperazin-2-yl)methanol dihydrochloride (232 mg, 1.15 mmol) to afford the title compound (170 mg, 0.48 mmol, 54% yield).

[1243] LC-MS (ESI): m / z (M+1): 358.6 (Method 2)

[1244] Intermediate 265: N-(4-Bromopyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide

[1245] Intermediate 265 was prepared following the procedure for the synthesis of Intermediate 176 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 150 mg, 0.6 mmol) and 1-methylpiperazine (120 mg, 1.2 mmol) to provide the title compound (168 mg, 0.54 mmol, y = 89%).

[1246] LC-MS (ESI): m / z (M+1): 313.3 (Method 2)

[1247] Intermediate 266: 6-Chloro-3-cyclopropylpyridazin-4-amine

[1248] K3PO4 (328 mg, 1.52 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 mL, 0.610 mmol) and 3,6-dichloropyridazin-4-amine (100 mg, 0.61 mmol) were mixed in 1,4-dioxane (3 mL) / H2O (1 mL). The reaction mixture was degassed with N2 for 2 min, then Pd(dppf)Cl2 DCM (25 mg, 0.03 mmol) was added and then heated at 100°C overnight. The mixture was cooled to room temperature, and then an additional 2 equivalents of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, K PO (328 mg, 1.52 mmol) and Pd(dppf)Cl DCM (25 mg, 0.03 mmol) were added, and then stirred at 100° C. for 6 hours. After cooling, the reaction was diluted with H 0 and EtOAC, and the organic phase was separated, dried, and evaporated under vacuum. The residue was purified by reverse phase flash chromatography on a Biotage C18 column (from H 0 + 0.1% NH OH to 20% MeCN) to provide 6-chloro-3-cyclopropylpyridazin-4-amine (57 mg, 0.34 mmol, 55% yield) as an off-white solid.

[1249] LC-MS (ESI): m / z (M+1): 170.0 (Method 2)

[1250] Intermediate 267: 6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-amine

[1251] A mixture of 5-chloro-2-fluorophenylboronic acid (76 mg, 0.44 mmol), 6-chloro-3-cyclopropylpyridazin-4-amine (Intermediate 266, 57 mg, 0.34 mmol) and Na2CO3 (53 mg, 0.50 mmol) in toluene (0.80 mL), EtOH (0.80 ml) and H2O (0.80 ml) was degassed with N2 for 2 minutes, PdCl2(PPh3)2 (24 mg, 0.03 mmol) was added, and the mixture was irradiated with microwaves at 90°C for 1 hour. Additional 5-chloro-2-fluorophenylboronic acid (76 mg, 0.44 mmol), Na2CO3 (53 mg, 0.50 mmol) and PdCl2(PPh3)2 (23.66 mg, 0.030 mmol) were added, and the mixture was irradiated at 90°C for 40 minutes. After cooling to room temperature, the mixture was treated with H2O and extracted with EtOAc. The organic layer was separated, dried, and evaporated. The residue was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O + 0.1% NH4OH to 80% MeCN) to provide 6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-amine (58 mg, 0.22 mmol, 65% yield) as a white solid.

[1252] LC-MS (ESI): m / z (M+1): 264.1 (Method 1)

[1253] Intermediate 268: Methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate

[1254] 1-(2,4-dimethoxyphenyl)methylamine (1.8mL, 7.97mmol) was added to a stirred solution of 4,6-dichloropyridazine-3-carboxylic acid methyl ester (1.5g, 7.25mmol) and DIPEA (3.27mL, 14.49mmol) in dry MeCN (20mL) at room temperature under N2, and the reactants were stirred for 3 hours. The solvent was removed under reduced pressure, the residue was treated with EtOAC, and washed with NH4Cl aqueous solution. The organic phase was separated, dried over Na2SO4, filtered, and evaporated. The residue was treated with hot EtOAc, cooled, added Et2O and the solid was filtered to provide 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylic acid methyl ester (1.2g, 3.55mmol, 49% yield).

[1255] LC-MS (ESI): m / z (M+1): 340.1 (Method 2)

[1256] Intermediate 269:Methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate

[1257] DIPEA (1.55 mL, 8.88 mmol) was added to a stirred mixture of methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate (Intermediate 268, 1.0 g, 2.96 mmol), 5-chloro-2-fluorophenylboronic acid (1.55 g, 8.88 mmol), and Pd(PPh3)4 (239 mg, 0.21 mmol) in dry 1,4-dioxane (15 mL). The reaction was flushed with N2, the vial was sealed, and microwave irradiated at 110°C for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue was treated with H2O and extracted with EtOAc, and the organic layer was separated, washed with aqueous NH4Cl solution, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 30% EtOAc as eluent) to afford methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate (710 mg, 1.64 mmol, 56% yield).

[1258] LC-MS (ESI): m / z (M+1): 432.2 (Method 1)

[1259] Intermediate 270: [6-(5-Chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol

[1260] A 2M solution of lithium aluminum hydride in THF (0.7 mL, 1.4 mmol) was added dropwise to a stirred solution of methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate (Intermediate 269, 600 mg, 1.15 mmol) in dry THF (10 mL) at 0°C under N2. After 1 hour, the reaction was warmed to room temperature and stirred for 1 hour. The mixture was then cooled to 0°C and 0.1 mL of a solution of H2O in THF, 0.1 mL of 15% NaOH and 0.3 mL of H2O were added sequentially. The reaction was warmed to room temperature for 1 hour. The mixture was stirred at 4°C for 1 hour. The mixture was filtered over a pad of Methylparaben, washed with THF. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 60% EtOAc) to afford [6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol (420 mg, 1.04 mmol, 90% yield).

[1261] LC-MS (ESI): m / z (M+1): 404.2 (Method 1)

[1262] Intermediate 271: [4-Amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol

[1263] TFA (1.0 mL, 17.4 mmol) was added to a stirred solution of [6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-yl]methanol (intermediate 270, 220 mg, 0.54 mmol) in DCM (4 mL) at room temperature under N. The reactant was stirred for 40 hours. The solvent was removed under reduced pressure, and the residue was treated with a NaHCO aqueous solution and extracted with EtOAc. The organic layer was separated, dried over NaSO, filtered, and evaporated to provide [4-amino-6-(5-chloro-2-fluorophenyl)pyridazine-3-yl]methanol (150 mg, recovery assumed quantitative).

[1264] LC-MS (ESI): m / z (M+1): 254.1 (Method 1)

[1265] Intermediate 272: 3-{[(tert-Butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine

[1266] Tert-Butyl(chloro)dimethylsilane (113.64 mg, 0.75 mmol) was added to a stirred solution of [4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol (Intermediate 271, 150 mg, 0.50 mmol), TEA (0.14 mL, 1.01 mmol) and a catalytic amount of DMAP in dry DCM (12.26 mL) at room temperature under N. After 24 hours, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 20% EtOAc) to provide 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (100 mg, 0.27 mmol, 54% yield).

[1267] LC-MS (ESI): m / z (M+1): 369.1 (Method 2)

[1268] Intermediate 273: N-{4-[(3-{[(tert-Butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide

[1269] Cs2CO3 (157 mg, 0.48 mmol) was added to a stirred mixture of N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 32, 94 mg, 0.29 mmol), 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 100 mg, 0.24 mmol), Pd(OAc)2 (3 mg, 0.01 mmol) and Xantphos (14 mg, 0.02 mmol) in 1,4-dioxane (6.77 mL) at room temperature. The mixture was degassed with N2, the vial was sealed and irradiated with microwaves (120°C for 2 hours). After cooling to room temperature, the mixture was heated to 40°C. The product was filtered over a pad of Celite®, washed with EtOAc, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on a Biotage NH silica gel column (DCM to 2% MeOH / 0.2% HO) to afford N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide (105 mg, 0.17 mmol, 71% yield).

[1270] LC-MS (ESI): m / z (M+1): 614.5 (Method 2)

[1271] Intermediate 274: N-(4-Bromopyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide

[1272] Intermediate 274 was prepared following the procedure used for the synthesis of Intermediate 21 starting from tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 197, 150 mg, 0.33 mmol) to provide the title compound (90 mg, 0.25 mmol, 77% yield).

[1273] LC-MS (ESI): m / z (M+1): 358.0 (Method 2)

[1274] Intermediate 275: Methyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate

[1275] Intermediate 275 was prepared following the procedure used for the synthesis of Intermediate 102 starting from N-(4-bromopyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide (Intermediate 274, 90 mg, 0.25 mmol) and methyl chloroformate (0.021 mL, 0.28 mmol) to provide the title compound (90 mg, 0.22 mmol, 86% yield).

[1276] LC-MS (ESI): m / z (M+1): 416.1 (Method 1)

[1277] Intermediate 276: Methyl N-[2-[4-[2-[[4-[[3-[[tert-Butyl(dimethyl)silyl]oxymethyl]-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino]pyridin-2-yl]amino]-2-oxoethyl]piperazin-1-yl]ethyl]-N-methylcarbamate

[1278] Intermediate 276 was prepared following the procedure used for the synthesis of Intermediate 31 starting from methyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 275, 90 mg, 0.22 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 70 mg, 0.19 mmol) to provide the title compound (20 mg, 0.03 mmol, 15% yield).

[1279] LC-MS (ESI): m / z (M+1): 701.4 (Method 1)

[1280] Intermediate 277: N-{4-[(3-{[(tert-Butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-2-(4-methylpiperazin-1-yl)acetamide

[1281] Intermediate 277 was prepared following the procedure used for the synthesis of Intermediate 273 starting from N-(4-bromopyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (Intermediate 265, 71 mg, 0.23 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 70 mg, 0.19 mmol) to afford the title compound (56 mg, 0.09 mmol, 49% yield).

[1282] LC-MS (ESI): m / z (M+1): 600.2 (Method 1)

[1283] Intermediate 278: 4-Bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline

[1284] A 33% solution of HBr in AcOH (0.63 mL, 2.53 mmol) was added to a stirred mixture of 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (Intermediate 23, 90 mg, 0.25 mmol) and sodium bromide (263 mg, 2.53 mmol) in MeCN (4 mL) at room temperature. The vial was sealed and the reaction was heated at 80 ° C for 12 hours. After cooling, the mixture was poured into a cold aqueous NaHCO solution and extracted with EtOAc. The organic layer was separated, dried over Na SO and evaporated to provide 4-bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (80 mg, 0.23 mmol, 90% yield).

[1285] LC-MS (ESI): m / z (M+1): 352.0 (Method 2)

[1286] Intermediate 279: N-(3-{[(tert-Butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine

[1287] Intermediate 279 was prepared following the procedure used for the synthesis of Intermediate 273 starting from 4-bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (Intermediate 278, 71 mg, 0.20 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 50 mg, 0.14 mmol) to provide the title compound (70 mg, 0.11 mmol, 81% yield).

[1288] LC-MS (ESI): m / z (M+1): 637.5 (Method 2)

[1289] Intermediate 280 :N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-2-(4-methyl-1,4-diazepan-1-yl)acetamide

[1290] Intermediate 280 was prepared following the procedure used for the synthesis of Intermediate 273 starting from N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide (Intermediate 175, 124 mg, 0.38 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 100 mg, 0.25 mmol) to afford the title compound (90 mg, 0.15 mmol, 56% yield).

[1291] LC-MS (ESI): m / z (M+1): 614.1 (Method 2)

[1292] Intermediate 281 :N-(4-bromopyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide

[1293] Intermediate 281 was prepared following the procedure used for the synthesis of Intermediate 176 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 100 mg, 0.4 mmol) and 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (Intermediate 210, 101 mg, 0.48 mmol) to provide the title compound (80 mg, 0.23 mmol, y = 57%).

[1294] LC-MS (ESI): m / z (M+1): 355.1 (Method 2)

[1295] Intermediate 282 :N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide

[1296] Intermediate 282 was prepared following the procedure used for the synthesis of Intermediate 273 starting from N-(4-bromopyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide (Intermediate 281, 48 mg, 0.14 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 50 mg, 0.14 mmol) to provide the title compound (45 mg, 0.07 mmol, 52% yield).

[1297] LC-MS (ESI): m / z (M+1): 640.5 (Method 2)

[1298] Intermediate 283:2-[5-(difluoromethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1299] In a vial, 1-bromo-5-difluoromethyl-2-fluorobenzene (0.5 g, 2.22 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.67 g, 2.64 mmol), Pd(dppf)Cl2 DCM (91 mg, 0.11 mmol) and potassium acetate (661 mg, 6.67 mmol) were added 1,2-dimethoxyethane (9 mL), the vial was sealed and stirred at 90 ° C for 7 hours. The reaction mixture was diluted with EtOAc and The organic solvent was concentrated under reduced pressure, and the crude material was purified by flash chromatography on a Biotage silica gel column (cyclohexane to 55% EtOAc) to afford 2-[5-(difluoromethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (376 mg, 1.38 mmol, 62% yield) as a whitish waxy solid.

[1300] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87-7.95 (m, 1H), 7.60-766 (m, 1H), 7.14 (t, J=8.69 Hz, 1H), 6.49-6.82 (m, 1H), 1.39 (s, 12H).

[1301] Intermediate 284 :N-(4-bromopyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propionamide

[1302] Intermediate 284 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 2-(1-piperazinyl)ethanol (229 mg, 1.76 mmol) in MeOH to afford the title compound (283 mg, 0.79 mmol, 90% yield).

[1303] LC-MS (ESI): m / z (M+1): 357.1 (Method 2)

[1304] Intermediate 285 :N-(4-bromopyridin-2-yl)-3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)propanamide

[1305] To N- (4- bromopyridin-2-yl) -3- [4- (2- hydroxyethyl) piperazine -1- base] propionamide (intermediate 284, 283mg, 0.79mmol) and TEA (0.28mL, 1.98mmol) in DCM (5mL) solution, add tert-butyl (chloro) dimethylsilane (239mg, 1.58mmol), and the mixture is stirred at room temperature overnight. The mixture is diluted with DCM and washed with saturated NaHCO3 aqueous solution. The organic phase is separated, filtered through a hydrophobic phase separator, and concentrated under reduced pressure. The crude material is purified by flash chromatography on Biotage NH silica gel column (from DCM to 2% MeOH) to provide N- (4- bromopyridin-2-yl) -3- (4- { 2- [(tert-butyldimethylsilyl) oxy] ethyl} piperazine -1- base) propionamide (365mg, 0.77mmol, 98% yield).

[1306] LC-MS (ESI): m / z (M+1): 471.3 (Method 2)

[1307] Intermediate 286 :3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide

[1308] Intermediate 286 was prepared following the procedure used for the synthesis of Intermediate 31 starting from N-(4-bromopyridin-2-yl)-3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)propanamide (Intermediate 285, 107 mg, 0.23 mmol) and 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine (Intermediate 293, 60 mg, 0.21 mmol) to afford the title compound (116 mg, 0.17 mmol, 83% yield).

[1309] LC-MS (ESI): m / z (M+1): 682.5 (Method 2)

[1310] Intermediate 287 :N-(4-bromopyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propionamide

[1311] Intermediate 287 was prepared following the procedure used for the synthesis of Intermediate 30 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 3-(1-piperazinyl)propionitrile (245 mg, 1.76 mmol) in MeOH to provide the title compound (277 mg, 0.76 mmol, 86% yield).

[1312] LC-MS (ESI): m / z (M+1): 366.1 (Method 2)

[1313] Intermediate 288 :2,5-dioxopyrrolidin-1-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate

[1314] Intermediate 288 was prepared according to the procedure: To a solution of bis-(2,5-dioxopyrrolidin-1-yl)carbonate (537 mg, 2.094 mmol) in dry THF (10 mL) was added 2-(4-methylpiperazin-1-yl)ethan-1-amine (300 mg, 2.094 mmol), and the reaction was stirred at 80° C. for 1 h. The resulting suspension was then directly carried on to the next step.

[1315] Intermediate 289: 1-(4-bromopyridin-2-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea

[1316] To a solution of 4-bromopyridin-2-amine (434 mg, 2.51 mmol) in dry THF (10 mL) previously cooled to -78 ° C, a 2M solution of LDA in THF (3.14 mL, 6.28 mmol) was added dropwise. The reactants were stirred for 10 min, and a solution of 2,5-dioxopyrrolidin-1-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate (Intermediate 288, 595 mg, 2.093 mmol) in THF (10 mL) was slowly added over 30 min. The reactants were stirred at -78 ° C for 30 min and stirred at room temperature for 12 h. The reactants were then poured into brine (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were filtered through a phase separation column and the solvent was removed under reduced pressure. The crude material was purified by NH flash chromatography (SNAP 50 g eluent DCM:EtOH from 100:0 to 95:5 in a gradient elution) to afford the title compound (120 mg, 0.351 mmol, 17% yield) as an orange solid.

[1317] LC-MS (ESI): m / z (M+1): 342.2, rt=0.30 min (Method 1).

[1318] Intermediate 290 :2,5-dioxopyrrolidin-1-yl ((1-methylpiperidin-4-yl)methyl)carbamate

[1319] To a solution of bis-(2,5-dioxopyrrolidin-1-yl)carbonate (0.999 g, 3.90 mmol) in dry THF (10 mL) was added (1-methylpiperidin-4-yl)methanamine (0.5 g, 3.90 mmol), and the reaction was stirred at 80° C. for 1 h. The resulting suspension was then directly carried to the next step.

[1320] Intermediate 291 :1-(4-bromopyridin-2-yl)-3-((1-methylpiperidin-4-yl)methyl)urea

[1321] Intermediate 291 was prepared following the procedure for the synthesis of Intermediate 289 starting from 4-bromopyridin-2-amine (0.809 g, 4.68 mmol) and using 2,5-dioxopyrrolidin-1-yl ((1-methylpiperidin-4-yl)methyl)carbamate (Intermediate 290, 1.05 g, 3.90 mmol). The crude material was purified by NH flash chromatography (SNAP 50 g eluent DCM:EtOH from 100:0 to 95:5 gradient elution) to afford the title compound (160 mg, 0.489 mmol, 12% yield) as an orange solid.

[1322] LC-MS (ESI): m / z (M+1): 326.9, rt=0.45 min (Method 1).

[1323] Intermediate 292 :6-Chloro-3-(trifluoromethyl)pyridazin-4-amine

[1324] To a solution of 6-chloropyridazin-4-amine (2 g, 15.44 mmol) in DCM (6 mL) were added water (2 mL) and zinc bis(trifluoromethylsulfinate) (7.68 g, 23.16 mmol), and the biphasic system was heated to 60°C. After 20 min, TFA (5.28 g, 46.3 mmol) and t-BuOOH (8.35 g, 93 mmol) were added, and the reaction was stirred for 6 h. Additional zinc bis(trifluoromethylsulfinate) (7.68 g, 23.16 mmol), TFA (5.28 g, 46.3 mmol), and t-BuOOH (8.35 g, 93 mmol) were added. Upon completion, the reaction was diluted with DCM and saturated aqueous NaHCO₃ (20 mL) was added. The two phases were separated, and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent removed under reduced pressure. The crude material was purified by C18 flash chromatography ((H2O / MeCN)) 95:5+0.1% HCOOH}:{(MeCN / H2O) 95:5+HCOOH 0.1%} from 100:0 to 70:30 to afford a nearly 1:1 mixture of two positional isomers, 6-chloro-5-(trifluoromethyl)pyridazin-4-amine and the title compound 6-chloro-3-(trifluoromethyl)pyridazin-4-amine (1.08 g).

[1325] LC-MS (ESI): m / z (M+1): 198.22, rt=0.60 min (Method 1).

[1326] Intermediate 293: 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine

[1327] To a mixture of 6-chloro-5-(trifluoromethyl)pyridazin-4-amine and 6-chloro-3-(trifluoromethyl)pyridazin-4-amine (Intermediate 292, 1.08 g, 5.26 mmol) in 1,4-dioxane (16 mL) / H₂O (4 mL) were added PdCl₂(dppf) (0.400 g, 0.547 mmol), K₂CO₃ (1.133 g, 8.20 mmol), and (2-chloro-5-fluorophenyl)boronic acid (0.715 g, 4.10 mmol), and the reaction was stirred at 110°C for 3 h. 1,4-dioxane was then removed under reduced pressure; the residue was diluted with DCM and saturated aqueous NaHCO₃ (20 mL) was added. The two phases were separated, and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The crude material was purified by C18 flash chromatography ((H2O / MeCN)) 95:5+0.1% HCOOH}:{(MeCN / H2O) 95:5+HCOOH 0.1%} from 100:0 to 60:40, affording 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine (150 mg, 0.514 mmol, 19% yield) as the first eluting positional isomer and 6-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridazin-4-amine (150 mg, 0.514 mmol, 19% yield) as the second eluting positional isomer.

[1328] LC-MS (ESI): m / z (M+1): 292.23, rt=0.85 min (Method 1).

[1329] Intermediate 294: Methyl 3-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)propanoate

[1330] To a solution of 4-methoxy-4-oxobutanoic acid (44.3 mg, 0.33 mmol), N-hydroxyphthalimide (54.7 mg, 0.33 mmol), and DMAP (1.4 mg, 0.01 mmol) in DMSO (1 mL) was added DIC (0.05 ml, 0.33 mmol), and the mixture was stirred at room temperature for 12 h. Then, a solution of 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 50 mg, 0.22 mmol), (1S)-(+)-10-camphorsulfonic acid (104 mg, 0.45 mmol), and 2,4,5,6-tetrakis(carbazol-9-yl)benzene-1,3-dicarbonitrile (17.4 mg, 0.02 mmol) in DMSO (1 mL) was added. The resulting solution was vigorously bubbled with nitrogen, sealed, and placed under two blue Kessil LED Photoredox light PR160L lamps (390-456 nm, 352 mW / cm 2 ). The reactant was stirred at 50 ° C for 3 h. The mixture was concentrated under reduced pressure and eluted with 7N NH3 in methanol through a 2g SCX column. The resulting solution was concentrated under reduced pressure and purified by flash chromatography on a Biotage NH-silica column (eluent: DCM: DCM / MeOH 9 / 1 from 100: 0 to 0: 100) to produce the title compound (30 mg, 0.097 mmol, 43.3% yield).

[1331] LC-MS (ESI): m / z (M+1): 309.8, rt=0.43 min (Method 1).

[1332] Intermediate 295: Methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)cyclohexane-1-carboxylate

[1333] Intermediate 295 was prepared following the procedure used for the synthesis of Intermediate 294 starting from methyl 4-methoxycarbonylcyclohexane-1-carboxylic acid (125 mg, 0.61 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 100 mg, 0.447 mmol) to afford methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)cyclohexane-1-carboxylate (30 mg, 0.08 mmol, 18% yield) as a mixture of cis-trans stereoisomers.

[1334] LC-MS (ESI): m / z (M+1): 364.2, rt = 0.57-0.60 min (Method 1).

[1335] Intermediate 296:4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)butanoic acid methyl ester

[1336] Intermediate 296 was prepared following the procedure used for the synthesis of Intermediate 294 starting from 5-methoxy-5-oxopentanoic acid (0.245 g, 1.676 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 250 mg, 1.118 mmol) to afford methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)butanoate (37 mg, 0.114 mmol, 10% yield) as a slightly yellow solid.

[1337] LC-MS (ESI): m / z (M+1): 323.9, rt=0.47 min (Method 1).

[1338] Intermediate 297 :cis-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylic acid ethyl ester

[1339] 1-Methylpiperazine (0.55mL, 5mmol) and 3-oxocyclobutane-1-ethyl carboxylate (950mg, 6.7mmol) are mixed in DCM (30mL) and stirred at room temperature for 15min. Sodium triacetoxyborohydride (2.12g, 10mmol) is added in batches, and the resulting reaction mixture is stirred at room temperature overnight. MeOH (30mL) is carefully added, and the mixture is stirred for 30min, and then it is concentrated under reduced pressure. The crude material is dissolved in MeOH and the solution is loaded onto SCX, washed with MeOH, and eluted with 1N NH3 solution in MeOH). The basic fraction is evaporated to provide a crude material, which is purified by flash chromatography on a Biotage NH silica gel column (from c-Hex to 30% EtOAc) to provide cis-3-(4-methylpiperazine-1-yl)cyclobutane-1-ethyl carboxylate (927mg, 4.1mmol, 82% yield) as a colorless oil.

[1340] LC-MS (ESI): m / z (M+1): 227.3 (Method 2)

[1341] Intermediate 298 :cis-N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide

[1342] Intermediate 298 was prepared following the procedure used for the synthesis of Intermediate 245 starting from cis-ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate (Intermediate 297, 300 mg, 1.33 mmol) and 4-bromopyridin-2-amine (577 mg, 3.34 mmol) to afford the title compound (221 mg, 0.63 mmol, 47% yield).

[1343] LC-MS (ESI): m / z (M+1): 354.1 (Method 2)

[1344] Intermediate 299 :4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylic acid methyl ester

[1345] Intermediate 299 was prepared following the procedure used for the synthesis of Intermediate 273 starting from methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate (Intermediate 261, 93 mg, 0.26 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 80 mg, 0.21 mmol) to afford the title compound (50 mg, 0.07 mmol, 44% yield).

[1346] LC-MS (ESI): m / z (M+1): 695.5 (Method 2)

[1347] Preparation of Examples

[1348] Embodiment 1: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide

[1349]

[1350] Intermediate 37 (57 mg, 0.18 mmol), Cs2CO3 (117 mg, 0.36 mmol), Xantphos (12 mg, 0.02 mmol) and intermediate 3 (40 mg, 0.18 mmol) were mixed in 1,4-dioxane (3 mL) and degassed with N2 for 5 min, then Pd(OAc)2 (2 mg, 0.01 mmol) was added. The resulting reaction mixture was heated at 100 ° C for 12 hours. The solid was filtered off, the volatiles were removed under vacuum and the residue was purified by flash chromatography on a Biotage NH silica gel column (from DCM to 5% MeOH) and then further purified by flash chromatography on a Biotage silica gel column (from cyclohexane to 100% EtOAC) to provide the title compound as a white solid.

[1351] LC-MS (ESI): m / z (M+1): 458.1 (Method 1)

[1352] 1 H NMR (400MHz, chloroform-d) δppm 11.22(s,1H),9.03(d,J=2.7Hz,1H),8.23(d,J=5.7Hz,1H),8.19(dd,J=6. 7,2.7Hz,1H),8.05(d,J=2.1Hz,1H),7.70(dd,J=2.5,1.5Hz,1H),7.42(dd d,J=8.8,4.2,2.8Hz,1H),7.15(dd,J=10.5,8.8Hz,1H),6.97(s,1H),6.95 (dd,J=5.7,2.2Hz,1H),3.88(t,J=4.5Hz,4H),2.73-2.81(m,2H),2.64(br s, 4H), 2.56-2.60 (m, 2H).

[1353] Example 2: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide

[1354]

[1355] Intermediate 31 (70 mg, 0.13 mmol) was dissolved in DCM (4 mL) and TFA (0.05 mL, 0.63 mmol) was added. The reaction solution was stirred at room temperature for 1 h. Volatiles were removed under vacuum and the residue was loaded onto an SCX, washed with MeOH and eluted with a solution of 1N NH3 in MeOH. The basic fraction was collected and evaporated to provide the title compound (56 mg, 0.12 mmol, 98% yield) as a white solid.

[1356] LC-MS (ESI): m / z (M+1): 456.2 (Method 1)

[1357] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.75(s,1H),9.88(s,1H),9.06(d,J=2.7Hz,1H),8.18(d,J=5.5Hz,1H),8.06( d,J=1.6Hz,1H),8.00(dd,J=6.4,2.9Hz,1H),7.67(dd,J=2.5,1.4Hz,1H),7.62- 7.66(m,1H),7.47(dd,J=10.6,8.9Hz,1H),7.01(dd,J=5.8,2.2Hz,1H),4.04-5. 96(m,1H),2.80(t,J=4.8Hz,4H),2.59-2.66(m,2H),2.52-2.57(m,2H),2.42(br s,4H).

[1358] Example 3: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(morpholin-4-yl)ethoxy]quinolin-4-amine

[1359]

[1360] A mixture of intermediate 3 (0.2 g, 0.89 mmol), intermediate 17 (376 mg, 1.03 mmol) and Cs2CO3 (586 mg, 1.79 mmol) in dry 1,4-dioxane (9 mL) was degassed with N2 for 2 min, then Pd(OAc)2 (10 mg, 0.04 mmol) and Xantphos (52 mg, 0.09 mmol) were added. The mixture was irradiated with microwaves (110°C, 2 h). Little conversion was observed, so more Pd(OAc)2 (10 mg, 0.04 mmol) and Xantphos (52 mg, 0.09 mmol) were added, and the mixture was irradiated again at 120°C for 1 h 30 min. The suspension was partitioned between EtOAc and water, and the entire mixture was filtered to remove some insoluble material. The organic phase was separated and the aqueous phase was extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated to give a crude product which was loaded onto an SCX column, washed with MeOH and eluted with a solution of 1N NH in MeOH. The basic fractions were collected and evaporated, and the residue was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O+0.1% NH4OH to 55% MeCN), and then by flash chromatography on a Biotage NH silica gel column (from DCM to 2% MeOH) to provide the title compound (92 mg, 0.19 mmol, 21% yield) as a yellow solid.

[1361] LC-MS (ESI): m / z (M+1): 480.3 (Method 1)

[1362] 1 H NMR(500MHz,DMSO-d6)δppm 9.78(br s,1H),9.19(br s,1H),8.66(br s,1H),8.18(d,J=9.3Hz,1H),8.00(dd,J=6.6,2.7Hz,1H),7.70(br s,1H),7.58-7.66(m,1H),7.46(dd,J=10.6,8.9Hz,1H),7.40(br s,2H),7.30(dd,J=9.1,1.9Hz,1H),4.27(t,J=5.8Hz,2H),3.51-3.71(m,4H),2.77(t,J=5.6Hz,2H),2.46-2.55(m,4H).

[1363] Embodiment 4: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(morpholin-4-yl)ethyl]quinoline-7-carboxamide

[1364]

[1365] Intermediate 14 (80 mg, 0.20 mmol) was dissolved in DMF (3 mL) and HATU (99 mg, 0.26 mmol) and DIPEA (0.14 mL, 0.80 mmol) were then added, followed by 2-(4-morpholinyl)ethylamine (0.03 mL, 0.26 mmol) after stirring for 5 min. The mixture was stirred at room temperature overnight, the volatiles were removed under vacuum, and the residue was dissolved in MeOH and loaded onto an SCX column, washed with MeOH and eluted with a solution of 1N NH in MeOH; the basic fraction was collected and evaporated to provide a yellow oil, which was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O+0.1% NH4OH to 50% MeCN) to provide the title compound (30 mg, 0.06 mmol, 30% yield).

[1366] LC-MS (ESI): m / z (M+1): 507.4 (Method 1)

[1367] 1 H NMR(500MHz,DMSO-d6)δppm 9.87(br s,1H),9.25(br s,1H),8.68-8.91(m,2H),8.50(br s,1H),8.37(d,J=8.8Hz,1H),7.97-8.09(m,2H),7.78(br s,1H),7.64(ddd,J=8.9,4.2,2.9Hz,2H),7.46(dd,J=10.6,8.9Hz,1H),3.58(t,J=4.5Hz,4H),3.46(q,J=6.6Hz,2H),2.51-2.55(m,2H),2.45(br s,4H).

[1368] Example 5: 2-(Morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate

[1369]

[1370] Intermediate 57 (50 mg, 0.125 mmol) was dissolved in DMF (3 mL) and HATU (62 mg, 0.16 mmol) and DIPEA (64 mg, 0.50 mmol) were added followed by 4-(2-hydroxyethyl)morpholine (21 mg, 0.16 mmol) after stirring for 5 min. The mixture was stirred at room temperature for 90 min, the volatiles were then removed under vacuum, and the residue was purified by reverse phase flash chromatography on a Biotage C18 column under basic conditions, which was then further purified by flash chromatography on a Biotage NH silica gel column (from DCM to 35% EtOAc) to provide the title compound (20 mg, 0.04 mmol, 31% yield).

[1371] LC-MS (ESI): m / z (M+1): 508.3 (Method 1)

[1372] 1 H NMR(400MHz,DMSO-d6)δppm 9.71-10.60(m,1H),9.24(br s,1H),9.01(d,J=1.5Hz,1H),8.58-8.92(m,1H),8.18-8.30(m,1H),7.96-8.15(m,2H),7.78(br s,1H),7.37-7.70(m,3H),4.48(t,J=5.8Hz,2H),3.50-3.62(m,4H),2.73(t,J=5.9Hz,2H),2.42-2.53(m,4H).

[1373] Example 6: 2-(Morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate

[1374]

[1375] The title compound (11 mg, 0.02 mmol, 17% yield) was prepared following the procedure used for the synthesis of Example 5 starting from intermediate 14 (50 mg, 0.12 mmol) and 4-(2-hydroxyethyl)morpholine (21 mg, 0.16 mmol).

[1376] LC-MS (ESI): m / z (M+1): 508.4 (Method 1)

[1377] 1H NMR (400MHz, DMSO-d6) δppm 9.74-10.13(m,1H),9.24(d,J=1.1Hz,1H),8.73-8.83(m,1H),8.55(br s,1H),8.44(d,J=8.8Hz,1H),8.09(d,J=8.3Hz,1H),8.01(dd,J=6.6,2.9Hz,1H),7.77(br s,1H),7.64(ddd,J=8.9,4.3,2.9Hz,2H),7.46(dd,J=10.6,8.9Hz,1H),4.49( t,J=5.7Hz,2H),3.54-3.62(m,4H),2.76(t,J=5.7Hz,2H),2.48-2.53(m,4H).

[1378] Example 7: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide

[1379]

[1380] Example 7 (35 mg, 0.09 mmol, 20% yield) was prepared according to the procedure used for the synthesis of Example 1 starting from Intermediate 44 (130 mg, 0.54 mmol) and Intermediate 3 (100 mg, 0.45 mmol).

[1381] LC-MS (ESI): m / z (M+1): 384.2 (Method 1)

[1382] 1 H NMR (400 MHz, DMSO-d 6) δppm 10.76(s,1H),9.85(s,1H),9.05(d,J=2.6Hz,1H),8.18(d,J=5.7Hz,1H),8.05(d,J=2.0Hz,1H),7.99(dd,J=6.6,2.9Hz, 1H),7.60-7.68(m,2H),7.46(dd,J=10.4,8.9Hz,1H),6.98(dd,J=5.6,2.1Hz,1H),1.95-2.06(m,1H),0.72-0.92(m,4H).

[1383] Example 8 N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-4-(morpholin-4-yl)butanamide

[1384]

[1385] Example 8 was prepared following the procedure used for the synthesis of Example 3 starting from Intermediate 42 (56 mg, 0.17 mmol) and Intermediate 3 (35 mg, 0.16 mmol) to provide the title compound (28 mg, 0.06 mmol, 38% yield).

[1386] LC-MS (ESI): m / z (M+1): 471.3 (Method 1)

[1387] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.43(s,1H),9.88(s,1H),9.05(d,J=2.7Hz,1H),8.17(d,J=5.5Hz,1H),8.07( d,J=1.6Hz,1H),8.00(dd,J=6.6,2.7Hz,1H),7.68(dd,J=2.7,1.4Hz,1H),7.61- 7.66(m,1H),7.46(dd,J=10.4,8.8Hz,1H),7.00(dd,J=5.8,2.2Hz,1H),3.52(t, J=4.5Hz, 4H), 2.40 (t, J=7.1Hz, 2H), 2.25-2.37 (m, 6H), 1.74 (quintet, J=7.2Hz, 2H)

[1388] Example 9: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine

[1389]

[1390] Example 9 was prepared following the procedure used for the synthesis of Example 2 starting from intermediate 19 (30 mg, 0.05 mmol) to provide the title compound (17 mg, 0.03 mmol, 69% yield).

[1391] LC-MS (ESI): m / z (M+1): 479.4 (Method 2)

[1392] 1H NMR (400MHz, DMSO-d6) δppm 9.65-9.90(m,1H),9.19(br s,1H),8.54-8.83(m,1H),8.18(d,J=9.2Hz,1H),8.00(dd,J=6.6,2.8Hz,1H),7.70(br s,1H),7.60-7.67(m,1H),7.45(dd,J=10.6,8.9Hz,1H),7.39(br s,2H),7.25-7.33(m,1H),4.25(t,J=5.7Hz,2H),2.58-2.88(m,7H),2.43(br s,4H).

[1393] Embodiment 10: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(piperazin-1-yl)ethyl]quinoline-7-carboxamide

[1394]

[1395] Example 10 was prepared following the procedure for the synthesis of Example 2 starting from intermediate 16 (48 mg, 0.08 mmol) to provide the title compound (15 mg, 0.03 mmol, 37% yield) as a yellow solid.

[1396] LC-MS (ESI): m / z (M+1): 506.4 (Method 1)

[1397] 1 H NMR (400MHz, chloroform-d) δppm 9.22(d,J=1.9Hz,1H),8.91(d,J=4.9Hz,1H),8.41(s,1H),8.17(dd,J=6.6,2.6Hz,1H),8.11(d,J=8.7Hz,1H),8.00(d,J=8.4Hz,1H),7.74(br s,2H),7.51(d,J=4.8Hz,1H),7.36-7.45(m,1H),7.20(t,J=4.3Hz,1H),7.13(dd,J=10. 4,9.0Hz,1H),3.64(q,J=5.3Hz,2H),2.93(t,J=4.7Hz,4H),2.61-2.73(m,2H),2.51(br s,4H).

[1398] Example 11: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide

[1399]

[1400] Example 11 was prepared following the procedure for the synthesis of Example 1 starting from Intermediate 32 (154 mg, 0.47 mmol) and Intermediate 3 (100 mg, 0.45 mmol) to provide the title compound (114 mg, 0.24 mmol, 54% yield) as a white solid.

[1401] LC-MS (ESI): m / z (M+1): 470.4 (Method 1)

[1402] 1 H NMR (400 MHz, chloroform-d) δ ppm 11.32(s,1H),9.04(d,J=2.6Hz,1H),8.24(d,J=5.5Hz,1H),8.18(dd,J=6.7,2.7 Hz,1H),8.05(d,J=2.0Hz,1H),7.70(dd,J=2.4,1.5Hz,1H),7.41(ddd,J=8.8,4.2 ,2.9Hz,1H),7.10-7.20(m,2H),6.95(dd,J=5.6,2.1Hz,1H),2.49-2.90(m,12H) ,2.37(s,3H).2.50-2.84(m,8H),2.45(q,J=7.26Hz,2H),1.12(t,J=7.26Hz,3H).

[1403] Example 12: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine

[1404]

[1405] Example 12 was prepared following the procedure for the synthesis of Example 3 starting from Intermediate 23 (159 mg, 0.52 mmol) and Intermediate 3 (100 mg, 0.43 mmol) to provide the title compound (80 mg, 0.16 mmol, 37% yield).

[1406] LC-MS (ESI): m / z (M+1): 493.1 (Method 1)

[1407] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76(s,1H),9.19(s,2H),8.67(s,1H),8.18(d,J=9.25Hz,2H),8.00(dd,J=6.5 8,2.78Hz,2H),7.69(s,2H),7.63(ddd,J=8.80,4.25,2.77Hz,2H),7.45(dd,J= 10.63,8.87Hz,3H),7.39(s,3H),7.29(d,J=9.24Hz,2H),4.25(t,J=5.74Hz,4H ), 2.76 (t, J = 5.68Hz, 4H), 2.52 (s, 13H), 2.33 (s, 4H), 2.15 (s, 6H), 1.23 (s, 1H).

[1408] Example 13: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]quinoline-7-carboxamide

[1409]

[1410] Example 13 was prepared following the procedure for the synthesis of Example 4 starting from Intermediate 15 (74 mg, 0.19 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (36 mg, 0.26 mmol) to provide the title compound (23 mg, 0.04 mmol, 24% yield).

[1411] LC-MS (ESI): m / z (M+1): 520.3 (Method 2)

[1412] 1 H NMR (400MHz, chloroform-d) δppm 9.26(d,J=2.64Hz,1H),8.87-8.97(m,1H),8.39(br.s,1H),8.09-8.21(m,2H),7.92-7.99(m,2H),7.77(br.s,1H),7.49-7.58 (m,1H),7.39-7.46(m,1H),7.08-7.21(m,2H),3.65(q,J=5.28Hz,2H),2.68(t,J=5.83Hz,2H),2.45-2.66(m,7H),2.33(s,3H).

[1413] Example 14: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]quinoline-7-carboxamide

[1414]

[1415] Example 14 was prepared following the procedure for the synthesis of Example 4 starting from Intermediate 15 (49 mg, 0.12 mmol) and 2-(1-methylpiperidin-4-yl)ethanamine (25 mg, 0.18 mmol) to provide the title compound (8.5 mg, 0.02 mmol, 13% yield).

[1416] LC-MS (ESI): m / z (M+1): 519.4 (Method 1)

[1417] 1 H NMR (400MHz, chloroform-d) δppm 9.23(d,J=2.53Hz,1H),8.89(d,J=4.51Hz,1H),8.36(br.s,1H),8.10-8.19(m,2H),7. 91-7.98(m,2H),7.75(br.s,1H),7.50(d,J=4.40Hz,1H),7.42(ddd,J=8.80,4.29,2.75 Hz,1H),7.13(dd,J=10.67,8.80Hz,1H),6.52(t,J=5.50Hz,1H)3.54-3.63(m,2H),2.84 -2.91(m,2H),2.29(s,3H)1.96(t,J=11.17Hz,2H)1.57-1.84(m,5H)1.35-1.43(m,2H).

[1418] Example 15: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide

[1419]

[1420] In a suitable vial, intermediate 33 (65mg, 0.25mmol), intermediate 47 (50mg, 0.28mmol), Xantphos (22mg, 0.04mmol) and K PO (109mg, 0.51mmol) are mixed in 1,4-dioxane (4mL). Use N 2 bubble 2min, then add Pd (dba) 3 (24mg, 0.03mmol), then bottle is sealed and microwave circulation is carried out at 100 DEG C for 5 hours. Reactant mixture is diluted with EtOAc and filtered. The filtrate is concentrated under reduced pressure and the crude material is purified by flash chromatography on Biotage NH silica gel column (from cyclohexane to 60% EtOAc) to provide title compound (32mg, 0.08mmol, 32% yield).

[1421] LC-MS (ESI): m / z (M+1): 413.3 (Method 1)

[1422] 1 H NMR(400MHz,DMSO-d6)δppm 10.72(s,1H),8.83(s,1H,)8.15(d,J=5.50Hz,1H),8.07(d,J=1.76Hz,1H),7.97(dd,J=6.49,2.75Hz,1H),7.71(s,1H),7.61(ddd,J=8.8 6,4.24,2.75Hz,1H),7.43(dd,J=10.56,8.80Hz,1H),6.96(dd,J=5.50,2.20Hz,1H),2.67(s,3H),1.93-2.10(m,1H),0.76-0.87(m,4H).

[1423] Example 16: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide

[1424]

[1425] Example 16 was prepared following the procedure for the synthesis of Example 15 starting from Intermediate 36 (113 mg, 0.43 mmol) and Intermediate 33 (100 mg, 0.39 mmol) to provide the title compound (734 mg, 0.15 mmol, 39% yield).

[1426] LC-MS (ESI): m / z (M+1): 484.3 (Method 1)

[1427] 1 H NMR(500MHz,DMSO-d6)δppm 10.63(s,1H),8.85(s,1H),8.14(d,J=5.8Hz,1H),8.08(d,J=1.6Hz,1H),7. 98(dd,J=6.5,2.8Hz,1H),7.71(d,J=1.0Hz,1H),7.60(ddd,J=8.9,4.2,2.7 Hz,1H),7.42(dd,J=10.5,8.9Hz,1H),6.97(dd,J=5.7,2.1Hz,1H),2.68(s, 3H),2.58-2.62(m,2H),2.51-2.54(m,2H),2.17-2.54(m,8H),2.14(s,3H).

[1428] Example 17: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinolin-4-amine

[1429]

[1430] Sodium triacetoxyborohydride (70.5 mg, 0.33 mmol) was added to a mixture of intermediate 26 (106 mg, 0.22 mmol) and paraformaldehyde (13 mg, 0.44 mmol) in DCM (10 mL) / MeOH (2 mL), followed by the addition of 1 drop of AcOH. The resulting mixture was stirred at room temperature overnight. The reaction was not complete, so more paraformaldehyde (13 mg, 0.44 mmol) and sodium triacetoxyborohydride (70.5 mg, 0.330 mmol) were added. After an additional 2 hours at room temperature, the mixture was quenched with saturated NaHCO solution, which was then diluted with DCM. The aqueous phase was extracted with more DCM, and the combined organic layers were washed with brine, dried over NaSO, and filtered. The solvent was evaporated to produce a yellow crude product, which was purified by reverse phase flash chromatography on a Biotage C18 column (from H2O + 0.1% HCOOH to 30% MeCN + 0.1% HCOOH). The appropriate fractions were evaporated and the resulting product was repurified by SCX column eluting with 1N NH 3 in MeOH to afford the title compound as a yellow solid (55 mg, 0.11 mmol, 50% yield).

[1431] LC-MS (ESI): m / z (M+1): 492.4 (Method 1)

[1432] 1H NMR (400MHz, DMSO-d6) δppm 9.78(br s,1H),9.18(br d,J=1.5Hz,1H),8.65(br s,1H),8.17(d,J=9.2Hz,1H),8.00(dd,J=6.6,2.7Hz,1H),7.69(br s,1H),7.63(ddd,J=8.9,4.2,2.8Hz,1H),7.45(dd,J=10.6,8.9Hz,1H),7.3 1-7.41(m,2...

Claims

1. Compounds of formula (I) and pharmaceutically acceptable salts thereof (I) in R1 is an aryl group optionally substituted by one or more groups, the aryl group is a phenyl group, the group is selected from a halogen atom, -(C1-C6)alkyl and -(C1-C6)haloalkyl; A is selected from the set consisting of: A1, A2, and A3 A1 A2 A3 R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6; X1 is C, CH or N; R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7; R 3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, -C(O)O-(C1-C6)alkyl, and -C(O)NH-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one -(C1-C6)alkyl; R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; R5 is H or -(C1-C6)alkyl; R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo; the N-oxide-heterocycloalkyl group represents a heterocycloalkyl group containing a nitrogen atom having an oxygen atom as a substituent; R7 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B ; -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups; - -(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; and - -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C -CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl; R A selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R B is a heterocycloalkyl group; R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

2. The compound of formula (I) and pharmaceutically acceptable salts thereof according to claim 1, wherein A is a group A1 A1 It is represented by formula (Ia) (him) R1 is an aryl group optionally substituted by one or more groups, the aryl group is a phenyl group, the group is selected from a halogen atom, -(C1-C6)alkyl and -(C1-C6)haloalkyl; R2 is selected from the group consisting of: -NR5C(O)R6 and -NR5R6; R5 is H or -(C1-C6)alkyl; R6 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B -NH-(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more -(C1-C6)alkyl; heteroaryl optionally substituted by one or more groups selected from -(C1-C6)alkylene-NR A R C and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-NR C -(C1-C6)alkylene-NR A R C ;-(C1-C6)alkylene-NR A -C(O)O-(C1-C6)alkyl; cycloalkyl optionally substituted with heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; heterocycloalkyl optionally substituted with one or more -(C1-C6)alkyl; -(C1-C6)alkylene-N-oxide-heterocycloalkyl; and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more groups Selected from -OH, halogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)OH, -C(O)O(C1-C6)alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-C(O)OR C 、-(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C , -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and oxo; the N-oxide-heterocycloalkyl group represents a heterocycloalkyl group containing a nitrogen atom having an oxygen atom as a substituent; R A is -(C1-C6)alkyl; R B is a heterocycloalkyl group; R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, cycloalkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -cycloalkyl-C(O)O-(C1-C6)alkyl and -(C1-C6)haloalkyl.

3. A compound selected from the group consisting of: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-4-(morpholin-4-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[methyl(oxetan-3-yl)amino]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-1-methylpiperidine-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-2-oxopiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-3-oxopiperazin-1-yl)propanamide; 3-(4-acetylpiperazin-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(3-methyl-1,3-diazinan-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylsulfonylpiperazin-1-yl)propanamide; 3-(3-acetyl-1,3-diazinan-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(3-methylsulfonyl-1,3-diazinan-1-yl)propanamide; N-4-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-N2-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; 3-[4-(2-aminoethyl)piperazin-1-yl]-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methylsulfonylethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-methylpiperazine-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-methylpiperidine-4-carboxamide; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-2-carboxylic acid methyl ester; 4-(3-((4-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyridin-2-yl)amino)-3-oxopropyl)piperazine-2-carboxylic acid; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{[2-(methylamino)ethyl]amino}propanamide; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid methyl ester; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid; Methyl 2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)acetate; Methyl 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate; Methyl 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazin-2-yl)acetate; 1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazine-2-carboxylic acid methyl ester; methyl 2-(1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazin-2-yl)acetate; Methyl 2-(1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{4-[2-(methylamino)ethyl]piperazin-1-yl}propanamide; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate; 2-[4-(2-aminoethyl)piperazin-1-yl]-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)acetamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1,1-dimethylpiperazin-1-ium chloride hydrochloride; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-(propan-2-yl)piperazine-2-carboxylic acid methyl ester; 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetic acid; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(morpholin-4-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(thiomorpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}propanamide hydrochloride; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid ethyl ester; 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}morpholin-4-ium-4-olate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid propan-2-yl ester; Cyclopropyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid oxetan-3-yl ester; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(1-oxo-1λ4-thiomorpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)propionamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methanesulfonylaminoethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4,4-difluoropiperidin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-hydroxypiperidin-1-yl)propanamide; 1-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea; 1-(4-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyridin-2-yl)-3-((1-methylpiperidin-4-yl)methyl)urea; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(3,4-dimethylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide; N-(4-{[6-(5-chloro-2,4-difluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-[2-(methylamino)ethyl]-1H-pyrazole-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(1-methylpiperidin-4-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(1,4-diazepan-1-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methyl-1,4-diazepan-1-yl)butanamide; cis-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(piperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-4-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-N-2-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl}pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide; N-(4-((6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methylsulfonylethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propanamide; Methyl 3-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanoylamino]pyridin-4-yl}amino)pyridazin-3-yl]propanoate; (1s,4s)-methyl 4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanoylamino)pyridin-4-yl)amino)pyridazin-3-yl)cyclohexane-1-carboxylate; Methyl (1r,4r)-4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanoylamino)pyridin-4-yl)amino)pyridazin-3-yl)cyclohexane-1-carboxylate; N-[4-({6-[5-(difluoromethyl)-2-fluorophenyl]-3-methylpyridazin-4-yl}amino)pyridin-2-yl]-3-(4-methylpiperazin-1-yl)propanamide; Methyl 4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanoylamino)pyridin-4-yl)amino)pyridazin-3-yl)butanoate.

4. The compound of formula (I) and pharmaceutically acceptable salts thereof according to claim 1, wherein A is a group A2 A2 It is represented by formula (Ib) (One) R1 is an aryl group optionally substituted by one or more groups, the aryl group is a phenyl group, the group is selected from a halogen atom and a -(C1-C6)alkyl group; X1 is C, CH or N; R3 is selected from the group consisting of: -C(O)NR5R7, -C(O)OR7, -OC(O)R7, -OR7, -NR5C(O)R7 and -OC(O)NR5R7; R 3’ is H or a member selected from the group consisting of: -(C1-C6)alkoxy, -OH, -C(O)O-(C1-C6)alkyl, and -C(O)NH-heterocycloalkyl, wherein the heterocycloalkyl is substituted with one -(C1-C6)alkyl; R5 is H or -(C1-C6)alkyl; R7 is selected from the group consisting of: -(C1-C6)alkylene-NR A R B ; -heterocycloalkyl optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkylene-SO2-(C1-C6)alkyl, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-NR A R C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C1-C6)alkylene-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally substituted with one or more -(C1-C6)alkyl groups; - -(C1-C6)alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; and - -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more groups selected from -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)alkylene-OH, -(C1-C6)alkylene-CN, -(C1-C6)haloalkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NH2, -(C1-C6)alkylene-NR A R C 、-(C1-C6)alkylene-CONR A R C 、-(C1-C6)alkylene-NR C CO-(C1-C6)alkyl, -(C1-C6)alkylene-NR C -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-NHSO2-(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkylene-SO2-(C1-C6)alkyl; R A selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R B is a heterocycloalkyl group; R c is H or a member selected from the group consisting of: -(C1-C6)alkyl and -(C1-C6)alkylene-OH; R8 is H or a member selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)alkylene-OH, and -(C1-C6)haloalkyl.

5. A compound selected from the group consisting of: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(morpholin-4-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(morpholin-4-yl)ethyl]quinoline-7-carboxamide; 2-(Morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate; 2-(Morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(piperazin-1-yl)ethyl]quinoline-7-carboxamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]quinoline-7-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]quinoline-7-carboxamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinolin-4-amine; 1-Methylpiperidin-4-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-(1-methylazetidin-3-yl)-1,7-naphthyridine-6-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-(1-methylpiperidin-4-yl)-1,7-naphthyridine-6-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-methylpiperazine-1-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-ethylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide; 1-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethan-1-one; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methanesulfonylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-{6-[2-fluoro-5-(propan-2-yl)phenyl]pyridazin-4-yl}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]-1-(4-methylpiperazin-1-yl)ethan-1-one; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-{2-[methyl(oxetan-3-yl)amino]ethoxy}quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]carbamate; N-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl N-methyl-N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[3-(3-methyl-1,3-diazinan-1-yl)propoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(2-methanesulfonylethyl)piperazine-1-carboxylate; (3R)-1-methylpyrrolidin-3-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}ethoxy)quinolin-4-amine; 1-(3-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-1,3-diazinan-1-yl)ethan-1-one; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(2-hydroxyethyl)piperazine-1-carboxylate; (3S)-1-methylpyrrolidin-3-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; Methyl 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)propanoate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(dimethylamino)ethyl]piperazine-1-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(3-methyl-1,3-diazinan-1-yl)ethoxy]quinolin-4-amine; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)-N-methylpropanamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate; 7-{2-[4-(2-aminoethyl)piperazin-1-yl]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine; N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]methanesulfonamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}ethoxy)quinolin-4-amine; N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]acetamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)propionitrile; 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethan-1-ol; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(1-methylpiperidin-4-yl)oxy]quinolin-4-amine; 2-{[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl](2-hydroxyethyl)amino}ethan-1-ol; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]carbamate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)pentane-1,5-diol; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(1-methylpiperidin-4-yl)methoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(3-methylimidazolidin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[(1-methylpiperidin-4-yl)methyl]piperazine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2,8-diazaspiro[4.5]decane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 8-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,6-diazaspiro[3.4]octane-6-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 3-(pyrrolidin-1-yl)azetidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(azetidin-1-yl)piperidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-6-ol; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 3-(pyrrolidin-1-yl)azetidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 4-(azetidin-1-yl)piperidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylic acid methyl ester; 1-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl) 3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylic acid methyl ester; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylic acid methyl ester; [6-(5-chloro-2-fluorophenyl)-4-({7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl}amino)pyridazin-3-yl]methanol; N-[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine.

6. The compound of formula (I) and pharmaceutically acceptable salts thereof according to claim 1, wherein A is a group A3 A3 It is represented by formula (Ic) (Ic) R1 is an aryl group optionally substituted by one or more halogen atoms, wherein the aryl group is a phenyl group; R4 is selected from the group consisting of: -C(O)NR5R7 and -C(O)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl; R5 is H or -(C1-C6)alkyl; R7 is selected from the group consisting of heterocycloalkyl substituted with one or more -(C1-C6)alkyl and -(C1-C6)alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more -(C1-C6)alkyl.

7. A compound selected from the group consisting of: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 6-(5-chloro-2-fluorophenyl)-N-[2-(4-methylpiperazine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyridazin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in admixture with one or more pharmaceutically acceptable carriers or excipients.

9. The pharmaceutical composition according to claim 8, which is intended for administration by inhalation.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 or 9 in the preparation of a medicament, wherein the medicament is used to prevent and / or treat a disease, disorder or condition mediated by the ALK5 signaling pathway in a mammal.

11. The use according to claim 10, wherein the medicament is for preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

12. The use according to claim 11, wherein the medicament is for preventing and / or treating fibrosis selected from the group consisting of pulmonary fibrosis, liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

13. The use according to claim 12, wherein the medicament is for preventing and / or treating idiopathic pulmonary fibrosis (IPF).

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