Pyridazinylamino derivatives as ALK5 inhibitors

Abstract

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

Description

[Technical field]

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

[0002] Transforming growth factor beta (TGFβ) is a protein that belongs to the TGFβ superfamily. It is involved in several processes, both cellular processes such as proliferation, migration and differentiation, as well as biological processes including wound healing, immunosuppression, carcinogenesis and extracellular matrix production.

[0003] The TGFβ superfamily also includes other members known as activins (Acts), among others (see, e.g., Hinck AP, FEBS Letters 586 (2012); 1860-1870). 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). TGFβR1 / ALK5 is recruited and activated through phosphorylation of its intracellular domain by TGFβR2, which in turn leads to phosphorylation of the receptor-activated (R)-Smad family, leading to activation of target gene transcription (see, e.g., Sheppard D., Proc Am Thorac Soc. (2006);(3):413-417). Similar to TGFβ signaling, the type I receptor for activin, ALK4, leads to activation of target gene transcription (see, e.g., Heldin CH et al., Cold Spring Harb Perspect Biol. (2016) Aug 1;8(8)). Several studies have linked excessive and / or dysregulated TGFβ activity to many diseases, including cancer and fibrosis (see, e.g., Syed V, J Cell Biochem. (2016) Jun;117(6):1279-87; Jakowlew SB. Cancer Metastasis Rev. (2006) Sep;25(3):435-57). Among fibrotic disorders, a key role for TGFβ has been demonstrated in organs such as the lung, heart, liver and kidney (see, e.g., Alhamad EH, J Thorac Dis. (2015);7(3):386-93). In particular, TGFβ expression is increased in fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic inflammatory conditions such as chronic obstructive pulmonary disease and asthma (see, e.g., Thomas BJ et al., Am J Respir Cell Mol Biol. (2016);(55):759-766). In the lung, TGFβ is expressed in several cell types, including epithelial cells, endothelial cells, connective tissue cells, macrophages, and fibroblasts. These cell populations may produce excess TGFβ in IPF human lung tissue.Furthermore, high levels of TGFβ have been detected in lung tissue and BAL of IPF patients (see, e.g., Bergeron A et al., Eur Respir J (2003);22:69-76). TGFβ gene expression and TGFβ protein production have been shown to be increased in various animal models of pulmonary fibrosis induced by bleomycin, silica, asbestos, and radiation (see, e.g., Wei F et al., Int Immunopharmacol. (2017) Jul;48:67-75; Choe JY et al., Inflamm Res. (2010) Mar;59(3):177-88; Wang X et al., Respir Res (2009);10, 36), and 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.). Conversely, TGFβ signaling inhibition achieved using knockout (KO) animals can block fibrosis development via TGFβ-related mechanisms (see, e.g., Bonniaud P et al., Am J Respir Crit Care Med (2005);171:889-898; 34). Similar results have been achieved with TGFβR1 inhibition in mouse bleomycin disease models (see, e.g., Wei Y et al., J Clin Invest. (2017);127(10):3675-3688). Activin signaling dysregulation, like TGFβ, is associated with fibroblast proliferation, myofibroblast differentiation and extracellular matrix (ECM) accumulation (see, e.g., Yamashita et al., J. Am. Soc. Nephrol. (2004) 15, 91-101).Moreover, overexpression of activin has been associated with pathology and fibrosis in various organs, such as the liver (see, e.g., Patella et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2006) 290, G137-G144), kidney (see, e.g., Agapova et al., Kidney Int. (2016) 89, 1231-1243), heart (see, e.g., Yndestad et al., Circulation (2004) 109, 1379-1385) and lung (see, e.g., de Kretser et al., Crit.Care (2013) 17:R263). Taken together, these data suggest the importance of ALK5 targeting in the pharmacological treatment of the above-mentioned diseases associated with dysregulated TGF signaling pathways. TGFβ signaling is strongly linked to cardiovascular homeostasis (see, for example, van Meeteren LA et al., Springer (2013)). Several studies in humans and mice have shown a key role for TGFβ in angiogenesis and vascular morphogenesis. Furthermore, TGFβ has a key role in cardiac valve development and functionality. Thus, selective control of the TGFβ pathway to target pathological effects while avoiding the suppression of signaling required for correct homeostasis is clearly important.

[0004] The answer to this critical point may be addressed by the use of an inhalation route to deliver anti-TGFβ drugs, which allows treatment of the affected lung compartment while bypassing cardiac exposure.

[0005] A variety of compounds have been cited in the literature as ALK5 and / or ALK4 receptor inhibitors.

[0006] 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, respectively, useful for the treatment of ALK4- or ALK5-mediated diseases, such as inflammatory or obstructive airways diseases, pulmonary hypertension and pulmonary fibrosis.

[0007] WO00 / 61576 and US2003 / 0149277 (Smithkline Beecham Corp) disclose triarylimidazole derivatives as ALK5 inhibitors, useful inter alia for the treatment of kidney disease, wound healing, renal disease, congestive heart failure, ulcers, neurological dysfunction and any disease in which fibrosis is a major contributing factor.

[0008] WO01 / 62756 (Smithkline Beecham PLC) discloses pyridinylimidazole derivatives as ALK5 inhibitors, useful inter alia for the treatment of kidney disease, wound healing, renal disease, congestive heart failure, ulcers, neurological dysfunction and any disease in which fibrosis plays a key role.

[0009] WO03 / 087304 (Biogen Inc.) discloses trisubstituted heteroaryls as ALK5 and / or ALK4 inhibitors useful for the treatment of, inter alia, idiopathic pulmonary fibrosis, diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, acute lung injury, post-infarction cardiac fibrosis, fibrotic cancer and fibroma.

[0010] Pyridazinylamino derivatives have been disclosed in the literature, but not as ALK5 inhibitors.

[0011] WO2005 / 033105 (Amgen) discloses, among other compounds, pyridazinylamino derivatives as vanilloid receptor ligands for the treatment of a number of diseases and disorders not involving fibrosis.

[0012] WO2002 / 022605 and WO2002 / 022602 (Vertex) describe pyridazine compounds as protein kinase inhibitors, useful inter alia for the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia.

[0013] WO02 / 24681 (Ortho-McNeil Pharmaceutical Inc.) describes pyridazine compounds useful as antitumor agents and as tyrosine kinase inhibitors for the treatment of diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.

[0014] Notably, ALK5 receptor inhibition may be useful in the treatment of fibrosis and diseases, disorders and conditions that result from fibrosis.

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

[0016] However, there is still the possibility to develop receptor ALK5 inhibitors characterized by good efficacy that are useful for the treatment of diseases or conditions associated with dysregulation of the ALK5 signaling pathway, in particular fibrosis. Summary of the Invention [Problem to be solved by the invention]

[0017] In particular, there is still the possibility of developing receptor ALK5 inhibitors useful for the treatment of diseases or conditions associated with dysregulation of ALK5 signaling in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), administered by the inhalation route and characterized by a good inhalation profile corresponding to good activity in the lungs, good lung retention and low metabolic stability to minimize systemic exposure and associated safety issues. [Means for solving the problem]

[0018] In this direction, we have surprisingly discovered a novel series of compounds of general formula (I) which solve the problem of providing potent inhibitors of the ALK5 receptor for administration by inhalation, which at the same time exhibit a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability as well as good selectivity across the kinome.

[0019] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] [During the ceremony, A is A1, A2, A3 and A4 [ka] selected from the group consisting of; R 1 is selected from the group consisting of aryl and pyridyl, wherein the aryl and pyridyl are optionally selected from the group consisting of halogen atoms and -(C 1 -C 6 ) alkyl; R 2 Ha-NR 5 C(O)R 6 , -NR 5 R 9 and -NH 2 selected from the group consisting of; X 1 is C or CH; X 2 is C, CH or N; R 3 -OR 7 and; R 4 is H or -C(O)O-(C 1 -C 6 ) alkyl; R 5 is H or -(C 1 -C 6 ) alkyl; R 6 is 1 or more -(C 1 -C6 ) alkyl substituted -(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 6 ) cycloalkyl;-(C 1 -C 6 ) Alkylene-NH 2 Optionally, one or more -(C 1 -C 6 )Alkylene-(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and -(C 3 -C 6 )cycloalkyl; and optionally one or more -(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6) alkyl, -(C 1 -C 6 ) alkylene-OH, -O-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 6 ) substituted with one or more groups selected from cycloalkyl and halogen atoms; R 7 Ha-(C 1 -C 6 ) alkyl and -(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 8 Ha-NR A R B ;-SH;-S-(C 1 -C 6 ) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH;-S-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; S-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally -C(O)OH, -C(O)O-(C 1 -C 6 ) Alkylene-NR A R C and -C(O)O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 ) alkylene-Si((C 1 -C 6 )Alkyl) 3 ;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6) alkylene-OH;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl;-S-(C 1 -C 6 ) alkylene-NH-C(O)-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-S-(C 1 -C 6 ) alkylene-NH-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and -OH; -O-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; -O-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally substituted with one or more -OH); -O-(C 1 -C 6 ) alkylene-aryl, where the aryl is -(C5 -C 6 ) heterocycloalkyl, 5 -C 6 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl; -O-(C 3 -C 9 )heterocycloalkyl; and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; R 9 is optionally -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 10 Ha-NR 5 C(O)R 6 and; R A is H or -(C 1 -C 6 ) alkyl; R B is H or -(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl;-(C 1 -C 6) alkylene-aryl, where the aryl is substituted with -OH; -(C 1 -C 6 ) alkylene-OH;-(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl;-(C 1 -C 6 ) alkylene-aryl-OCO-(C 1 -C 6 ) alkyl; and -(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) substituted with one or more groups selected from haloalkyl and oxo; or R A and R B are combined with the nitrogen atom to which they are attached to form -(C 3 -C 6 ) heterocycloalkyl, where -(C 3 -C 6 )Heterocycloalkyl is optionally -C(O)OH, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and oxo; or 3 -C 6)Heterocycloalkyl can be further fused -(C )heterocycloalkyl, where two adjacent carbon atoms are optionally substituted and optionally substituted with oxo. 5 -C 6 ) forming a heterocycloalkyl; R C Ha-(C 1 -C 6 ) alkyl. and pharma- ceutically acceptable salts thereof.

[0020] In a second aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof in admixture with one or more pharma- ceutically acceptable carriers or excipients.

[0021] In a third aspect, the present invention relates to a compound of formula (I) and a pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable salt thereof for use as a medicament.

[0022] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof or pharmaceutical compositions comprising compounds of formula (I) and pharma-ceutically acceptable salts thereof for use in the prophylaxis and / or treatment of a disease, disorder or condition mediated by the ALK5 receptor in a mammal.

[0023] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the prophylaxis and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0024] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the prophylaxis and / or treatment of idiopathic pulmonary fibrosis (IPF). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include stereoisomers, tautomers, or pharma- ceutically acceptable salts or solvates thereof.

[0026] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include compounds of formula (Ia), (Iaa), (Ib), (Iba), (Ic), (Ica) and (Id).

[0027] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) where the parent compound, if any, has a free acid or basic group suitably modified to the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0028] Suitable examples of such salts may include inorganic or organic acid addition salts of basic residues such as amino groups and inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0029] Cations of inorganic bases which may be suitably used in the preparation of salts include those of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0030] Those obtained by reaction of the main compound which functions 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.

[0031] The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, organic or inorganic. This physical association includes hydrogen bonds. In some cases, the solvate may be isolated, 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.

[0032] The term "stereoisomers" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0033] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0034] The term "diastereomer" refers to stereoisomers that are not mirror images.

[0035] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric species, wherein the composition is devoid of optical activity.

[0036] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" described herein are used herein to refer to the atomic configurations relative to a core molecule and are intended to be used as defined in the literature (IUP AC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0037] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by shifting of atoms or groups within the molecules.

[0038] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine, and iodine atoms.

[0039] The term “(C x -C y "(x)alkyl" (where x and y are integers) refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

[0040] The term “(C x -C y )Alkoxy" (where x and y are integers) refers to a linear or branched hydrocarbon of the indicated number of carbons attached to the remainder of the molecule via an oxygen bridge.

[0041] The term “(C x -C y )alkylene" (where x and y are integers) has a total of two unsatisfied valences, such as a divalent methylene radical (C x -C y ) alkyl group.

[0042] The expression “(C x -C y (C)haloalkyl" (wherein x and y are integers) refers to a "(C)haloalkyl" as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. x -C y Therefore, the "(C x -C y Examples of "haloalkyl" groups include halogenated, polyhalogenated, and fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl.

[0043] The term “(C x -C y )Cycloalkyl" (where x and y are integers) refers to a saturated cyclic hydrocarbon group containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0044] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 ring atoms, in which the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0045] The term "heteroaryl" refers to a mono- 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 one monocyclic aryl ring fused through a common bond.

[0046] The term “(C x -C y (C)heterocycloalkyl" (where x and y are integers) refers to a saturated or partially unsaturated monocyclic (C) heterocycloalkyl in which at least one ring carbon atom is replaced by at least one heteroatom (e.g., N, S, or O) or may bear an -oxo (=O) substituent. x -C y The heterocycloalkyl group may be further optionally substituted at any available position of the ring, i.e., at any available carbon atom or heteroatom for substitution. Substitution is achieved by the substitution of two (C x -C y ) heterocycloalkyl ring or one (C x -C y ) heterocycloalkyl and one (C x -C y ) The cycloalkyl rings may be on a carbon atom, including spiro disubstitution, forming a bicyclic ring system connected via one carbon atom. Substitution may also be on two adjacent carbon atoms forming further fused 5-6 membered heterocycloalkyl rings. Examples of spiro rings include, but are not limited to, for example, 6-methyl-2,6-diazaspiro[3.3]heptan-2-yl and 2-methyl-2,8-diazaspiro[4.5]decane; examples of fused rings include, for example, 2,2-dimethyl-2H-1,3-benzodioxol-5-yl. Additionally, the heterocycloalkyl may be a diazabicyclo ring or a cyclic carboxylic acid. Examples of diazabicyclo rings include, but are not limited to, 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl and 6-methyl-3,6-diazabicyclo[3.2.2]nonan-3-yl; examples of suitable cyclic carboxylic acids include, for example, 1,3-dioxalan-2-one and 4-methyl-1,3-dioxol-2-one.

[0047] Throughout this specification, the use of an asterisk "*" in the definitions of structural formulas indicates the point of attachment of the radical group to the remainder of the molecule.

[0048] A dash ("-") that is not between two letters or symbols is meant to represent a point of attachment for a substituent.

[0049] Carbonyl groups are preferably represented herein as -C(O)- as alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0050] Generally, the group within the brackets is a side chain group that is not included in the chain; brackets are used to aid in the clarity of linear chemical formulas when considered useful; for example, a sulfonyl group, --SO. 2 - is used to disambiguate, for example, from the sulfine group -S(O)O-. 2 - Also expressed as

[0051] The present invention relates to novel compounds that differ from structures disclosed in the literature at least in a common novel core scaffold. Indeed, the present invention relates to compounds that are [pyridazin-4-yl]amino derivatives that are receptor ALK5 inhibitors, with therapeutically desirable characteristics that make them particularly promising in some fibrotic diseases, including idiopathic pulmonary fibrosis (IPF).

[0052] The compounds of the present invention are active and potent as ALK5 receptor inhibitors and exhibit improved properties such as good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability and good selectivity across the kinome.In this regard, the prior art does not describe or suggest the pyridazinylamino derivatives of general formula (I) of the present invention having inhibitory activity on the receptor ALK5, which solves the above-mentioned needs.

[0053] Amgen discloses, among other compounds, pyridazinylamino derivatives. The compounds of formula (I) of the present invention differ from those of Amgen in at least the substituents of rings A1, A2 and A3. Amgen discloses the compounds as vanilloid receptor ligands for treating a number of diseases and disorders. Amgen does not disclose the compounds as ALK5 inhibitors, nor as compounds for treating fibrosis.

[0054] Vertex describes, inter alia, pyridazine derivatives. The compounds of formula (I) of the present invention differ from those of Vertex at least by the presence of a pyridyl or pyridyl-fused group connected to the amino linker carrying the pyridazine ring, instead of a triazole group. The Vertex compounds are described as protein kinase inhibitors useful for the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia. Vertex does not describe the compounds as ALK5 inhibitors, nor for the treatment of fibrosis.

[0055] Ortho-McNeil describes pyridazine compounds. The compounds of formula (I) of the present invention differ from those of Ortho-McNeil in the position of at least two nitrogen atoms in the pyridazine ring. 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 the compounds as ALK5 inhibitors, nor as compounds for the treatment of fibrosis.

[0056] More specifically, the present invention relates to a series of compounds having inhibitory activity against the ALK5 receptor, represented by the general formula (I) detailed below. Advantageously, the inhibitory action of the ALK5 receptor can be effective in the treatment of diseases in which these receptors play an important role in the pathogenesis, such as fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0057] Unlike the analogous compounds in the prior art, the compound of formula (I) of the present invention can act as an antagonist of ALK5 receptor, as recognized by those skilled in the art who are searching for suitable and effective compounds that are particularly useful for the treatment of fibrosis, especially idiopathic pulmonary fibrosis.As shown in the experimental section, especially in Table 4, the compound of formula (I) of the present invention shows a significant efficacy of about less than 10 nM in terms of the inhibitory activity of the receptor ALK5, confirming that it can inhibit the ALK5 receptor involved in fibrosis and diseases caused by fibrosis.As shown in the experimental section, especially in Comparative Examples, especially in Table 5, contrary to compound C1, which is characterized by the lack of pyrimidinyl, pyridinyl or pyridinyl fused group linked to the amino group carrying the pyridazine ring, the presence of pyrimidinyl, pyridinyl or pyridinyl fused group linked to the amino group carrying the pyridazine ring in the compound of the present invention unexpectedly and significantly determines the associated increase in the inhibitory activity of ALK5 receptor. Advantageously, the compounds of the present invention have extremely high efficacy and can be administered to humans at low doses compared to the compounds of the prior art, thus reducing the adverse events that typically occur when drugs are administered at high doses.In addition to being significantly more potent in their inhibitory activity against the ALK5 receptor, the compounds of the present invention are also characterized by a good inhalation profile, allowing them to act efficiently in the pulmonary compartment, while at the same time having low metabolic stability that allows them to minimize the disadvantages associated with systemic exposure, such as safety and tolerability issues.

[0058] Thus, the compounds of the present invention will be recognized by those skilled in the art searching for suitable and effective compounds useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, that are administered in particular by the inhalation route and that are characterized by a good inhalation profile corresponding to good pulmonary activity, good pulmonary retention and low metabolic stability that minimizes systemic exposure and associated safety issues.

[0059] Thus, in one embodiment, the present invention provides a compound of general formula (I): [ka] [During the ceremony, A is A1, A2, A3 and A4 [ka] selected from the group consisting of; R 1 is selected from the group consisting of aryl and pyridyl, wherein the aryl and pyridyl are optionally selected from the group consisting of halogen atoms and -(C 1 -C 6 ) alkyl; R 2 -NR 5 C(O)R 6 , -NR 5 R 9 and -NH 2 selected from the group consisting of; X 1 is C or CH; X 2 is C, CH or N; R 3 -OR 7 and; R 4 is H or -C(O)O-(C 1 -C 6 ) alkyl; R 5 is H or -(C 1 -C 6 ) alkyl; R 6 is 1 or more -(C 1 -C 6 ) alkyl substituted -(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -C(O)O-(C1 -C 6 ) alkyl and -(C 3 -C 6 ) cycloalkyl;-(C 1 -C 6 ) Alkylene-NH 2 Optionally, one or more -(C 1 -C 6 )Alkylene-(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and -(C 3 -C 6 )cycloalkyl; and optionally one or more -(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -O-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 6 ) substituted with one or more groups selected from cycloalkyl and halogen atoms; R 7 Ha-(C 1 -C 6 ) alkyl and -(C 1 -C 6 )Alkylene-(C 3-C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 8 Ha-NR A R B ;-SH;-S-(C 1 -C 6 ) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH;-S-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C6 ) alkyl, -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; S-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally -C(O)OH, -C(O)O-(C 1 -C 6 ) Alkylene-NR A R C and -C(O)O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 ) alkylene-Si((C 1 -C 6 )Alkyl) 3 ;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkylene-OH;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl;-S-(C 1 -C 6 ) alkylene-NH-C(O)-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9)heterocycloalkyl is optionally substituted with one or more oxo;-S-(C 1 -C 6 ) alkylene-NH-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C6 )Alkylene-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and -OH; -O-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; -O-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally substituted with one or more -OH); -O-(C 1 -C 6 ) alkylene-aryl, where the aryl is -(C 5 -C 6 ) heterocycloalkyl, 5 -C 6 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl; -O-(C 3 -C 9 )heterocycloalkyl; and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6) substituted with one or more groups selected from alkyl and oxo; R 9 is optionally -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 10 Ha-NR 5 C(O)R 6 and; R A is H or -(C 1 -C 6 ) alkyl; R B is H or is optionally substituted with one or more groups selected from halogen and -OH -(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl;-(C 1 -C 6 ) alkylene-aryl, where the aryl is substituted with -OH; -(C 1 -C 6 ) alkylene-OH;-(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl;-(C 1 -C 6 ) alkylene-aryl-OCO-(C 1 -C 6 ) alkyl; and -(C 1 -C 6 )Alkylene-(C 3 -C 9)heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) substituted with one or more groups selected from haloalkyl and oxo; or R A and R B are combined with the nitrogen atom to which they are attached to form -(C 3 -C 6 ) heterocycloalkyl, where -(C 3 -C 6 )Heterocycloalkyl is optionally -C(O)OH, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and oxo; or 3 -C 6 )Heterocycloalkyl can be further fused -(C )heterocycloalkyl, where two adjacent carbon atoms are optionally substituted and optionally substituted with oxo. 5 -C 6 ) forming a heterocycloalkyl; R C Ha-(C 1 -C 6 ) alkyl. and pharma- ceutically acceptable salts thereof.

[0060] In a more preferred embodiment, the present invention provides a 1 is phenyl substituted with fluorine and chlorine.

[0061] In another preferred embodiment, the present invention provides 1is pyridyl substituted with fluorine and methyl.

[0062] In another preferred embodiment, the present invention relates to a compound of formula (I) comprising R 8 Ga-NR A R B ;-SH;-S-(C 1 -C 6 ) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH;-S-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C6 ) alkylene substituted with one or more groups selected from -OH and -OH; S-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally -C(O)OH, -C(O)O-(C 1 -C 6 ) Alkylene-NR A R C and -C(O)O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 ) alkylene-Si((C 1 -C 6 )Alkyl) 3 ;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkylene-OH;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl;-S-(C 1 -C 6 ) alkylene-NH-C(O)-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-S-(C 1-C 6 ) alkylene-NH-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6) alkyl; -O-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and -OH; -O-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; -O-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally substituted with one or more -OH); -O-(C 1 -C 6 ) alkylene-aryl, where the aryl is -(C 5 -C 6 ) heterocycloalkyl, 5 -C 6 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl; -O-(C 3 -C 9 )heterocycloalkyl; and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6) substituted with one or more groups selected from alkyl and oxo.

[0063] In a particularly preferred embodiment, the present invention relates to a compound in which A is A1 [ka] and formula (Ia) [ka] [During the ceremony, R 1 is selected from the group consisting of aryl and pyridyl, wherein the aryl and pyridyl are optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and halogen atoms; R 2 Ha-NR 5 C(O)R 6 , -NR 5 R 9 and -NH 2 selected from the group consisting of; R 5 is H or -(C 1 -C 6 ) alkyl; R 6 is 1 or more -(C 1 -C 6 ) alkyl substituted -(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6) haloalkyl, -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 6 ) cycloalkyl;-(C 1 -C 6 ) Alkylene-NH 2 Optionally, one or more -(C 1 -C 6 )Alkylene-(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and -(C 3 -C 6 )cycloalkyl; and optionally one or more -(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -O-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 6 ) substituted with one or more groups selected from cycloalkyl and halogen atoms; R 8 Ha-NR A R B ;-SH;-S-(C 1 -C 6) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH;-S-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; S-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally -C(O)OH, -C(O)O-(C 1 -C 6 ) Alkylene-NR A R Cand -C(O)O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 ) alkylene-Si((C 1 -C 6 )Alkyl) 3 ;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkylene-OH;-S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl;-S-(C 1 -C 6 ) alkylene-NH-C(O)-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-S-(C 1 -C 6 ) alkylene-NH-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-O-(C 1 -C 6 ) alkyl; -O-(C1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and -OH; -O-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkylene substituted with one or more groups selected from -OH and -OH; -O-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally substituted with one or more -OH); -O-(C 1 -C 6 ) alkylene-aryl, where the aryl is -(C 5 -C 6 ) heterocycloalkyl, 5 -C 6 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 ) alkyl; -O-(C 3 -C 9 )heterocycloalkyl; and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; R 9 is optionally -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9)heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R A is H or -(C 1 -C 6 ) alkyl; R B is H or is optionally substituted with one or more groups selected from halogen and -OH -(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl;-(C 1 -C 6 ) alkylene-aryl, where the aryl is substituted with -OH; -(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; and -(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; or R A and R B together with the nitrogen atom to which they are attached, -(C 3 -C 6 )heterocycloalkyl (wherein the -(C 3 -C 6 )Heterocycloalkyl is optionally -C(O)OH, -(C 1 -C6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; R C Ha-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof:

[0064] In another particularly preferred embodiment, the present invention relates to compounds of formula (Ia) and pharma- ceutically acceptable salts thereof, wherein R 1 is selected from the group consisting of aryl and pyridyl, wherein the aryl and pyridyl are optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and halogen atoms; R 2 Ha-NR 5 C(O)R 6 and -NH 2 selected from the group consisting of; R 5 is H or -(C 1 -C 6 ) alkyl; R 6 is 1 or more -(C 1 -C 6 )alkyl-substituted heterocycloalkyl and -(C 1 -C 6 ) alkylene-heterocycloalkyl, where the heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -C(O)O-(C 1 -C 6 )alkyl, -cycloalkyl and -(C 1 -C 6) Alkylene-NH 2 substituted with; R 8 Ha-NR A R B ;-S-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 ) alkylene-OH;-S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH;-O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O)2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl and -O-(C 1 -C 6 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally has one or more —(C 1 -C 6 ) substituted with alkyl; R A is H or -(C 1 -C 6 ) alkyl; R B is J or -(C 1 -C 6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl; R C Ha-(C 1 -C 6 ) alkyl; Concerning compounds.

[0065] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ia) listed in Table 1 below and its pharma- ceutically acceptable salts. These compounds are particularly active at the ALK5 receptor, as shown in Table 4.

[0066] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

[0067] In an even more preferred embodiment, the present invention relates to a method for the preparation of [ka] and formula (Iaa) [ka] [During the ceremony, R 1 is selected from the group consisting of aryl and pyridyl, wherein the aryl and pyridyl are optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and halogen atoms; R 2 -NR 5 C(O)R 6 , -NR 5 R 9 and -NH 2 selected from the group consisting of; R 5 is H or -(C 1 -C 6 ) alkyl; R 6 is 1 or more -(C 1 -C 6 ) alkyl substituted -(C 3 -C 9 )heterocycloalkyl;-(C1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 6 ) cycloalkyl;-(C 1 -C 6 ) Alkylene-NH 2 Optionally, one or more -(C 1 -C 6 )Alkylene-(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and -(C 3 -C 6 )cycloalkyl; and optionally one or more -(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -O-(C 1 -C 6) alkyl, -C(O)OH, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) substituted with one or more groups selected from haloalkyl and halogen atoms; R 8 -NR A R B ;-SH;-S-(C 1 -C 6 ) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH;-S-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and oxo; -S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl;S-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 ) cycloalkyl is optionally substituted with one or more -OH; -O-(C1 -C 6 ) alkyl;S-(C 1 -C 6 ) alkylene-aryl, wherein the aryl is optionally substituted with one or more -C(O)OH; -O-(C 1 -C 6 ) haloalkyl; -S-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkylene-OH;-O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 ) alkylene-NH-C(O)-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl is optionally substituted with one or more oxo;-O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6) alkyl; -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 )Alkylene-(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 6 )Cycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and -OH; -O-(C 1 -C 6 ) alkylene-aryl (wherein the aryl is optionally substituted with one or more -OH); -O-(C 1 -C 6 ) alkylene-aryl, where the aryl is -(C 5 -C 6 ) heterocycloalkyl, 5 -C 6 )heterocycloalkyl is optionally oxo and -(C 1 -C 6 )alkyl; optionally substituted with one or more groups selected from -C(O)OH and -C(O)O-(C 1 -C 6 ) alkyl; 3 -C 9 )heterocycloalkyl; -O-(C 3 -C 9 )heterocycloalkyl; and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9)heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; R 9 is optionally -C(O)O-(C 1 -C 6 ) alkyl and -(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R A is H or -(C 1 -C 6 ) alkyl; R B is H or is optionally substituted with one or more groups selected from halogen and -OH -(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl;-(C 1 -C 6 ) alkylene-aryl, where the aryl is substituted with -OH; -(C 3 -C 9 )heterocycloalkyl;-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; and -(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C1 -C 6 ) alkylene-OH, -(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; or R A and R B together with the nitrogen atom to which they are attached, -(C 3 -C 6 )heterocycloalkyl (wherein the -(C 3 -C 6 )Heterocycloalkyl is optionally -C(O)OH, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; R C Ha-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof:

[0068] In a more preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein R 2 -NR 5 C(O)R 6 and R 5 is H or -(C 1 -C 6 ) alkyl, R 6-(4-methylpiperazin-1-yl)ethyl, -[4-(2-aminoethyl)piperazin-1-yl]-ethyl, methyl(2-(4-ethylpiperazin-1-yl)ethyl)carbamate, methyl 4-Ethyl-1-methylpiperazine-2-carboxylate, -[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl, -[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl, -(4-methylpiperazin-1-yl)propyl, -(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methyl, -(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl, -2-methyl-2,8-diazaspiro[4.5]decane, -(4-methyl-1,4-diazepan-1-yl)methyl, -(morpholin-4-yl)ethyl, cyclopropyl, -(piperazin-1-yl)methyl, -(( 4-Methyl-1,4-diazepan-1-yl)methyl), -(2-(piperazin-1-yl)ethyl), -((6-methyl-3,6-diazabicyclo[3.2.2]nonan-3-yl)methyl), -(3-(4-methylpiperazin-1-yl)cyclobutyl), -(2-(4-methyl-1,4-diazepan-1-yl)ethyl), -3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutyl, -3-(thiomorpholin-4-yl)cyclobutyl, -3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutyl, -[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl, -(2-(piperazin-1-yl)ethyl), -3-(4-methyl-1,4-diazepan-1-yl)cyclobutyl, -3-[4-(propan-2-yl)piperazin-1-yl]cyclobutyl, 3-(4-ethylpiperazin-1-yl)cyclobutyl, -3-(4-cyclopropylpiperazin-1-yl)cyclobutyl, -3-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]cyclobutyl, -3-(4-methoxypiperidin-1-yl)cyclobutyl, ethyl-(cyclobutyl)piperidine-4-carboxylate, -(cyclobutyl)piperidine-4-carboxylic acid, -3-(4-methylpiperidin-1-yl)cyclobutyl, -3-[4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl]cyclobutyl, -3 -[3-(2-fluoroethyl)-4-methylpiperazin-1-yl]cyclobutyl, -3-{5-methyl-5,8-diazaspiro[3.5]nonan-8-yl}cyclobutyl, -3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}cyclobutyl, -(3,5-dimethylpiperazin-1-yl)ethyl, -3-[(4-methylpiperazin-1-yl)methyl]bicyclobutyl is selected from the group consisting of -3-[(4-cyclopropylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentyl, -3-(4-methylpiperazin-1-yl)cyclopentyl, -3-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl}bicyclo[1.1.1]pentyl and -(3,5-dimethylpiperazin-1-yl)methyl; R. 8are -(2-hydroxyethoxy), -[3-(methylsulfanyl)propoxy], -(3-methanesulfonylpropoxy), -(2-aminoethoxy), -(2-methanesulfonamidoethoxy), -[2-(dimethylamino)ethoxy], -methoxy, methyl 2-Methoxyacetate, -methylsulfanyl, -methanesulfonyl, -methylsulfoximine, -[(2-hydroxyethyl)sulfanyl], -[(3-hydroxypropyl)sulfanyl], -(methylamino), -(dimethylamino), -(2-methoxyethoxy), -[2-(4-methylpiperazin-1-yl)ethoxy], -[2-(dimethylamino)ethoxy], -[(1-methylazetidin-3-yl)methoxy], -(2,2,2-trifluoroethoxy), -(2,2-difluoroethoxy), -[2-(pyrrolidin-1-yl)ethoxy], -(3-methanesulfinylpropoxy), - [3-(N,N,N-trimethylaminium)ethoxy], -[2-(4-methylpiperazin-1-yl)ethoxy], -(3-hydroxycyclobutyl)methoxy, -(tetrahydrofuran-3-yl)oxy, -[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy], -(2,3-dihydroxypropoxy), -[(2-oxo-1,3-dioxolan-4-yl)methoxy], -[3-(hydroxymethyl)cyclobutoxy], -[(3-hydroxyphenyl)methoxy], -[(1-hydroxy-2-methylpropan-2-yl)sulfanyl], -[3-(hydroxymethyl)azetidin-1-yl], methyl Azetidine-3-carboxylate, azetidine-3-carboxylic acid, propan-2-yl azetidine-3-carboxylate, -{[(3-hydroxyphenyl)methyl]amino}, -{[(3-hydroxyphenyl)methyl](methyl)amino}, -{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}, -[methyl(oxolan-3-yl)amino], -{methyl[(2-oxooxolan-3-yl)methyl]amino}, -[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino], -{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}, -[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methoxy], -[(3-hydroxy-3-methylcyclobutyl)methoxy], -[(methylbicyclo[1.1.1]pentane-1-carboxylate)methoxy], -{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}, methyl Morpholine-2-carboxylate, morpholine-2-carboxylic acid, -{[ethyl-2,2-dimethylpropanoate](methyl)amino}, propan-2-yl azetidine-2-carboxylate, azetidine-2-carboxylic acid, -({[3-(hydroxymethyl)-2-oxooxolan-3-yl]methyl}(methyl)amino), -{[(3-hydroxycyclobutyl)methyl]sulfanyl}, -sulfanyl, -{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]sulfanyl}, -[(3-methyl-2-oxooxolan-3-yl)sulfanyl], -{[2-(2-hydroxyethoxy)ethyl]sulfa The present invention relates to a compound selected from the group consisting of N-[2-(sulfanyl)ethyl]-5-oxooxolane-3-carboxamide, -3-[(sulfanyl)methyl]benzoic acid, -{[(3-methyl-2-oxoxolan-3-yl)methyl]sulfanyl}, -({[3-(methoxymethyl)-2-oxoxolan-3-yl]methyl}(methyl)amino), -4-[(sulfanyl)methyl]benzoic acid, -{[(6-oxooxan-2-yl)methyl]sulfanyl} and N-[2-(sulfanyl)ethyl]-5-oxooxolane-3-carboxamide.

[0069] In a more preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein R 2 Ha-NR 5 C(O)R 6 and R 5 is H or -(C 1 -C 6) alkyl, R 6 is selected from the group consisting of -(4-methylpiperazin-1-yl)ethyl, -(4-methyl-1,4-diazepan-1-yl)methyl, -(-3,5-dimethylpiperazin-1-yl)ethyl, -[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl and ethyl-(cyclobutyl)piperidine-4-carboxylate; R 8 relates to a compound selected from the group consisting of -methylsulfanyl, -[(2-hydroxyethyl)sulfanyl], -[(2-oxo-1,3-dioxolan-4-yl)methoxy], -{[(6-oxooxan-2-yl)methyl]sulfanyl}, -{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]sulfanyl}, -{[(3-methyl-2-oxoxolan-3-yl)methyl]sulfanyl} and N-[2-(sulfanyl)ethyl]-5-oxoxolane-3-carboxamide.

[0070] In another preferred embodiment, the present invention provides 2 Ga-NH 2 The present invention relates to compounds of formula (Iaa),

[0071] In an equally preferred embodiment, the present invention provides a method for the preparation of a compound according to the present invention, wherein A is A2 [ka] and formula (Ib) [ka] [During the ceremony, X 1 is C or CH; R 3 -OR 7 and; R 7 Ha-(C 1 -C 6 ) alkyl and -(C 1 -C 6 )Alkylene-(C 3 -C 9)heterocycloalkyl, wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 8 -NR A R B , -O-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) haloalkyl, -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH), -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) Alkylene-NR A R B , -O-(C 1 -C 6 ) Alkylene-N + R A R B R C , -O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6)Alkylene-O-(C 1 -C 6 ) alkyl and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) substituted with alkyl; R A is H or -(C 1 -C 6 ) alkyl; R B is J or -(C 1 -C 6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl; R C Ha-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof:

[0072] In a particularly preferred embodiment, the present invention relates to a method for the preparation of [ka] and formula (Iba) [ka] [During the ceremony, R 3 -OR 7 and; R 7 Ha-(C 1 -C 6 ) alkyl and -(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted; R 8 Ha-NR A R B , -S-(C 1 -C 6 ) alkyl, -S-(C 1 -C 6 ) alkylene-OH, -S(O)=NH-(C 1 -C 6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl, -S(O)-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) haloalkyl, -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH), -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) Alkylene-NR A R B , -O-(C 1 -C 6 ) Alkylene-N + R A R B R C , -O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl, -O-(C 1 -C 6) Alkylene-S(O) 2 -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) Alkylene-NH-S(O) 2 -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) substituted with alkyl; R A is H or -(C 1 -C 6 ) alkyl; R B is J or -(C 1 -C 6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl; R C Ha-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (Ib) and pharma- ceutically acceptable salts thereof:

[0073] In a more preferred embodiment, the present invention relates to a compound of formula (Iba), wherein R 3 -OR 7 and R 7 is selected from the group consisting of methyl and -7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl; R 8is selected from the group consisting of methoxy, -(2-hydroxyethoxy), -(2,2-difluoroethoxy), -(2-aminoethoxy), -(2-methanesulfonamidoethoxy), -(2-methoxyethoxy), -[2-(4-methylpiperazin-1-yl)ethoxy], -[2-(dimethylamino)ethoxy] and -(2,2,2-trifluoroethoxy).

[0074] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iba) listed below in Table 2 and its pharma- ceutically acceptable salts. These compounds are particularly active at the ALK5 receptor, as shown in Table 4.

[0075] [Table 2-1] [Table 2-2]

[0076] According to another preferred embodiment, the present invention relates to a compound in which A is A3 [ka] and formula (Ic) [ka] [During the ceremony, R 1 is selected from the group consisting of aryl and pyridyl, wherein said aryl and pyridyl are optionally substituted with one or more halogen atoms; X 2 is C, CH or N; R 4 is H or -C(O)O-(C 1 -C 6 ) alkyl; R 8 Ha-NR A R B ;-S-(C 1 -C 6) alkylene-aryl, where the aryl is optionally -C(O)O-(C 1 -C 6 ) Alkylene-NR A R C and -C(O)O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl, wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; —O—(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) haloalkyl; -O-(C 1 -C 6 ) alkylene-OH (wherein the -O-(C 1 -C 6 ) alkylene is substituted with one or more -OH; -O-(C 1 -C 6 ) alkylene-C(O)O-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-NR A R B ;-O-(C 1 -C 6 ) Alkylene-N + R A R B R C ;-O-(C 1 -C 6 )Alkylene-S-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) alkylene-S(O)-(C 1 -C 6 ) alkyl; -O-(C 1 -C 6 ) Alkylene-S(O) 2 -(C 1 -C 6) alkyl; -O-(C 1 -C 6 )Alkylene-O-(C 1 -C 6 ) alkyl and -O-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) substituted with alkyl; R A is H or -(C 1 -C 6 ) alkyl; R B is J or -(C 1 -C 6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl; R C Ha-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof:

[0077] In a more preferred embodiment, the present invention relates to a compound of formula (Ic) 8 is selected from the group consisting of -[3-(dimethylamino)propoxy], -[3-(N,N,N-trimethylamino)propoxy], -[2-(4-methylpiperazin-1-yl)ethoxy], -[2-(dimethylamino)ethoxy], (1-methylpiperidin-4-yl)methyl 4-[(sulfanyl)methyl]benzoate and 2-(dimethylamino)ethyl 4-[(sulfanyl)methyl]benzoate.

[0078] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ic) listed in Table 3 below and its pharma- ceutically acceptable salts. These compounds are particularly active at the ALK5 receptor, as shown in Table 4.

[0079] [Table 3]

[0080] In a particularly preferred embodiment, the present invention relates to a method for the treatment of osteoarthritis, [ka] and the formula (Ica) [ka] [In the formula, X 2 is C and R 4 is H or -C(O)O-(C 1 -C 6 ) alkyl. The present invention relates to compounds of formula (Ic) and pharma- ceutically acceptable salts thereof:

[0081] In a further preferred embodiment, the present invention provides 4 is H.

[0082] In a further preferred embodiment, the present invention provides 4 is methyl carboxylate.

[0083] In a further preferred embodiment, the present invention relates to a compound of formula (Ica), 8is selected from the group consisting of -[3-(dimethylamino)propoxy], -[3-(N,N,N-trimethylamino)propoxy], -[2-(4-methylpiperazin-1-yl)ethoxy], -[2-(dimethylamino)ethoxy], (1-methylpiperidin-4-yl)methyl 4-[(sulfanyl)methyl]benzoate and 2-(dimethylamino)ethyl 4-[(sulfanyl)methyl]benzoate.

[0084] In another particularly preferred embodiment, the present invention provides [ka] and formula (Id) [ka] [During the ceremony, R 1 is aryl optionally substituted with one or more halogen atoms; R 10 Ha-NR 5 C(O)R 6 and; R 5 is H; R 6 is 1 or more -(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl and -(C 3 -C 6 ) cycloalkyl;-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C6 ) alkyl); and optionally one or more -(C 1 -C 6 )Alkylene-(C 3 -C 9 ) heterocycloalkyl substituted -(C 3 -C 6 ) cycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) substituted with alkyl; R 8 -NR A R B ;-S-(C 1 -C 6 ) alkyl (wherein the -(C 1 -C 6 ) alkyl is optionally substituted with one or more -OH; -S-(C 1 -C 6 ) alkylene-OH (wherein the -(C 1 -C 6 ) alkylene optionally has one or more -(C 1 -C 6 ) alkyl substituted);-S-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )heterocycloalkyl optionally contains one or more -(C 1 -C 6 ) alkyl substituted);-S(O)=NH-(C 1 -C 6 ) alkyl; -S(O) 2 -(C 1 -C 6 ) alkyl; -S(O)-(C 1 -C 6 ) alkyl; -S-(C 1 -C 6 ) alkylene-Si((C 1 -C 6 )Alkyl) 3selected from the group consisting of; R A is H or -(C 1 -C 6 ) alkyl; R B Ha-(C 1 -C 6 )Alkylene-(C 3 -C 9 )heterocycloalkyl (wherein the -(C 3 -C 9 )Heterocycloalkyl is optionally -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo; or R A and R B are combined with the nitrogen atom to which they are attached to form -(C 3 -C 6 ) heterocycloalkyl, where -(C 3 -C 6 )Heterocycloalkyl is optionally -C(O)OH, -(C 1 -C 6 ) alkylene-OH, -C(O)O-(C 1 -C 6 ) alkyl and oxo; or 3 -C 6 )Heterocycloalkyl can be further fused -(C )heterocycloalkyl, where two adjacent carbon atoms are optionally substituted and optionally substituted with oxo. 5 -C 6 ) to form a heterocycloalkyl. The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof:

[0085] In a more preferred embodiment, the present invention relates to a compound of formula (Id) 6is selected from the group consisting of -(4-methylpiperazin-1-yl)cyclobutane, -(4-methylpiperazin-1-yl)ethyl, -(3,5-dimethylpiperazin-1-yl)ethyl, -(4-cyclopropylpiperazin-1-yl)cyclobutene, -[(4-methylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentane, -(3,5-dimethylpiperazin-1-yl)cyclobutane, and -(4-methyl-1,4-diazepan-1-yl)methyl; and R 8 is selected from the group consisting of -(2-hydroxyethyl)sulfanyl, N-methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino and -[2-(trimethylsilyl)ethyl]sulfanyl.

[0086] In a more preferred embodiment, the present invention relates to a compound of formula (Id) 6 is selected from the group consisting of -(4-methylpiperazin-1-yl)ethyl and -(3,5-dimethylpiperazin-1-yl)ethyl; R 8 is selected from the group consisting of -(2-hydroxyethyl)sulfanyl and N-methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino.

[0087] According to a preferred embodiment, the present invention relates to at least one compound of formula (Id) listed in Table 6 below, and its pharma- ceutically acceptable salts. These compounds are particularly active at the ALK5 receptor, as shown in Table 4.

[0088] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0089] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the following general methods and methods detailed in the schemes shown below, or using slight modifications that are readily available to those of skill in the art. Although specific embodiments of the present invention may be shown or described herein, those of skill in the art will recognize that all embodiments or aspects of the present invention can be obtained by using the methods described herein or by using other known methods, reagents, and starting materials. When typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used, unless otherwise indicated. Although optimal reaction conditions may vary with the particular reactants or solvents used, such conditions can be readily determined by one of skill in the art by routine optimization procedures. Thus, the methods described below should not be viewed as limiting the scope of synthetic methods available for the preparation of the compounds of the present invention.

[0090] In some instances, steps are necessary to mask or protect sensitive or reactive moieties, typically using known protecting groups (PG) according to general principles of chemistry (Protective groups in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0091] The compounds of formula (I) of the present invention have been found to be surprisingly effective in inhibiting the receptor ALK5. Advantageously, the inhibition of ALK5 can result in the effective treatment of diseases or conditions in which the ALK5 receptor is involved. In this regard, the compounds of formula (I) of the present invention have a pIC 50 (I C 50 , the negative logarithm of the half-maximal inhibitory concentration), followed by pK i (Dissociation function K i It has been found according to the present invention that the compounds of the present invention have an inhibitory potency of ALK5, which is expressed as a pK of 8.5 to 9.4, more preferably 9.5 to 9.9, and even more preferably 10 or more. ihas.

[0092] In one embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament.Thus, the present invention preferably relates to a compound of formula (I) in the manufacture of a medicament for use in the prophylaxis and / or treatment of a disease, disorder or condition associated with the ALK5 signaling pathway.

[0093] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prevention and / or treatment of a disease, disorder or condition associated with the ALK5 signaling pathway.

[0094] In certain embodiments, the present invention relates to compounds of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0095] 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, including, but not limited to, fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0096] Preferably, the compounds of formula (I) of the present invention or pharmaceutical compositions comprising the compounds of formula (I) are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0097] More preferably, the compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) of the present invention are useful for the treatment of idiopathic pulmonary fibrosis (IPF).

[0098] As used herein, a "safe and effective amount" with respect to a compound of formula (I) or a pharma- ceutically acceptable salt thereof or other pharma- ceutical active agent means an amount of the compound that is sufficient to treat the patient's condition but low enough to avoid serious side effects, yet can be routinely determined by one of skill in the art.

[0099] The compounds of formula (I) may be administered once or according to a dosing regimen in which they are administered several times at various intervals over a period of time.Typical daily dosages may vary depending on the route of administration chosen.

[0100] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in admixture with at least one pharma- ceutically acceptable carrier or excipient.

[0101] In certain embodiments, the present invention relates to pharmaceutical compositions of a compound of formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0102] The administration of the compound of the present invention and its pharmaceutical compositions can be achieved, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and infusion) and by inhalation, depending on the need of the patient.Preferably, the compound of the present invention is administered orally or by inhalation.More preferably, the compound of the present invention is administered by inhalation.

[0103] In certain preferred embodiments, the pharmaceutical compositions of the compounds of Formula (I) are solid oral dosage forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0104] In certain embodiments, the pharmaceutical composition of the compound of Formula (I) is a tablet.

[0105] The compounds of the present invention may be administered alone or in combination with a variety of pharma- ceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known additives including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, colorants, flavoring agents, lubricants and the like.

[0106] In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as aqueous and non-aqueous solutions, emulsions and suspensions.Such liquid dosage forms may also contain suitable known inert diluents, such as water, and suitable known additives, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compound of the present invention.

[0107] In a further embodiment the pharmaceutical composition of a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered dose aerosol or a propellant-free inhalable formulation.

[0108] For administration as a dry powder, single or multi-dose inhalers known from the prior art can be utilized, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0109] A diluent or carrier which is chemically inert towards the compound of the invention, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to powders of the compound of the invention.

[0110] Inhalation aerosols containing a propellant gas, such as hydrofluoroalkanes, may contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients, such as cosolvents, stabilizers and other additives if desired.

[0111] Propellant-free inhalation formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles and may be delivered by jet or ultrasonic nebulizers or soft mist nebulizers known from the prior art.

[0112] The compounds of the invention may be administered as the sole active agent or in combination with other pharma- ceutical active ingredients.

[0113] The dosage of the compounds of the present invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, and the like, among others.

[0114] The present invention also relates to a device containing a pharmaceutical composition comprising a compound of formula (I) of the present invention in the form of a single or multiple dose dry powder inhaler or a metered dose inhaler.

[0115] All preferred groups or embodiments described above for the compounds of formula (I) may be combined with one another and apply mutatis mutandis.

[0116] In a first embodiment of the present invention, compounds of formula (I) may be prepared by the following synthetic route as depicted in Scheme 1. [ka]

[0117] Compounds of formula (III) can be obtained by reaction of commercially available compound (II) with an appropriate alcohol, amine or thiol under nucleophilic aromatic substitution (SNAr). Typical reaction conditions are NaH or K 2 CO 3 The reaction includes a suitable base such as ethyl acetate, a suitable solvent such as DMF or THF, and a suitable temperature, typically room temperature to 130° C. Reaction of compound (III) under metal catalyzed cross-coupling conditions gives compound (IV). A typical cross-coupling reaction can be a Suzuki coupling or similar reaction described in “Transition Metals for 15 Organic Synthesis”, 2nd Ed, 1, 2004. Representative Suzuki reaction conditions include the reaction of compound (III) with a suitable boronic acid in a mixed solvent such as 1,4-dioxane and water with K 2 CO 3 and bases such as PdCl 2 (PPh 3 )2 Finally, compounds of formula (I) can be obtained by reacting compounds of formula (IV) with an appropriate halide under standard Buchwald-Hartwig amination conditions. Typical Buchwald-Hartwig conditions include the reaction of Cs with a Pd catalyst in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 100° C. 2 CO 3 a suitable base such as Xantphos, a suitable ligand agent such as Pd(OAc) 2 Alternatively, compounds of formula (I) can be obtained starting from commercially available compound (V). In this case, the SNAr of compound (V) with 2,4-dimethoxybenzylamine in a suitable solvent such as THF, typically at 50° C., can give compound (VI). 8 Introduction of Cs can be achieved, for example, by a metal-catalyzed cross-coupling reaction such as the Buchwald-Hartwig amination with a suitable amine or by an SNAr with a suitable nucleophile. Representative Buchwald-Hartwig amination conditions are 2 CO 3 Suitable bases such as Pd 2 (dba) 3The reaction involves the use of a palladium catalyst such as tBuXPhos and a suitable ligand such as tBuXPhos. Such reactions are usually carried out in a suitable solvent such as toluene at a suitable temperature such as, for example, 90° C. Typical SNAr conditions include a suitable base such as NaH in a suitable solvent such as DMF at a suitable temperature such as, for example, 130° C. Reaction of a compound of formula (VII) with a suitable boronic acid under Suzuki cross-coupling conditions as described above can provide compound (VIII). Removal of the 2,4-dimethoxybenzyl protecting group under acidic conditions such as, for example, TFA in DCM at room temperature provides a compound of formula (IV), which can be reacted with a suitable halide under Buchwald-Hartwig amination conditions as described above to provide a compound of formula (I). Alternatively, a compound of formula (IV) can be reacted under Sandmeyer conditions to provide compound (X). Typical Sandmeyer reaction conditions include the presence of tert-butyl nitrite, a suitable catalytic copper salt such as copper(II) bromide, a suitable solvent such as MeCN, and a suitable temperature such as, for example, 25° C. Finally, insertion of group A into compounds of formula (X) can be achieved by reaction with a suitable amine under standard Buchwald-Hartwig amination conditions to give compounds of formula (I). In this case, typical Buchwald-Hartwig conditions include, for example, K 2 O 4 at a suitable temperature, such as 110° C., in a suitable solvent, such as 1,2-dimethoxyethane. 3 PO 4 a suitable base such as xanthophos, a suitable ligand agent such as Pd 2 (dba) 3 In some cases, the compound of formula (VII) may first be subjected to deprotection under acidic conditions as described above to give compound (III). In these cases, compound (III) may then be reacted with a suitable halide under Buchwald-Hartwig amination conditions to give compound (IX). Typical Buchwald-Hartwig conditions include the presence of a suitable base such as cesium carbonate, a suitable ligand agent such as Xantphos and Pd(OAc) at a suitable temperature such as 100° C. in a suitable solvent such as 1,4-dioxane. 2Compound (IX) can be subjected to a metal catalyzed cross-coupling reaction in the presence of a suitable catalyst such as R 1 A cross-coupling reaction may be a Suzuki or Stille coupling. Representative Suzuki reaction conditions are described above, while typical Stille coupling conditions involve the reaction of an appropriate stannane with Pd(dppf)Cl in a suitable solvent such as DMF at a suitable temperature, e.g., 100° C. 2 The present invention includes the presence of a suitable catalyst such as

[0118] In another embodiment, compounds of formula (I) can be prepared as depicted in Scheme 2. [ka]

[0119] Compounds of formula (XII) can be obtained from commercially available compound (XI) by SNAr with a suitable amine in the presence of a suitable base such as DIPEA in a suitable solvent such as 1,2-dimethoxyethane at a suitable temperature such as 80-110° C. R 1 The introduction of can be achieved by reacting compound (XII) in a metal catalyzed cross-coupling reaction such as Suzuki coupling under the reaction conditions described above. Ester hydrolysis of compound (XIII) under acidic or basic conditions well known to those skilled in the art gives the corresponding carboxylic acid (XIV), which can be subjected to Curtius rearrangement in the presence of a suitable base such as diphenylphosphoryl azide (DPPA), triethylamine, in a suitable solvent such as t-BuOH at a suitable temperature such as 90° C. to give compounds of formula (IV). Finally, reaction of compound (IV) under standard Buchwald-Hartwig amination conditions as described above gives compounds of formula (I).

[0120] In another embodiment, compounds of formula (I) can be obtained as depicted in Scheme 3. [ka]

[0121] Compounds of formula (XV) can be obtained from commercially available compound (II) by SNAr with a suitable protected thiol in a suitable solvent such as DMF in the presence of a suitable base such as NaH at a suitable temperature such as 0-25° C. R 1 Introduction of can be achieved by reacting compound (XV) in a metal catalyzed cross-coupling reaction, such as Suzuki coupling, under the reaction conditions described above.

[0122] Compounds of formula (XVI) can be reacted with an appropriate halide under Buchwald-Hartwig amination under conditions fully described above to give compounds of formula (XVII). Thiol deprotection following standard literature conditions such as the use of tetrabutylammonium fluoride (TBAF) in a suitable solvent such as THF at a suitable temperature such as room temperature can give compounds (XVIII). In this case, R to give compounds of formula (I) can be used. 8 The final introduction of, for example, Na 2 CO 3 Alternatively, compound of formula (XVI) can be first alkylated with a suitable alkylating agent in a suitable solvent such as DMF at a suitable temperature, for example 25-60° C., with or without a suitable base, for example 25° C. Alternatively, compound of formula (XVI) can be first alkylated with di-tert-butyl dicarbonate (Boc anhydride, Boc) in the presence of a base, for example triethylamine, in a suitable solvent such as DCM at a suitable temperature, for example 25° C. 2O) to give compound (XIX). Compounds of formula (XX) can be achieved by S-deprotection of compound (XIX) under standard literature conditions as described above, which can be reacted under Mitsunobu reaction conditions with an appropriate alcohol to give compound (XXI). Representative Mitsunobu conditions include the use of an appropriate azodicarboxylate reagent, such as triphenylphosphine, diisopropyl azodicarboxylate (DIAD), in a suitable polar aprotic solvent such as THF, at a suitable temperature, such as 55° C. N-deprotection of compound (XXI) under acidic conditions, such as TFA in DCM, at room temperature, can give compound (IV). Finally, reaction of compound (IV) under standard Buchwald-Hartwig amination conditions as fully described above can give compound (I).

[0123] In a further embodiment, compounds of formula (I) can be prepared as depicted in Scheme 4. [ka]

[0124] Compounds of formula (XXIII) can be obtained from commercially available compound (XXII) by alkylation with a suitable alkylating agent in the presence of a suitable base such as NaH in a suitable solvent such as THF at a suitable temperature such as 0-40°C. Compound (XXIII) can be subjected to Buchwald-Hartwig amination in the presence of a suitable amine to give compound (IX). Typical Buchwald-Hartwig conditions include K amination in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 120°C. 3 PO 4 a suitable base such as xanthophos, a suitable ligand agent such as Pd 2 (dba) 3 Finally, compounds of formula (I) can be obtained from compound (IX) as depicted in Scheme 1.

[0125] In other embodiments, R 8 -S(O)=NH-(C 1 -C6 ) alkyl, -S(O) 2 -(C 1 -C 6 ) alkyl and -S(O)-(C 1 -C 6 Compounds of formula (I) selected from the group consisting of: ) alkyl can be obtained as depicted in Scheme 5. [ka]

[0126] Compound (VI) can be subjected to an SNAr reaction in the presence of sodium methanethiolate in a suitable solvent such as DMF, typically at 25° C., to give compound (XXIV), which can be reacted with an appropriate boronic acid in a Suzuki cross-coupling reaction to give a compound of formula (XXV). Typical Suzuki reaction conditions are fully described in the scheme above. 8 -S(O) 2 -(C 1 -C 6 ) alkyl and -S(O)-(C 1 -C 6 ) alkyl, compound (XXV) can first be deprotected under acidic conditions, e.g., TFA in DCM at room temperature, to give compound (XXVI). Buchwald-Hartwig amination in the presence of a suitable halide can give compound (XXVII). Typical Buchwald-Hartwig conditions include the use of Cs in a suitable solvent, e.g., 1,4-dioxane, at a suitable temperature, e.g., 100°C. 2 CO 3 a suitable base such as Xantphos, a suitable ligand agent such as Pd(OAc) 2 The reaction of compound (XXVII) with oxone in a mixture of methanol and water at a suitable temperature, for example 25° C. (登録商標) By oxidation with a suitable oxidizing agent such as R 8 -S(O) 2 -(C 1 -C 6 ) alkyl and -S(O)-(C 1 -C6 ) alkyl. 8 -S(O)=NH-(C 1 -C 6 ) alkyl, the compound of formula (XXV) is first reacted with oxone under the reaction conditions described above. (登録商標) with a suitable oxidizing agent such as to give compound (XXVIII). Compound (XXIX) can be obtained by sulfoxide imination of compound (XXVIII). Prototypic reaction conditions include the combination of 1,3-bis(1,1-dimethylethyl)imidodicarbonate, a suitable nitrogen source such as ammonium acetate, a suitable catalyst such as rhodium(II) acetate dimer with magnesium oxide and iodobenzene diacetate in a suitable solvent such as DCM at a suitable temperature such as 40° C. Removal of the 2,4-dimethoxybenzyl protecting group from compound (XXIX) to give compound (XXX) can be achieved under standard literature conditions such as reaction with cerium(IV) ammonium nitrate (CAN) in a suitable mixture of solvents such as MeCN and water at room temperature. Insertion of group A into compounds of formula (XXX) can be achieved by reaction with a suitable halide under standard Buchwald-Hartwig amination conditions as described above to give compounds of formula (XXXI). Finally, removal of the Boc protecting group under acidic conditions, e.g., TFA in DCM at room temperature, affords R 8 -S(O)=NH-(C 1 -C 6 ) alkyl.

[0127] Various aspects of the invention described herein are illustrated by the following examples, which are not intended to limit the invention in any way.

[0128] Preparation of intermediates and example compounds Chemical names of compounds were generated with Structure To Name Enterprise 10.0 Cambridge Software. All reagents whose synthesis is not described in the experimental section are either commercially available or are known compounds or can be prepared from known compounds by methods known to those skilled in the art.

[0129] Acronyms - Meanings Boc = tert-butyloxycarbonyl; c-Hex = cyclohexane; Cs 2 CO 3 = cesium carbonate;DCM = dichloromethane;de = diastereomeric excess;DIPEA = N,N-diisopropylethylamine;DMAP = 4-(dimethylamino)pyridine;DMF = dimethylformamide;DMSO = dimethylsulfoxide;ee = enantiomeric excess;EtOAc = ethyl acetate;HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;HCOOH = formic acid;h = hours;hrs = hours;HCl = hydrochloric acid;H 2 = Hydrogen; H 2 O=water;Int=intermediate;K 2 CO 3 = potassium carbonate; K 3 PO 4 = tripotassium phosphate; KF = potassium fluoride; LC-MS = liquid chromatography / mass spectrometry; MeCN = acetonitrile; MeOH = methanol; N 2 = nitrogen; NaH = sodium hydride; Na 2 SO 4 = sodium sulfate; NaHCO 3 = sodium bicarbonate; Na 2 CO 3 = Sodium carbonate; Na 2 S 2 O 8 = sodium persulfate; NH 3 = ammonia; NH 4 Cl = ammonium chloride; NH 4 OH = ammonium hydroxide; NMP = 1-methyl-2-pyrrolidone; MW = microwave; PdCl 2 (PPh 3 ) 2 = Bis(triphenylphosphine)palladium(II) dichloride; Pd 2 (dba) 3 = Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2= [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl 2 DCM = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; Pd(OAc) 2 = Palladium(II) acetate; Pd(PPh 3 ) 4 = Tetrakis(triphenylphosphine)palladium(0); PL-HCO 3 = polymer supported bicarbonate; PPh 3 = triphenylphosphine; RT = room temperature; SCX = strong cation exchange; tBuXPhos = di-tert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0130] General Experimental Details and Methods Analysis method Analytical equipment, materials and methods 1H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHZ (proton frequency) equipped with a self-shielded Z-gradient coil 5 mm 1H / nX broadband probehead for inverse detection, a deuterium digital lock channel unit, a quadrature digital detection unit and transmitter offset frequency shift, or an Agilent VNMRS-500 or a Bruker Avance 400 or an Agilent Inova 600 operating at 600 MHz equipped with a 5 mm PFG PENTA Probe spectrometer. Chemical shifts are reported as δ values ​​(ppm) relative to trimethylsilane (TMS) as the 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, br. d=broad doublet, br. t=broad triplet, br. dd=broad doublet-doublet, nd=undetermined, dd=double-doublet, dt=triplet doublet, ddd=doublet-doublet-doublet doublet, quin=quintet, td=triplet doublet, tt=triplet triplet, dq=quartet doublet, spt=septent).

[0131] LC / UV / MS analysis method LC / MS retention times were estimated to be subject to experimental error of +0.5 min. LCMS may be recorded under the following conditions: Diode array DAD chromatographic traces, mass chromatograms and mass spectra may be recorded on a Micromass ZQ operated in positive and / or negative electrospray ES ionization mode. TM or UPLC / PDA / MS Acquity coupled to a Waters SQD single quadrupole mass spectrometer. TM System and / or ZQ operated in positive and / or negative ES ionization modes TM Acquisition was performed on a Fractionlynx system used in analytical mode in conjunction with a single quadrupole. The quality control method used was operated under low or high pH conditions: Method 1, low pH condition Column: Acquity CSH C18 2.1×50 mm 1.7 μm, column temperature was 40°C; mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B was MeCN + 0.1% HCOOH. Flow rate was 1 mL / min. Gradient table was 97% A 3% B for t=0 min, 0.1% A 99.9% B for t=1.5 min, 0.1% A 99.9% B for t=1.9 min and 97% A 3% B for t=2 min. UV detection range was 210-350 nm, ES+ / ES- range was 100-1500 AMU.

[0132] Method 2, high pH conditions: Column: Acquity Kinetex 1.7 μm EVO C18 100A, 2.1 × 50 mm, column temperature was 40 °C; mobile phase solvent A was 10 mM NH adjusted to pH = 10 with ammonia. 4 HCO 3 Aqueous, mobile phase solvent B was MeCN. The flow rate was 1 mL / min. The gradient table was 97% A 3% B for t = 0 min, 0.1% A 99.9% B for t = 1.5 min, 0.1% A 99.9% B for t = 1.9 min, and 97% A 3% B for t = 2 min. The UV detection range was 210-350 nm, and the ES+ / ES- range was 100-1500 AMU.

[0133] Method 3, low pH condition Column: Acquity CSH C18 2.1×50 mm 1.7 μm, column temperature was 40°C; mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B was MeCN + 0.1% HCOOH. Flow rate was 0.9 mL / min. Gradient table was 97% A 3% B for t=0 min, 0.1% A 99.9% B for t=1.4 min, 0.1% A 99.9% B for t=1.9 min and 97% A 3% B for t=2 min. UV detection range was 210-350 nm, ES+ / ES- range was 100-1000 AMU.

[0134] Method 4, high pH conditions: Column: Acquity Kinetex 1.7 μm EVO C18 100A, 2.1 × 50 mm, column temperature was 40 °C; mobile phase solvent A was 10 mM NH adjusted to pH = 10 with ammonia. 4 HCO 3 Aqueous, mobile phase solvent B was MeCN. The flow rate was 0.9 mL / min. The gradient table was 97% A 3% B for t = 0 min, 0.1% A 99.9% B for t = 1.4 min, 0.1% A 99.9% B for t = 1.9 min, and 97% A 3% B for t = 2 min. The UV detection range was 210-350 nm, and the ES+ / ES- range was 100-1000 AMU.

[0135] Preparation of intermediates Intermediate 1: N-(4-bromopyridin-2-yl)prop-2-enamide [ka] A mixture of 4-bromo-2-pyridinamine (3.0 g, 17.3 mmol) and TEA (7.25 mL, 52.0 mmol) in dry DCM (80 mL) was dissolved in N 2 The mixture was stirred at 0° C. under reduced pressure, then a solution of 3-chloropropanoyl chloride (1.83 mL, 19.1 mmol) in DCM (20 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h. Water was added, the organic solution was separated, washed with brine, and added with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was evaporated and the product was purified by flash chromatography on a Biotage silica cartridge (c-Hex to 25% EtOAc) to give the title compound (2.4 g, 10.6 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 226.9 (Method 1)

[0136] Intermediate 2: N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 1 (1.8 g, 6.90 mmol) was dissolved in THF (8 mL) and 1-methylpiperazine (1.15 mL, 10.4 mmol) was added and the reaction was stirred for 3 h at 65° C. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 50% EtOAc) to give the title compound (2.4 g, recovery assumed to be quantitative). LC-MS (ESI): m / z (M+1): 327.2 (Method 1)

[0137] Intermediate 3: 2-[(4-amino-6-chloropyridazin-3-yl)oxy]ethan-1-ol [ka] NaH (60% dispersion in oil) (268 mg, 6.71 mmol) was dissolved in N 2 To the stirred ethane-1,2-diol (4.0 mL, 71.5 mmol) was added portionwise. After 30 min, 3,6-dichloropyridazin-4-amine (1.0 g, 6.1 mmol) was added. The reaction was heated at 100° C. for 1 h. After cooling, the mixture was treated with cold water and the pH was adjusted to 7-8 using 1N HCl. The resulting solid was filtered, washed with water and c-Hex, then collected and dried to give the title compound (900 mg, 4.75 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 190.2 (Method 2)

[0138] Intermediate 4: 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}ethan-1-ol [ka] A mixture of 5-chloro-2-fluorobenzeneboronic acid (825 mg, 4.73 mmol), KF (537 mg, 9.1 mmol) and intermediate 3 (750 mg, 3.64 mmol) in MeCN (10 mL) and H 2 Dissolve the solution in N2O (2 mL) 2Degass for 2 min with PdCl 2 (PPh 3 ) 2 (256 mg, 0.36 mmol) was added and the mixture was irradiated in a microwave at 110° C. for 1 h 15 min. After cooling, the solvent was removed under reduced pressure. The residue was treated with EtOAc / MeOH and washed with celite. (登録商標) The organic solvent was evaporated and the residue was purified by flash chromatography on a Biotage silica cartridge (100% EtOAc) to give the title compound (350 mg, 1.23 mmol, 34% yield). LC-MS (ESI): m / z (M+1): 284.0 (Method 2)

[0139] Intermediate 5: 4-Chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline [ka] 4-Chloro-7-hydroxyquinoline (200 mg, 1.11 mmol) was added to stirring PPh 3 A mixture of 2-(4-methylpiperazin-1-yl)ethanol (177 mg, 1.22 mmol) and 2-(4-methylpiperazin-1-yl)ethanol (380 mg, 1.45 mmol) in THF (6.67 mL) and NMP (0.67 mL) was added at RT with 2 Diisopropyl azodicarboxylate (0.23 mL, 1.17 mmol) was then added dropwise and the resulting mixture was stirred at RT for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered and evaporated under reduced pressure. The residue was diluted with water and acidified with 1N HCl under stirring. The aqueous phase was diluted with Et 2 O and the organic layer was discarded. The aqueous phase was then washed with 33% NH 4 The mixture was treated with aqueous OH until the pH reached 9-10, and extracted with DCM. The combined organic layers were washed with Na 2 SO 4 Drying at rt, filtration and evaporation gave the title compound (290 mg, 0.95 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 306.1 (Method 1)

[0140] Intermediate 6: 3,6-Dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] To a solution of 3,4,6-trichloropyridazine (5 g, 27.3 mmol) in dry THF (54.5 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (12.3 mL, 81.8 mmol). The mixture was heated at 50° C. for 15 min. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic phase was filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (0% to 40% EtOAc% in c-Hex). After evaporation, a solid precipitated and was triturated with DCM and EtOAc to give a first crop. The filtrate was evaporated and repurified by flash chromatography on a Biotage silica cartridge (0% to 5% MeOH in DCM). The product so obtained was combined with the first batch to give the title compound (8.33 g, 26.5 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 314.1 (Method 2)

[0141] Intermediate 7: 6-Chloro-3-(2,2-difluoroethoxy)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 6 (550 mg, 1.75 mmol), tBuXPhos (89 mg, 0.21 mmol), Pd 2 (dba) 3 (96 mg, 0.11 mmol), Cs 2 CO 3 A mixture of (1.72 g, 5.25 mmol) was suspended in toluene (11 mL). The mixture was degassed (vacuum / N 2), 2,2-difluoroethanol (144 μL, 2.28 mmol) was added via syringe and the mixture was heated at 90° C. overnight. The mixture was diluted with EtOAc and washed with Celite. (登録商標) The mixture was filtered through a pad and the cake was washed with EtOAc. The organic phase was washed with brine, filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (0% to 50% EtOAc in c-Hex) to give the title compound (570 mg, 1.58 mmol, 90% yield). LC-MS (ESI): m / z (M+1): 360.2 (Method 1)

[0142] Intermediate 8: 6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] In a round-bottom flask, add intermediate 7 (484 mg, 1.35 mmol), 5-chloro-2-fluorobenzeneboronic acid (352 mg, 2.02 mmol), Pd(dppf)Cl 2 DCM (197 mg, 0.27 mmol) and K 2 CO 3 (558 mg, 4.04 mmol) in a mixture of 1,4-dioxane (8.2 mL) and H 2 Degas the solution (vacuum / N) with HO (2.1 mL). 2 ) and stirred at 110° C. for 2 hours. The mixture was diluted with EtOAc and (登録商標) The crude material was purified by flash chromatography on a Biotage silica NH cartridge (0% to 20% EtOAc in c-Hex) and then further purified by flash chromatography on a Biotage silica cartridge (0% to 2% MeOH in DCM) to give the title compound (417 mg, 0.92 mmol, 68% yield). LC-MS (ESI): m / z (M+1): 454.2 (Method 1)

[0143] Intermediate 9: 6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-amine [ka] Intermediate 8 (332 mg, 0.73 mmol) was dissolved in a mixture DCM (6.4 mL) / TFA (1.6 mL) (8:2). The mixture was left at RT for 48 h. Volatiles were evaporated under reduced pressure. The residual material was loaded onto SCX (2 g), washed with MeOH and diluted with 1N NH 3 The mixture was eluted with MeOH in 100 ml of 1,0 ... LC-MS (ESI): m / z (M+1): 304.1 (Method 1)

[0144] Intermediate 10: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(methylsulfanyl)propoxy]pyridazin-4-amine [ka] To a solution of 3-methylsulfanylpropan-1-ol (0.15 mL, 1.43 mmol) in DMF (2.1 mL) was added 60% dispersion of NaH in oil (57 mg, 1.43 mmol) and the mixture was stirred at RT for 1.5 h (until gas evolution ceased). Intermediate 6 (150 mg, 0.48 mmol) dissolved in DMF (0.90 mL) was then added and the mixture was stirred at 130° C. for 5 h. The mixture was allowed to reach RT and saturated NaHCO 3 The crude material was purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2HO+0.1%HCOOH to 70%MeCN+0.1%HCOOH). Evaporation of the appropriate fractions gave the title compound (50 mg, 0.13 mmol, 27% yield). LC-MS (ESI): m / z (M+1): 384.2 (Method 1)

[0145] Intermediate 11: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(methylsulfanyl)propoxy]pyridazin-4-amine [ka] Intermediate 11 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (17 mg, 0.02 mmol) starting from intermediate 10 (45 mg, 0.12 mmol) and 5-chloro-2-fluorobenzeneboronic acid (27 mg, 0.15 mmol) to afford the title compound (40 mg, 0.08 mmol, 71% yield). LC-MS (ESI): m / z (M+1): 478.2 (Method 1)

[0146] Intermediate 12: 6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-amine [ka] Intermediate 12 was prepared starting from intermediate 11 (40 mg, 0.08 mmol) according to the method used for the synthesis of intermediate 9 to give the title compound (24 mg, 0.07 mmol, 87% yield). LC-MS (ESI): m / z (M+1): 328.1 (Method 1).

[0147] Intermediate 13: 2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)oxy]ethan-1-ol [ka] NaH, 60% dispersion in oil (140 mg, 3.5 mmol) was dissolved in N 2 To the stirred ethane-1,2-diol (8 mL, 3.18 mmol) was added portionwise. After 30 min, intermediate 6 (1 g, 3.18 mmol) was added. The reaction was heated at 100° C. for 1 h. After cooling, the mixture was treated with cold water and extracted with EtOAc. The organic layer was separated and washed with Na 2 SO 4 The residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH / 0.3% H 2 O) to give the title compound (1.1 g, estimated quantitative recovery). LC-MS (ESI): m / z (M+1): 340.1 (Method 1)

[0148] Intermediate 14: 2-{2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)oxy]ethyl}-2,3-dihydro-1H-isoindole-1,3-dione [ka] N 2 Diisopropyl azodicarboxylate (1.16 mL, 5.89 mmol) was added to a mixture of intermediate 13 (1 g, 2.94 mmol), phthalimide (476 mg, 3.24 mmol) and PPh under stirring at RT. 3 (1.54 g, 5.89 mmol) in dry THF (20 mL). After 2 h, the solvent was removed under reduced pressure. The residue was treated with EtOH and the mixture was heated at reflux for 10 min. After cooling, the solid was filtered and washed with EtOH / cyclohexane to give the title compound (950 mg, 2.03 mmol, 69% yield). LC-MS (ESI): m / z (M+1): 469.2 (Method 1)

[0149] Intermediate 15:2-[(2-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]oxy}ethyl)carbamoyl]benzoic acid [ka] K 2 CO 3 (989 mg, 7.16 mmol) was added to a stirred solution of intermediate 14 (1.13 g, 2.39 mmol), 5-chloro-2-fluorobenzeneboronic acid (624 mg, 3.58 mmol) and Pd(dppf)Cl 2 (350 mg, 0.48 mmol) in a mixture of 1,4-dioxane (74.6 mL) and H 2 The reaction was then diluted with N 2 The vial was degassed by bubbling, then sealed and heated at 110° C. for 2 h. After cooling, the mixture was diluted with EtOAc and H 2 The mixture was diluted with O. The phases were separated and the aqueous phase was treated with aqueous citric acid and extracted with EtOAc. The organic layer was separated and diluted with Na 2 SO 4 Drying at rt, filtration and evaporation gave the title compound (330 mg, 0.57 mmol, 24% yield). LC-MS (ESI): m / z (M+1): 581.3 (Method 1)

[0150] Intermediate 16: 2-(2-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]oxy}ethyl)-2,3-dihydro-1H-isoindole-1,3-dione [ka] DIPEA (556 μL, 3.2 mmol) was added to a stirred solution of intermediate 14 (750 mg, 1.6 mmol), 5-chloro-2-fluorobenzeneboronic acid (558 mg, 3.2 mmol) and Pd(PPh 3 ) 4(92 mg, 0.08 mmol) in 1,4-dioxane (30 mL) was added at RT. The reaction was cooled to room temperature and cooled to RT. 2 The vial was degassed by bubbling. The vial was sealed and heated at 110° C. for 20 h. After cooling, the solvent was removed under reduced pressure. The residue was treated with EtOAc and purified by H 2 The organic layer was separated and washed with Na 2 SO 4 The residue was purified by flash chromatography on a Biotage silica NH cartridge (0% to 50% EtOAc in c-Hex) to give the title compound (760 mg, 1.35 mmol, 84% yield). LC-MS (ESI): m / z (M+1): 469.2 (Method 1)

[0151] Intermediate 17: 2-(2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}ethyl)-2,3-dihydro-1H-isoindole-1,3-dione [ka] Method A Intermediate 15 (330 mg, 0.40 mmol) was treated with 4N HCl in 1,4-dioxane (3.0 mL) at 90° C. for 7 h. The solvent was removed under reduced pressure. The residue was treated with NaHCO 3 The organic layer was separated and washed with Na 2 SO 4 Drying at rt, filtration and evaporation gave the title compound (100 mg, 0.22 mmol, 61% yield).

[0152] Method B TFA (3 mL, 39.2 mmol) was added to a stirring solution of intermediate 16 (720 mg, 1.23 mmol) in DCM (4 mL) at RT with N 2 The reaction was stirred for 40 h. The solvent was removed under reduced pressure. The residue was treated with water, washed with EtOAc and the organic layer was discarded. The aqueous phase was diluted with 33% NH 4 OH H 2The mixture was treated with 2,4-dichloromethane (DCM) until pH 10 and extracted with DCM. The organic layer was separated and diluted with Na 2 SO 4 Drying at 40° C. and evaporation afforded the title compound (360 mg, 0.87 mmol, 71% yield). LC-MS (ESI): m / z (M+1): 413.1 (Method 1)

[0153] Intermediate 18: 2-(2-{[6-(5-chloro-2-fluorophenyl)-4-({7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl}amino)pyridazin-3-yl]oxy}ethyl)-2,3-dihydro-1H-isoindole-1,3-dione [ka] Cs 2 CO 3 (238 mg, 0.73 mmol) was added to a stirred flask of Intermediate 17 (150 mg, 0.36 mmol), Intermediate 5 (122 mg, 0.40 mmol), Pd(OAc) 2 (4 mg, 0.02 mmol) and Xantphos (21 mg, 0.40 mmol) in 1,4-dioxane (10 mL) at RT. The mixture was cooled to RT with N 2 After degassing by bubbling, the vial was sealed and irradiated in a MW apparatus at 110° C. for 2 h. After cooling, the mixture was (登録商標) The mixture was filtered through a pad and washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 2% MeOH / 0.2% H 2 O) to afford the title compound (170 mg, 0.25 mmol, 69% yield). LC-MS (ESI): m / z (M+1): 682.4 (Method 2)

[0154] Intermediate 19: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(3-methanesulfonylpropoxy)pyridazin-4-amine [ka] Intermediate 19 was prepared according to the method used for the synthesis of intermediate 10 from intermediate 6 (300 mg, 0.95 mmol) and 3-(methylsulfonyl)-1-propanol (396 mg, 2.86 mmol) starting at 110° C. to give the title compound (65 mg, 0.16 mmol, 16% yield). LC-MS (ESI): m / z (M+1): 416.1 (Method 1).

[0155] Intermediate 20: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(3-methanesulfonylpropoxy)pyridazin-4-amine [ka] Intermediate 20 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (23 mg, 0.03 mmol) starting from intermediate 19 (65 mg, 0.16 mmol) and 5-chloro-2-fluorobenzeneboronic acid (35 mg, 0.20 mmol) to afford the title compound (45 mg, 0.09 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 510.1 (Method 1)

[0156] Intermediate 21: 6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfonylpropoxy)pyridazin-4-amine [ka] Intermediate 21 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(3-methanesulfonylpropoxy)pyridazin-4-amine (Intermediate 20, 45 mg, 0.09 mmol) to give the title compound (30 mg, 0.08 mmol, 95% yield). LC-MS (ESI): m / z (M+1): 360.0 (Method 2).

[0157] Intermediate 22: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 22 was prepared according to the method used for the synthesis of Intermediate 18 starting from 2-(2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}ethyl)-2,3-dihydro-1H-isoindole-1,3-dione (Intermediate 17, 200 mg, 0.48 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 190 mg, 0.58 mmol) to give the title compound (120 mg, 0.18 mmol, 38% yield). LC-MS (ESI): m / z (M+1): 659.4 (Method 2)

[0158] Intermediate 23: Methyl 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate [ka] To an ice-cold suspension of methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.0 g, 4.75 mmol) in dry THF (35 mL) was added 60% dispersion of NaH in oil (0.28 g, 7.12 mmol) and the mixture was stirred for 30 min, after which 2-(chloromethoxy)ethyl-trimethylsilane (1.09 mL, 6.17 mmol) was added. The reaction mixture was allowed to reach RT and stirred at RT for 3 h. The mixture was diluted with saturated NH 4It was quenched with aqueous Cl, diluted with EtOAc and washed with brine (1x). The organic phase was dried and concentrated under reduced pressure as a solid and allowed to stand at RT overnight. The next day a UPLC check showed complete conversion to the described regioisomer. The residue was purified by flash chromatography on a Biotage silica cartridge (c-Hex~10% EtOAc) to give the title compound (820 mg, 2.41 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 341.1 (Method 1) 1 H NMR (500 MHz, chloroform-d) δ ppm 8.38 (d, J = 5.1 Hz, 1 H), 7.40 (s, 1 H), 7.20 (d, J = 5.1 Hz, 1 H), 6.14 (s, 2 H), 3.97 (s, 3 H), 3.52 - 3.58 (m, 2 H), 0.85 - 0.92 (m, 2 H), -0.11 - -0.05 (m, 9 H).

[0159] Intermediate 24: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(dimethylamino)propoxy]pyridazin-4-amine [ka] Intermediate 24 was prepared according to the method used in the synthesis of Intermediate 7 from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 1 g, 3.18 mmol) and 3-(dimethylamino)propan-1-ol (0.49 mL, 4.14 mmol) starting at 120° C. to give the title compound (400 mg, 1.05 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 381.2 (Method 1)

[0160] Intermediate 25: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(dimethylamino)propoxy]pyridazin-4-amine [ka] Intermediate 25 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (154 mg, 0.21 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(dimethylamino)propoxy]pyridazin-4-amine (Intermediate 24, 400 mg, 1.05 mmol) and 5-chloro-2-fluorobenzeneboronic acid (275 mg, 1.58 mmol) to give the title compound (250 mg, 0.53 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 475.0 (Method 1)

[0161] Intermediate 26: 6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-amine [ka] Intermediate 26 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[3-(dimethylamino)propoxy]pyridazin-4-amine (Intermediate 25, 250 mg, 0.53 mmol) to give the title compound (150 mg, 0.46 mmol, 88% yield). LC-MS (ESI): m / z (M+1): 325.3 (Method 2).

[0162] Intermediate 27: Methyl 4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate [ka] Intermediate 27 was prepared according to the method used for the synthesis of Intermediate 18 starting from 6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-amine (Intermediate 26, 80 mg, 0.24 mmol) and methyl 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Intermediate 23, 93 mg, 0.26 mmol) to give the title compound (70 mg, 0.11 mmol, 47% yield). LC-MS (ESI): m / z (M+1): 629.5 (Method 1).

[0163] Intermediate 28: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine [ka] Intermediate 28 was prepared according to the method used for the synthesis of Intermediate 10 starting from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 700 mg, 2.23 mmol) and 2-(dimethylamino)ethanol (0.67 mL, 6.68 mmol) to give the title compound (850 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 367.2 (Method 1)

[0164] Intermediate 29: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine [ka] Intermediate 29 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(339 mg, 0.46 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine (Intermediate 28, 850 mg, 2.23 mmol) and 5-chloro-2-fluorobenzeneboronic acid (606 mg, 3.48 mmol) to give the title compound (600 mg, 1.30 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 461.8 (Method 2)

[0165] Intermediate 30: 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine [ka] Intermediate 30 was prepared starting from intermediate 29 (600 mg, 1.30 mmol) according to the method used for the synthesis of intermediate 9 to give the title compound (330 mg, 1.06 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 311.5 (Method 2).

[0166] Intermediate 31: 1-tert-Butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate [ka] To a suspension of methyl-4-boc-piperazine-2-carboxylate (150 mg, 0.61 mmol) in MeOH (2.05 mL) was added acetic acid (0.11 mL, 1.84 mmol) and 37% w / w aqueous formaldehyde (0.23 mL, 3.07 mmol). The mixture was stirred at RT for 30 min, after which sodium cyanoborohydride (77 mg, 1.23 mmol) was added. The suspension quickly became a solution. After 1 h, the volatiles were removed under reduced pressure. The residue was dissolved in DCM and saturated NaHCO 3The organic phase was filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (0% to 5% MeOH in DCM) to give the title compound (124 mg, 0.48 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 258.5 (Method 1)

[0167] Intermediate 32: Methyl 1-methylpiperazine-2-carboxylate dihydrochloride [ka] A solution of 1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (Intermediate 31 (1.15 g, 4.45 mmol) in 4 M HCl in 1,4-dioxane (5.6 mL, 22.3 mmol) and MeOH (11 mL) was stirred at RT for 2 h. The volatiles were removed under reduced pressure to give the title compound (Intermediate 32, 1.3 g, recovery assumed quantitative), which was used in the next step without further purification. LC-MS (ESI): m / z (M free base+1): 159.1 (Method 2)

[0168] Intermediate 33: N-(4-bromopyridin-2-yl)-2-chloroacetamide [ka] 2-Chloroacetyl chloride (0.25 mL, 3.18 mmol) was added dropwise to a solution of 4-bromo-2-pyridinamine (500 mg, 2.89 mmol) and TEA (1.21 mL, 8.67 mmol) in dry DCM (14.5 mL) at 0° C. The mixture was stirred at RT for 3 h. The mixture was diluted with DCM and washed with saturated NaHCO 3 It was washed with aqueous solution and brine. The organic phase was filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 10% EtOAc) to give the title compound (470 mg, 1.88 mmol, 65% yield). LC-MS (ESI): m / z (M+1): 249.0 (Method 2)

[0169] Intermediate 34: Methyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1-methylpiperazine-2-carboxylate [ka] N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 250 mg, 1 mmol) and K 2 CO 3 To a suspension of (692 mg, 5.01 mmol) in DMF (5 mL) was added methyl 1-methylpiperazine-2-carboxylate dihydrochloride (Intermediate 32, 347 mg, 1.5 mmol). The reaction was stirred at RT overnight. The mixture was diluted with EtOAc and added NaHCO 3 Washed with saturated aqueous solution (3x) and brine (1x). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (0% to 25% EtOAc in c-Hex) to give the title compound (240 mg, 0.65 mmol, 64% yield). LC-MS (ESI): m / z (M+1): 371.4 (Method 2)

[0170] Intermediate 35: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-methoxypyridazin-4-amine [ka] A 25% solution of sodium methoxide in MeOH (0.8 mL, 3.5 mmol) was added to a suspension of 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 1 g, 3.18 mmol) in MeOH (10.64 mL). The vial was sealed and irradiated in a MW apparatus at 120° C. for 1 h. The volatiles were removed under reduced pressure to give the title compound (1.3 g, internal NaCl, recovery assumed quantitative) which was used directly in the next step. LC-MS (ESI): m / z (M+1): 310.5 (Method 2)

[0171] Intermediate 36: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-methoxypyridazin-4-amine [ka] Intermediate 36 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (339 mg, 0.46 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-methoxypyridazin-4-amine (Intermediate 35, 3.18 mmol) and 5-chloro-2-fluorobenzeneboronic acid (832 mg, 4.77 mmol) to afford the title compound (630 mg, 1.56 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 404.2 (Method 1)

[0172] Intermediate 37: 6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-amine [ka] Intermediate 37 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-methoxypyridazin-4-amine (Intermediate 36, 630 mg, 1.56 mmol) to afford the title compound (387 mg, 1.53 mmol, 98% yield). LC-MS (ESI): m / z (M+1): 254.1 (Method 1)

[0173] Intermediate 38: N-(4-bromopyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide [ka] Intermediate 38 was prepared according to the method used for the synthesis of Intermediate 2 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 1, 200 mg, 0.88 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (200 mg, 1.19 mmol) to give the title compound (346 mg, 0.86 mmol, 99%). LC-MS (ESI): m / z (M+1): 395.2 (Method 1).

[0174] Intermediate 39: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate [ka] N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 759 mg, 3.08 mmol), 1-piperazinecarboxylic acid tert-butyl ester (1.15 g, 6.16 mmol) and K 2 CO 3 A solution of the mixture (1.28 g, 9.25 mmol) in dry DMF (15 mL) was 2 The mixture was stirred at RT overnight under reduced pressure. 3 Poured into aqueous solution and extracted with EtOAc. The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex~45% EtOAc) to give the title compound (1.05 g, 2.64 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 399.2 (Method 1)

[0175] Intermediate 40: N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide [ka] tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (Intermediate 39, 1.05 g, 2.64 mmol) was dissolved in a mixture of DCM (20 mL) and TFA (5.05 mL, 66.1 mmol) and stirred at RT for 1 h. The volatiles were evaporated under reduced pressure and the residue was loaded onto an SCX cartridge (10 g), washed with MeOH and diluted with 2N NH 3 The mixture was eluted with MeOH in 10 ml of 100% methanol. The basic fractions were evaporated under reduced pressure to give the title compound (795 mg, 2.66 mmol, assumed quantitative recovery), which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 299.1 (Method 2)

[0176] Intermediate 41: N-(4-bromopyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide [ka] To a mixture of N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 40, 200 mg, 0.67 mmol) and TEA (0.14 mL, 1 mmol) in THF (6 mL) was added trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (0.11 mL, 0.74 mmol) and the mixture was stirred at RT overnight. Volatiles were removed under reduced pressure and the crude was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex~30% EtOAc). Evaporation of appropriate fractions afforded the title compound (204 mg, 0.54 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 381.3 (Method 2)

[0177] Intermediate 42: (3-Methyloxetan-3-yl)methyl 2-(acetyloxy)acetate [ka] Process 1 To an ice-cold solution of 2-hydroxyacetic acid (1.5 g, 19.7 mmol) in pyridine (6 mL) was added acetic acid acetyl ester (1.92 mL, 20.3 mmol), then the mixture was allowed to reach RT and stirred overnight. The mixture was diluted with EtOAc and saturated NaHCO 3 The aqueous layer was partitioned into 1N HCl and then separated. The aqueous layer was adjusted to pH=2-3 with 1N HCl and extracted with EtOAc (2×90 mL) and DCM (2×90 mL). The combined organic phase was washed with Na 2 SO 4 After 2 h, the mixture was dried over 1000 ml and concentrated under reduced pressure to give a crude product containing 2-(acetyloxy)acetic acid (1.41 g, 11.9 mmol, 60% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.53 (s, 2H), 2.07 (s, 3H)

[0178] Process 2 To a solution of 2-acetyloxyacetic acid (1.41 g, 11.9 mmol), (3-methyl-3-oxetanyl)methanol (1.78 mL, 17.9 mmol) and DMAP (145 mg, 1.19 mmol) in DCM (22 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.65 g, 19.0 mmol) and the mixture was stirred at RT overnight. The mixture was diluted with saturated NaHCO 3 It was washed with aqueous solution, 0.1N HCl and finally with brine. The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica cartridge (DCM to 4% MeOH). Evaporation of the appropriate fractions afforded the title compound (1.90 g, 9.38 mmol, 79% yield) as a colorless oil that slowly solidified. LC-MS (ESI): m / z (M+1): 203.0 (Method 1) 1H NMR (400 MHz, chloroform-d) δ ppm 4.67 (s, 2H), 4.53 (d, J = 5.79 Hz, 2H), 4.41 (d, J = 6.06 Hz, 2H), 4.28 (s, 2H), 2.19 (s, 3H), 1.36 (s, 3H)

[0179] Intermediate 43: {4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methyl acetate [ka] To an ice-cold solution of ((3-methyloxetan-3-yl)methyl 2-(acetyloxy)acetate (Intermediate 42, 1.9 g, 9.38 mmol) in DCM (20 mL) was slowly added boron trifluoride diethyl etherate (0.12 mL, 0.94 mmol). The mixture was allowed to reach RT and stirred for 4 h. The reaction was cooled to 0 °C and quenched with TEA (1.5 equiv.) with stirring for 15 min. The mixture was diluted with DCM and washed with water (2x) and brine (2x), then the organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica cartridge (c-Hex ~ 70% EtOAc). Evaporation of the appropriate fractions afforded the title compound (1.14 g, 5.63 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 203.0 (Method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 4.13 (s, 2H), 3.97 (s, 6H), 2.15 (s, 3H), 0.85 (s, 3H)

[0180] Intermediate 44: {4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methanol [ka] To an ice-cold solution of {4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methyl acetate (Intermediate 43, 1.14 g, 5.63 mmol) in MeOH (20 mL) was added 60% dispersion NaH in oil (22.5 mg, 0.56 mmol) and the mixture was allowed to reach RT and stirred for 2 h. Volatiles were removed under reduced pressure and the crude was purified by flash chromatography on a Biotage silica cartridge (DCM to 4% MeOH). Evaporation of appropriate fractions afforded the title compound (768 mg, 4.79 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 161.0 (Method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 3.98 (s, 6H), 3.60 (d, J = 6.77 Hz, 2H), 1.87 (t, J = 6.81 Hz, 1H), 0.86 (s, 3H)

[0181] Intermediate 45: 6-Chloro-3-({4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methoxy)pyridazin-4-amine [ka] Intermediate 45 was prepared according to the method used for the synthesis of Intermediate 10 starting from 3,6-dichloropyridazin-4-amine (116 mg, 0.71 mmol) and 2{4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methanol (Intermediate 44, 340 mg, 2.12 mmol) to give the title compound (320 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 288.0 (Method 2)

[0182] Intermediate 46: 6-(5-chloro-2-fluorophenyl)-3-({4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methoxy)pyridazin-4-amine [ka] Intermediate 46 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (103 mg, 0.14 mmol) starting from 6-chloro-3-({4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methoxy)pyridazin-4-amine (Intermediate 45, 0.71 mmol) and 5-chloro-2-fluorobenzeneboronic acid (185 mg, 1.06 mmol) to give the title compound (117 mg, 0.31 mmol, 43% yield). LC-MS (ESI): m / z (M+1): 382.1 (Method 1)

[0183] Intermediate 47: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] 6-(5-chloro-2-fluorophenyl)-3-({4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl}methoxy)pyridazin-4-amine (Intermediate 46, 50 mg, 0.13 mmol), N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 48 mg, 0.14 mmol), Pd(OAc) 2 (1.8 mg, 0.01 mmol), Xantphos (9.1 mg, 0.02 mmol) and Cs 2 CO 3 A solution of the mixture (85 mg, 0.26 mmol) in 1,4-dioxane (1 mL) was degassed (vacuum / N 2 ) and heated at 100° C. for 2 hours. The mixture was filtered through a celite (登録商標)The mixture was filtered through a pad and washed with EtOAc; the filtrate was concentrated under reduced pressure and the crude was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 2% MeOH). Appropriate fractions were collected and purified by preparative HPLC to give the title compound (41 mg, 0.07 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 628.2 (Method 2).

[0184] Intermediate 48: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(methylsulfanyl)pyridazin-4-amine [ka] A mixture of 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 450 mg, 1.43 mmol) and sodium thiomethoxide (250 mg, 3.58 mmol) in DMF (9.6 mL) was stirred at RT for 16 h. The mixture was diluted with saturated NaHCO 3 The organic phase was diluted with aqueous Na 2 SO 4 The crude product was purified by flash chromatography on a Biotage silica cartridge (c-Hex to 50% EtOAc) and then further purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 The mixture was purified using a 20 mL elution column (97% MeCN+0.1% HCOOH to 97% MeCN+0.1% HCOOH). The appropriate fractions were pooled, diluted with DCM, and diluted with saturated NaHCO 3 Washing with aqueous solution and concentration under reduced pressure gave the title compound (240 mg, 0.74 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 326.1 (Method 1)

[0185] Intermediate 49: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(methylsulfanyl)pyridazin-4-amine [ka] Intermediate 49 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (108 mg, 0.15 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(methylsulfanyl)pyridazin-4-amine (Intermediate 48, 240 mg, 0.74 mmol) and 5-chloro-2-fluorobenzeneboronic acid (167 mg, 0.96 mmol) to give the title compound (133 mg, 0.32 mmol, 43% yield). LC-MS (ESI): m / z (M+1): 420.2 (Method 1)

[0186] Intermediate 50: 6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-amine [ka] Intermediate 50 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(methylsulfanyl)pyridazin-4-amine (Intermediate 49, 133 mg, 0.32 mmol) to give the title compound (98 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 270.1 (Method 1)

[0187] Intermediate 51: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methanesulfinylpyridazin-4-yl]amino}pyridin-2-yl)prop-2-enamide [ka] N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Example 16, 97 mg, 0.19 mmol) in MeOH (2.8 mL) and H 2 A solution of 2H2O (0.94 mL) was treated with Oxone® (173 mg, 0.56 mmol) and stirred at RT for 16 h. Oxone® (29 mg, 0.09 mmol) was added and the mixture was stirred for 2 h. Oxone® (29 mg, 0.09 mmol) was added again and the mixture was stirred for 2 h. Oxone® (11.5 mg, 0.04 mmol) was added again. A concomitant retro-Michael reaction occurred during the oxidation. The mixture was diluted with water and extracted with DCM. The organic phase was diluted with Na 2 SO 4 The crude product was purified by flash chromatography on a Biotage silica cartridge (DCM to 10% MeOH) to give the title compound (50 mg, 0.12 mmol, 62% yield. LC-MS (ESI): m / z (M+1): 432.2 (Method 2).

[0188] Intermediate 52: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methanesulfonylpyridazin-4-yl]amino}pyridin-2-yl)prop-2-enamide [ka] A mixture of N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methanesulfinylpyridazin-4-yl]amino}pyridin-2-yl)prop-2-enamide (Intermediate 51, 31 mg, 0.07 mmol) in MeOH (0.54 mL) and H 2 The solution of 2H2O (0.18 mL) was treated with Oxone® (44 mg, 0.14 mmol) and stirred at RT for 16 h. 2 The mixture was diluted with O and extracted with EtOAc. The organic phase was washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound (33 mg, recovery assumed to be quantitative). LC-MS (ESI): m / z (M+1): 448.2 (Method 2)

[0189] Intermediate 53: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-methanesulfinylpyridazin-4-amine [ka] 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(methylsulfanyl)pyridazin-4-amine (Intermediate 49, 269 mg, 0.64 mmol) in MeOH (4.67 mL) and H 2 A solution of 2H2O (1.56 mL) was treated with Oxone® (256 mg, 0.83 mmol) and stirred at RT for 2 h. The mixture was diluted with water, extracted with EtOAc, and saturated NaHCO 3 The organic phase was washed with Na 2 SO 4 The crude was purified by flash chromatography on a Biotage silica cartridge (c-Hex~30% EtOAc) to give the title compound (242 mg, 0.55 mmol, 87% yield). LC-MS (ESI): m / z (M+1): 436.2 (Method 1).

[0190] Intermediate 54: tert-Butyl N-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl](methyl)oxo-lambda 6 -Sulfanilidene}carbamate [ka] A solution of 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-methanesulfinylpyridazin-4-amine (Intermediate 53, 242 mg, 0.56 mmol), magnesium oxide (89 mg, 2.22 mmol), rhodium(II) acetate dimer (12 mg, 0.03 mmol), carbamic acid tert-butyl ester (97 mg, 0.83 mmol) and (diacetoxyiodo)benzene (268 mg, 0.83 mmol) in anhydrous DCM (5.6 mL) was stirred at 40° C. for 16 h. The mixture was diluted with water and extracted with DCM. The organic phase was diluted with Na 2 SO 4 The crude product was purified by flash chromatography on a Biotage silica cartridge (c-Hex~30% EtOAc) to give the title compound (77 mg, 0.14 mmol, 25% yield). LC-MS (ESI): m / z (M+1): 551.2 (Method 1).

[0191] Intermediate 55: tert-Butyl N-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)oxo-lambda 6 -Sulfanilidene}carbamate [ka] tert-Butyl N-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl](methyl)oxo-lambda 6 -sulfanylidene}carbamate (Intermediate 54, 77 mg, 0.14 mmol) in MeCN (2.2 mL) and H 2 The 0 (0.2 mL) solution was treated with cerium(IV) ammonium nitrate (230 mg, 0.42 mmol) and the mixture was stirred at RT for 1 h. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with Na 2 SO 4The crude product was purified by flash chromatography on a Biotage silica cartridge (c-Hex~30% EtOAc) to give the title compound (42 mg, 0.10 mmol, 75% yield). LC-MS (ESI): m / z (M+1): 401.1 (Method 1).

[0192] Intermediate 56: tert-Butyl N-{[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl](methyl)oxo-lambda 6 -Sulfanilidene}carbamate [ka] Intermediate 56 was prepared following the method used for the synthesis of Intermediate 47 starting from Intermediate 55 (17 mg, 0.04 mmol) and Intermediate 2 (15 mg, 0.05 mmol) to give the title compound (28 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 647.3 (Method 2)

[0193] Intermediate 57: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate [ka] Intermediate 57 was prepared according to the method used for the synthesis of Intermediate 2 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 1, 350 mg, 1.54 mmol) and 1-piperazinecarboxylic acid tert-butyl ester (373 mg, 2.0 mmol) to give the title compound (658 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 413.2 (Method 1)

[0194] Intermediate 58:N-(4-bromopyridin-2-yl)-3-(piperazin-1-yl)propanamide [ka] Intermediate 58 was prepared following the method used for the synthesis of intermediate 40 starting from intermediate 57 (650 mg, 1.41 mmol) to give the title compound (488 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 313.5 (Method 2)

[0195] Intermediate 59: tert-Butyl N-[2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate [ka] To a solution of N-(4-bromopyridin-2-yl)-3-(piperazin-1-yl)propanamide (Intermediate 58, 140 mg, 0.45 mmol) in MeOH (1.5 mL) was added acetic acid (0.08 mL, 1.34 mmol) and tert-butyl N-(2-oxoethyl)carbamate (107 mg, 0.67 mmol). The mixture was stirred at RT for 30 min, after which sodium cyanoborohydride (42 mg, 0.67 mmol) was added. After 30 min, more tert-butyl N-(2-oxoethyl)carbamate (53 mg, 0.34 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) were added again. After 30 min, the volatiles were removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 30% EtOAc) to afford the title compound (79 mg, 0.17 mmol, 39% yield). LC-MS (ESI): m / z (M+1): 456.4 (Method 2)

[0196] Intermediate 60:tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate [ka] Intermediate 60 was prepared following the method used for the synthesis of Intermediate 47, starting from Intermediate 50 (42 mg, 0.16 mmol) and Intermediate 59 (78 mg, 0.17 mmol) to give the title compound (115 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 645.4 (Method 2)

[0197] Intermediate 61: 2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)sulfanyl]ethan-1-ol [ka] To a solution of 2-mercaptoethanol (0.13 mL, 1.78 mmol) in DMF (8 mL) was added 60% dispersion of NaH in oil (71.3 mg, 1.78 mmol) and the mixture was stirred at RT for 1 h. 3,6-Dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 400 mg, 1.27 mmol) dissolved in DMF (2 mL) was added and the mixture was stirred at RT overnight. The mixture was diluted with saturated NaHCO 3 Poured into aqueous solution and extracted with EtOAc. The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was washed with a small amount of DCM and filtered to give the first crop as a solid. The filtrate was concentrated under reduced pressure and purified by flash chromatography on a Biotage silica cartridge (c-Hex~100% EtOAc). The product so obtained was combined with the first batch to give the title compound (257 mg, 0.29 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 356.1 (Method 1)

[0198] Intermediate 62: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] To a solution of 2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)sulfanyl]ethan-1-ol (Intermediate 61, 257 mg, 0.29 mmol) in DCM (7 mL) was added TEA (0.25 mL, 1.81 mmol) followed by tert-butyl-chloro-dimethylsilane (218 mg, 1.44 mmol). The mixture was stirred at RT overnight, diluted with DCM and washed with saturated NH 4 Cl (aq). The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica cartridge (c-Hex~25% EtOAc). Evaporation of the appropriate fractions afforded the title compound (227 mg, 0.48 mmol, 67% yield). LC-MS (ESI): m / z (M+1): 470.2 (Method 1)

[0199] Intermediate 63: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 63 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (71 mg, 0.10 mmol) starting from intermediate 62 (227 mg, 0.48 mmol) and 5-chloro-2-fluorobenzeneboronic acid (126 mg, 0.72 mmol) to afford the title compound (158 mg, 0.28 mmol, 58% yield). LC-MS (ESI): m / z (M+1): 564.1 (Method 1)

[0200] Intermediate 64: 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]sulfanyl}ethan-1-ol [ka] To a solution of intermediate 63 (158 mg, 0.28 mmol) in MeCN (2.7 mL) and buffer solution (pH = 9, 0.6 mL) was added ammonium cerium(IV) nitrate (181 mg, 0.70 mmol) and the mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc and saturated NaHCO 3 The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica cartridge (DCM to 50% EtOAc). Evaporation of the appropriate fractions afforded the title compound (63 mg, 0.21 mmol, 75% yield). LC-MS (ESI): m / z (M+1): 300.0 (Method 1)

[0201] Intermediate 65: 2-[(tert-butyldimethylsilyl)oxy]ethane-1-thiol [ka] To a stirred solution of 2-mercaptoethanol (1.8 mL, 25.6 mmol) and imidazole (3.49 g, 51.2 mmol) in DCM (20 mL) was added tert-butyl-chloro-dimethylsilane (4.24 g, 28.2 mmol). The reaction was stirred at RT overnight. Water was added, the phases were separated and the organic phase was washed with more water. The organic phase was filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (c-Hex~20% EtOAc) to give the title compound (3.70 g, 19.2 mmol, 76% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.74 (t, J = 6.38 Hz, 2 H) 2.64 (dt, J = 8.31, 6.41 Hz, 2 H) 1.49 - 1.58 (m, 1 H) 0.92 (s, 9 H) 0.09 (s, 6 H)

[0202] Intermediate 66: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-chloropyridazin-4-amine [ka] Intermediate 66 was prepared according to the method used for the synthesis of Intermediate 61 starting from 3,6-dichloropyridazin-4-amine (1.7 g, 10.4 mmol) and Intermediate 65 (2.99 g, 15.6 mmol) to give the title compound (2.56 g, 8.01 mmol, 77% yield). LC-MS (ESI): m / z (M+1): 320.9 (Method 1).

[0203] Intermediate 67: 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Method A Intermediate 67 was prepared according to the method used for the synthesis of Intermediate 62 starting from 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]sulfanyl}ethan-1-ol (Intermediate 64, 63 mg, 0.21 mmol) to afford the title compound (80 mg, 0.19 mmol, 92% yield).

[0204] Method B Intermediate 67 was also prepared by the synthesis of intermediate 8 using the method used to synthesize Pd(dppf)Cl 2(1.35 g, 1.85 mmol) starting from intermediate 66 (2.96 g, 9.25 mmol) and 5-chloro-2-fluorobenzeneboronic acid (2.42 g, 13.88 mmol) to afford the title compound (2.3 g, 5.56 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 414.1 (Method 1)

[0205] Intermediate 68: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 68 was prepared following the method used for the synthesis of Intermediate 47, starting from Intermediate 67 (80 mg, 0.19 mmol) and Intermediate 2 (70 mg, 0.21 mmol) to give the title compound (134 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 660.2 (Method 2)

[0206] Intermediate 69: N-(4-bromopyridin-2-yl)-4-chlorobutanamide [ka] 4-Chlorobutanoyl chloride (0.71 mL, 6.36 mmol) was dissolved in N 2 To a stirred solution of 4-bromopyridin-2-amine (1 g, 5.78 mmol), TEA (2.42 mL, 17.3 mmol) in dry DCM (30 mL) was added dropwise under reduced pressure. The resulting mixture was stirred at RT overnight. Further 4-chlorobutanoyl chloride (0.3 ml, 2.6 mmol) was added at 0° C. The mixture was stirred at RT for 3 h. The mixture was then diluted with more DCM and washed with brine. The organic phase was separated and washed with Na 2 SO 4Dry at 40° C. and filter. Evaporation of the solvent gave a crude oil which was purified by flash chromatography on a Biotage silica cartridge (c-Hex~30% EtOAc) to give the title compound (1.29 g, 4.65 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 276.9 (Method 1).

[0207] Intermediate 70: N-(4-bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide [ka] A solution of N-(4-bromopyridin-2-yl)-4-chlorobutanamide (Intermediate 69, 500 mg, 1.8 mmol), 1-methylpiperazine (2.0 mL, 18.0 mmol) and TEA (0.75 mL, 5.4 mmol) in THF (7.2 mL) was heated at 70° C. for 24 h. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The organic phase was washed with brine, separated, filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex~40% EtOAc) to give the title compound (475 mg, 1.39 mmol, 77% yield). LC-MS (ESI): m / z (M+1): 341.6 (Method 2)

[0208] Intermediate 71: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide [ka] Intermediate 71 was prepared following the method used for the synthesis of intermediate 47 starting from intermediate 67 (80 mg, 0.19 mmol) and intermediate 70 (73 mg, 0.21 mmol) to afford the title compound (98 mg, 0.14 mmol, 75% yield). LC-MS (ESI): m / z (M+1): 674.3 (Method 2)

[0209] Intermediate 72: N-(4-bromopyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide [ka] TEA (0.87 mL, 6.25 mmol) was added to a stirring solution of 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (386 mg, 2.08 mmol) in dry MeCN (8 mL) at RT with N 2 After 10 min, the reaction was cooled in an ice bath and N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 350 mg, 1.39 mmol) was added followed by a catalytic amount of potassium iodide. The reaction mixture was allowed to reach RT and stirred at this temperature for 2 h. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 45% EtOAc) to give the title compound (330 mg, 1.01 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 325.0 (Method 2)

[0210] Intermediate 73: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide [ka] Intermediate 73 was prepared according to the method used in the synthesis of intermediate 47 starting from intermediate 67 (210 mg, 0.51 mmol) and intermediate 72 (318 mg, 0.56 mmol) to afford the title compound (224 mg, 0.34 mmol, 67% yield). LC-MS (ESI): m / z (M+1): 658.3 (Method 2)

[0211] Intermediate 74: 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride [ka] 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (1 g, 3.65 mmol) was placed on an SCX and cooled with 1N NH 3 The mixture was concentrated under reduced pressure to give the title compound (330 mg, 1.78 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 113.2 (Method 2).

[0212] Intermediate 75: N-(4-bromopyridin-2-yl)-2-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}acetamide [ka] Intermediate 75 was prepared following the method used for the synthesis of intermediate 39 starting from intermediate 33 (200 mg, 0.79 mmol) and intermediate 74 (220 mg, 1.19 mmol) to afford the title compound (160 mg, 0.49 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 325.1 (Method 2)

[0213] Intermediate 76:N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}acetamide [ka] Intermediate 76 was prepared following the method used for the synthesis of intermediate 47 starting from intermediate 67 (180 mg, 0.43 mmol) and intermediate 75 (155 mg, 0.48 mmol) to afford the title compound (160 mg, 0.24 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 658.3 (Method 2)

[0214] Intermediate 77: N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide [ka] A solution of 4-bromo-2-pyridinamine (780 mg, 4.51 mmol) and TEA (0.69 mL, 4.96 mmol) in THF (23 mL) was treated with 2,2,2-trichloroacetyl chloride (0.48 mL, 4.28 mmol) at 0° C. The mixture was stirred at the same temperature for 10 min and then at RT for 4 h. The mixture was cooled to 0° C. and carefully diluted with water and then saturated NaHCO 3 The mixture was extracted with EtOAc and 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage silica NH (c-Hex to 100% EtOAc) to give the title compound (1.10 g, 3.45 mmol, 77% yield). LC-MS (ESI): m / z (M+1): 316.8 (Method 1)

[0215] Intermediate 78:tert-Butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate [ka] Intermediate 78 was prepared according to the method used for the synthesis of intermediate 31 starting from tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (3.16 g, 13.15 mmol) and 37% w / w aqueous formaldehyde (4.95 mL, 65.8 mmol) to give the title compound (1.37 g, 5.41 mmol, 41% yield). LC-MS (ESI): m / z (M+1): 255.4 (Method 2).

[0216] Intermediate 79: 2-Methyl-2,8-diazaspiro[4.5]decane dihydrochloride [ka] Intermediate 79 was prepared according to the method used for the synthesis of Intermediate 32 starting from tert-butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (Intermediate 78, 1.37 g, 5.4 mmol) to afford the title compound (912 mg, 4 mmol, 74% yield). 1 H NMR (500 MHz, methanol-d 4 ) δ ppm 3.76 (ddd, J = 11.7, 7.8, 3.9 Hz, 1 H), 3.69 (d, J = 12.1 Hz, 1 H), 3.18 - 3.29 (m, 5 H), 3.04 (d, J = 12.1 Hz, 1 H), 2.97 (s, 3 H), 2.15 - 2.26 (m, 1 H), 1.87 - 2.10 (m, 5 H)

[0217] Intermediate 80: N-(4-bromopyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide [ka] A mixture of N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 77, 200 mg, 0.63 mmol) and 2-methyl-2,8-diazaspiro[4.5]decane dihydrochloride (Intermediate 79, 157 mg, 0.69 mmol) in DMSO (4.2 mL) and Na 2 CO 3 The (233 mg, 2.2 mmol) solution was stirred at 100 °C for 2.5 h. The mixture was diluted with saturated NaHCO 3 The organic phase was treated with Na 2 SO 4 The crude product was purified by flash chromatography on Biotage silica NH (EtOAc to 10% MeOH) and then further purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 HO+0.1%HCOOH to 20%MeCN+0.1%HCOOH) and purified PL-HCO 3 Elution through the cartridge gave the title compound (103 mg, 0.29 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 353.1 (Method 1)

[0218] Intermediate 81: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide [ka] Intermediate 81 was prepared following the method used for the synthesis of intermediate 47 starting from intermediate 67 (100 mg, 0.24 mmol) and intermediate 80 (95 mg, 0.27 mmol) to afford the title compound (130 mg, 0.19 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 686.3 (Method 2)

[0219] Intermediate 82: N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide [ka] N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 300 mg, 1.20 mmol) was added to a stirred solution of 1-methyl-1,4-diazepane (275 mg, 2.40 mmol) in dry DMF (4.55 mL) at RT. After 3 h, the mixture was cooled to RT and cooled to RT. 2 The mixture was treated with 200 mL of ethyl acetate and extracted with EtOAc. The organic layer was separated, washed with water and 2 SO 4 It was dried at 40° C., filtered and evaporated. The crude material was purified by flash chromatography on Biotage silica NH (c-Hex to 40% EtOAc) to give (209 mg, 0.64 mmol, 53% yield). LC-MS (ESI): m / z (M+1): 327.4 (Method 2)

[0220] Intermediate 83: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide [ka] Intermediate 83 was prepared following the method used for the synthesis of Intermediate 47, starting from Intermediate 67 (100 mg, 0.24 mmol) and Intermediate 82 (87 mg, 0.27 mmol) to give the title compound (213 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 660.3 (Method 2)

[0221] Intermediate 84: 3-[(tert-butyldimethylsilyl)oxy]propane-1-thiol [ka] Intermediate 84 was also prepared following the method used for the synthesis of intermediate 65 starting from 3-mercapto-1-propanol (1 g, 10.85 mmol) to give the title compound (1.8 g, 8.72 mmol, 80% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 3.72 (t, J = 5.94 Hz, 2 H) 2.56 - 2.68 (m, 2 H) 1.77 - 1.86 (m, 2 H) 1.34 (t, J = 7.92 Hz, 1 H) 0.90 (s, 9 H) 0.07 (s, 6 H)

[0222] Intermediate 85: 3-[3-[tert-butyl(dimethyl)silyl]oxypropylsulfanyl]-6-chloropyridazin-4-amine [ka] Intermediate 85 was prepared starting from intermediate 84 (1.8 g, 8.73 mmol) according to the method used for the synthesis of intermediate 61 to give the title compound (1.62 g, 4.84 mmol, 83% yield). LC-MS (ESI): m / z (M+1): 334.2 (Method 1).

[0223] Intermediate 86: 3-({3-[(tert-butyldimethylsilyl)oxy]propyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Intermediate 86 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (214 mg, 0.29 mmol) starting from intermediate 85 (488 mg, 1.86 mmol) and 5-chloro-2-fluorobenzeneboronic acid (382 mg, 2.19 mmol) to afford the title compound (300 mg, 0.70 mmol, 48% yield). LC-MS (ESI): m / z (M+1): 428.2 (Method 1)

[0224] Intermediate 87: N-(4-{[3-({3-[(tert-butyldimethylsilyl)oxy]propyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 87 was prepared following the method used for the synthesis of Intermediate 47 starting from Intermediate 86 (100 mg, 0.23 mmol) and Intermediate 2 (84 mg, 0.26 mmol) to afford the title compound (150 mg, 0.022 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 674.5 (Method 2)

[0225] Intermediate 88: 6-Chloro-N4-(2,4-dimethoxybenzyl)-N3-methylpyridazine-3,4-diamine [ka] To a solution of 3,6-dichloro-N-(2,4-dimethoxybenzyl)pyridazin-4-amine (Intermediate 6, 1.2 g, 3.82 mmol) in dry NMP (10 mL) was added TEA (0.532 mL, 3.82 mmol) and 33 wt.% methanamine in absolute ethanol (0.713 mL, 5.73 mmol) and the reaction was heated at 125° C. for 12 h. The reaction was then subjected to reverse phase flash chromatography on a Biotage C18 cartridge (H 2 HO+0.1%HCOOH to 40%MeCN+0.1%HCOOH) to give the title compound (0.6 g, 1.943 mmol, 51% yield) and 6-chloro-N4-(2,4-dimethoxybenzyl)-N3-methylpyridazine-3,4-diamine (0.6 g, 1.943 mmol, 51% yield) as a regioisomeric mixture. LC-MS (ESI): m / z (M+1): 308.9 (Method 1)

[0226] Intermediate 89: 6-(2-chloro-5-fluorophenyl)-N4-(2,4-dimethoxybenzyl)-N3-methylpyridazine-3,4-diamine [ka] Intermediate 89 was prepared according to the method used for the synthesis of intermediate 8, starting from intermediate 88 (600 mg, 1.943 mmol) and using 5-chloro-2-fluorophenyl)boronic acid (1.016 g, 5.83 mmol). 2 Purification with 50% MeCN+0.1% HCOOH to 40% MeCN+0.1% HCOOH afforded the title compound (400 mg, 0.993 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 403.0 (Method 1)

[0227] Intermediate 90: 6-(2-chloro-5-fluorophenyl)-N3-methylpyridazine-3,4-diamine [ka] Intermediate 90 was prepared according to the method used for the synthesis of intermediate 9, starting from intermediate 89 (0.160 g, 0.397 mmol) and using butanol (2 mL) as the solvent. 2 Purification with 30% MeCN+0.1% HCOOH (30% MeCN+0.1% HCOOH) afforded the title compound (100 mg, 0.397 mmol, recovery estimated to be quantitative). LC-MS (ESI): m / z (M+1): 252.9 (Method 1)

[0228] Intermediate 91: 6-Chloro-N4-(2,4-dimethoxybenzyl)-N3,N3-dimethylpyridazine-3,4-diamine [ka] Intermediate 91 was prepared according to the method used for the synthesis of intermediate 88, starting from intermediate 6 (1.0 g, 3.18 mmol) using 2.0 M dimethylamine in THF. Reverse phase flash chromatography on a Biotage C18 cartridge (H 2 Purification with 100% MeCN+0.1% HCOOH (1:3) to 100% MeCN+0.1% HCOOH gave the title compound (172 mg, 0.533 mmol, 17% yield). LC-MS (ESI): m / z (M+1): 322.9 (Method 1).

[0229] Intermediate 92: 6-(5-chloro-2-fluorophenyl)-N4-(2,4-dimethoxybenzyl)-N3,N3-dimethylpyridazine-3,4-diamine [ka] Intermediate 92 was prepared starting from intermediate 91 (170 mg, 0.527 mmol) according to the method used for the synthesis of intermediate 8. Reverse phase flash chromatography on a Biotage C18 cartridge (H 2 Purification with 50% MeCN+0.1% HCOOH to 40% MeCN+0.1% HCOOH gave the title compound (120 mg, 0.288 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 417.1 (Method 1).

[0230] Intermediate 93: Methyl 3,6-dichloropyridazine-4-carboxylate [ka] A solution of 2M (trimethylsilyl)diazomethane in hexanes (7.12 mL, 14.2 mmol) was added dropwise to a stirred solution of 3,6-dichloro-4-pyridazinecarboxylic acid (2.5 g, 12.9 mmol) in MeOH (2.62 mL) / DCM (15 mL). The resulting solution was stirred at RT for 1 h, then a further 5 mL of 2M (trimethylsilyl)diazomethane in hexanes was added dropwise and stirred for 1 h. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on Biotage silica (c-Hex to 25% EtOAc) to give the title compound (1.55 g, 7.49 mmol, 58% yield). LC-MS (ESI): m / z (M+1): 207.1 (Method 1)

[0231] Intermediate 94: Methyl 6-chloro-3-(dimethylamino)pyridazine-4-carboxylate [ka] A mixture of methyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 93, 138 mg, 0.67 mmol), DIPEA (0.17 mL, 1 mmol) and 2 M dimethylamine in THF (0.33 mL, 0.67 mmol) in dry 1,2-dimethoxyethane (2 mL) was heated at 80° C. for 18 h. Volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on Biotage silica (c-Hex to 25% EtOAc) to give the title compound (130 mg, 0.60 mmol, 90% yield). LC-MS (ESI): m / z (M+1): 216.2 (Method 1)

[0232] Intermediate 95: Methyl 6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazine-4-carboxylate [ka] Intermediate 95 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(85 mg, 0.12 mmol) starting from methyl 6-chloro-3-(dimethylamino)pyridazine-4-carboxylate (Intermediate 94, 125 mg, 0.58 mmol) and 5-chloro-2-fluorobenzeneboronic acid (202 mg, 1.16 mmol) to give the title compound (153 mg, 0.49 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 310.1 (Method 1)

[0233] Intermediate 96: 6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazine-4-carboxylic acid [ka] Lithium hydroxide hydrate (40.6 mg, 0.97 mmol) was dissolved in methyl 6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazine-4-carboxylate (Intermediate 95, 150 mg, 0.48 mmol) and 2 A solution of 0.71 mL of HO and MeOH (4.29 mL) was added. The resulting solution was stirred at RT overnight. The volatiles were removed under reduced pressure; the residue was diluted with EtOAc and washed with saturated NH 4 Cl solution was added until pH 7. A suspension was observed and the volatiles were removed under reduced pressure and the residue purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 0 to 50% MeCN) to give the title compound (140 mg, 0.47 mmol, 98% yield). LC-MS (ESI): m / z (M+1): 296.1 (Method 1)

[0234] Intermediate 97: 6-(5-chloro-2-fluorophenyl)-N3,N3-dimethylpyridazine-3,4-diamine [ka] Method A Intermediate 97 was prepared starting from intermediate 92 (0.120 g, 0.288 mmol) according to the method used for the synthesis of intermediate 9. Reverse phase flash chromatography on a Biotage C18 cartridge (H 2 Purification with 30% MeCN+0.1% HCOOH (30% MeCN+0.1% HCOOH) afforded the title compound (77 mg, 0.288 mmol, recovery estimated to be quantitative).

[0235] Method B TEA (79.2 μL, 0.57 mmol) and diphenylphosphoryl azide (112 μL, 0.52 mmol) were added to a solution of 6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazine-4-carboxylic acid (Intermediate 96, 140 mg, 0.47 mmol) in DMF (2 mL). The resulting solution was stirred at RT for 4 h and then H 2 HO (1.1 mL) was added and the mixture was heated at 65 °C for 1.5 h. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography on a Biotage C18 cartridge (HO+0.1% HCOOH to 30% MeCN+0.1% HCOOH). The appropriate fractions were evaporated and the residue was then loaded onto an SCX, washed with MeOH and diluted with 1N NH 3 in MeOH. Evaporation of the basic fractions afforded the title compound (34 mg, 0.13 mmol, 27% yield). LC-MS (ESI): m / z (M+1): 267.2 (Method 1)

[0236] Intermediate 98: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-chloropyridazin-4-yl)carbamate [ka] 6-Chloropyridazin-4-amine (2.0 g, 15.44 mmol) was dissolved in THF (80 mL) and 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 h. The THF was then evaporated and the residue was dissolved in EtOAc and saturated NH 4 Partitioned with Cl solution, the organic phase was dried, evaporated and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~30% EtOAc) to give the title compound (3.96 g, 12.01 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 330.1 (Method 1).

[0237] Intermediate 99: tert-Butyl N-[(tert-butoxy)carbonyl]-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]carbamate [ka] Intermediate 99 was prepared starting from intermediate 98 (1.0 g, 3.03 mmol) according to the method used for the synthesis of intermediate 8. Purification by flash chromatography on a Biotage silica cartridge (cHex~30% EtOAc) afforded the title compound (1.1 g, 2.6 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 330.1 (Method 1).

[0238] Intermediate 100: 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Intermediate 99 (1.1 g, 2.6 mmol) was dissolved in DCM (10 mL) and TFA (3.0 mL, 39.18 mmol) and the reaction was stirred for 5 h, then an additional 2 mL of TFA was added and the reaction was stirred overnight at RT. The next day, the volatiles were removed under reduced pressure and the residue was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH and washed with 1N NH 3 in MeOH; the basic fractions were collected to give the title compound (530 mg, 2.37 mmol, 91% yield). LC-MS (ESI): m / z (M+1): 224 (Method 2)

[0239] Intermediate 101: 2-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine [ka] 2-Chloro-1H-imidazo[4,5-b]pyridine (200 mg, 1.3 mmol) was dissolved in N 2 The mixture was suspended in THF (8 mL) under reduced pressure and DIPEA (0.68 mL, 3.91 mmol) was added followed by 2-(chloromethoxy)ethyl-trimethylsilane (0.3 mL, 1.69 mmol). The reaction mixture was stirred at reflux for 4 h. Then, RT was allowed to reach, water and EtOAc were added, the product was extracted several times with EtOAc, and the organic phases were collected, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~100% EtOAc) to give the title compound (180 mg, 0.63 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 284. 2 (Method 1) 1H NMR (400 MHz, chloroform-d) δ ppm 8.40 (dd, J = 4.8, 1.3 Hz, 1 H), 7.99 (dd, J = 8.0, 1.4 Hz, 1 H), 7.29 (d, J = 5.0 Hz, 1 H), 5.71 (s, 2 H), 3.61 - 3.72 (m, 2 H), 0.91 - 1.00 (m, 2 H), -0.05 (s, 9 H)

[0240] Intermediate 102: 6-(5-chloro-2-fluorophenyl)-N-(3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-2-yl)pyridazin-4-amine [ka] Intermediate 102 was prepared according to the method used for the synthesis of Intermediate 18 starting from Intermediate 101 (113 mg, 0.40 mmol) and Intermediate 100 (70 mg, 0.31 mmol) to afford the title compound (35 mg, 0.07 mmol, 24% yield). LC-MS (ESI): m / z (M+1): 471.4 (Method 1)

[0241] Intermediate 103: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(4-chloropyrimidin-2-yl)carbamate [ka] Intermediate 103 was prepared starting from 4-chloro-2-pyrimidinamine (200 mg, 1.54 mmol) according to the method used for the synthesis of intermediate 98. Purification by flash chromatography on a Biotage silica cartridge (cHex~20% EtOAc) afforded the title compound (500 mg, 1.52 mmol, 98% yield). LC-MS (ESI): m / z (M+1): 330.3 (Method 1)

[0242] Intermediate 104:tert-Butyl N-[(tert-butoxy)carbonyl]-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyrimidin-2-yl)carbamate [ka] Intermediate 104 was prepared according to the method used for the synthesis of Intermediate 8 starting from Intermediate 103 (113 mg, 0.34 mmol) and Intermediate 100 (70 mg, 0.31 mmol) to afford the title compound (30 mg, 0.06 mmol, 18% yield). LC-MS (ESI): m / z (M+1): 517.4 (Method 1)

[0243] Intermediate 105: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(2-methoxyethoxy)pyridazin-4-amine [ka] Intermediate 105 was prepared according to the method used for the synthesis of Intermediate 7 starting from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 1 g, 3.18 mmol) and 2-methoxyethanol (0.33 mL, 4.14 mmol) to afford the title compound (776 mg, 2.20 mmol, 69% yield). LC-MS (ESI): m / z (M+1): 354.2 (Method 1)

[0244] Intermediate 106: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(2-methoxyethoxy)pyridazin-4-amine [ka] Intermediate 106 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(286 mg, 0.39 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(2-methoxyethoxy)pyridazin-4-amine (Intermediate 105, 691 mg, 1.95 mmol) and 5-chloro-2-fluorobenzeneboronic acid (511 mg, 2.93 mmol) to give the title compound (607 mg, 1.35 mmol, 69% yield). LC-MS (ESI): m / z (M+1): 448.3 (Method 1)

[0245] Intermediate 107: 6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-amine [ka] Intermediate 107 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(2-methoxyethoxy)pyridazin-4-amine (Intermediate 106, 607 mg, 1.35 mmol) to afford the title compound (350 mg, 1.18 mmol, 87% yield). LC-MS (ESI): m / z (M+1): 298.1 (Method 1)

[0246] Intermediate 108: N-(4-bromopyridin-2-yl)-3-(morpholin-4-yl)propanamide [ka] Intermediate 108 was prepared according to the method used for the synthesis of Intermediate 2 starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 1, 450 mg, 1.98 mmol) and morpholine (0.38 mL, 4.36 mmol) to give the title compound (540 mg, 1.72 mmol, 87% yield). LC-MS (ESI): m / z (M+1): 314.1 (Method 1).

[0247] Intermediate 109:6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine [ka] To a solution of 2-(4-methylpiperazin-1-yl)ethan-1-ol (1.38 g, 9.55 mmol) in DMF (7 mL) was added 60% NaH in oil dispersion (382 mg, 9.55 mmol) and the mixture was stirred at RT for 1.5 h. 3,6-Dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 1 g, 3.18 mmol) dissolved in DMF (3 mL) was added and the mixture was stirred at 130 °C overnight. The mixture was cooled to RT and saturated NaHCO 3 Poured into aqueous solution and extracted with EtOAc. The organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH). Evaporation of the appropriate fractions afforded the title compound (608 mg, 1.44 mmol, 45% yield). LC-MS (ESI): m / z (M+1): 422.6 (Method 1)

[0248] Intermediate 110: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine [ka] Intermediate 110 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(211 mg, 0.29 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine (Intermediate 109, 608 mg, 1.44 mmol) and 5-chloro-2-fluorobenzeneboronic acid (376 mg, 2.16 mmol) to give the title compound (457 mg, 0.89 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 516.3 (Method 2)

[0249] Intermediate 111: 6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine [ka] Intermediate 111 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine (Intermediate 110, 457 mg, 0.89 mmol) to give the title compound (281 mg, 0.77 mmol, 87% yield). LC-MS (ESI): m / z (M+1): 366.2 (Method 2).

[0250] Intermediate 112: N-(4-bromopyridin-2-yl)cyclopropanecarboxamide [ka] To an ice-cold solution of a mixture of 4-bromopyridin-2-amine (500 mg, 2.89 mmol) and pyridine (0.7 mL, 8.67 mmol) in DCM (15 mL) was added cyclopropanecarbonyl chloride (0.31 mL, 3.47 mmol) dropwise and the mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH 4After washing with aqueous Cl, the organic phase was separated, filtered through a hydrophobic phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica cartridge (DCM to 15% EtOAc). Evaporation of the appropriate fractions afforded the title compound (712 mg, 2.95 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 240.9 (Method 1)

[0251] Intermediate 113: 4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] Intermediate 113 was prepared according to the method used for the synthesis of intermediate 23 starting from a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.55 mmol) and 2-(chloromethoxy)ethyl-trimethylsilane (1.5 mL, 8.52 mmol) in DMF (16 mL) to give the title compound (1.96 g, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 283.1 (Method 1)

[0252] Intermediate 114: 6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridazin-4-amine [ka] Intermediate 114 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-amine (Intermediate 111, 90 mg, 0.25 mmol) and 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (Intermediate 113, 83 mg, 0.3 mmol) to give the title compound (79 mg, 0.13 mmol, 52% yield). LC-MS (ESI): m / z (M+1): 612.5 (Method 2)

[0253] Intermediate 115: 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridazin-4-amine [ka] Intermediate 115 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine (Intermediate 30, 110 mg, 0.35 mmol) and 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (Intermediate 113, 120 mg, 0.42 mmol) to give the title compound (84 mg, 0.15 mmol, 43% yield). LC-MS (ESI): m / z (M+1): 557.3 (Method 2)

[0254] Intermediate 116: 4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyridine [ka] 4-Chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.26 mmol) and K 2 CO 3A mixture of (1.35 g, 9.77 mmol) in DMF (16.7 mL) was stirred at RT for 30 min, then 2-(chloromethoxy)ethyl-trimethylsilane (0.92 mL, 5.2 mmol) was added and the mixture was stirred at RT for 7 h. The mixture was diluted with EtOAc and saturated NaHCO 3 The crude was washed with hexanes (3x) and brine (1x). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The crude was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex~15% EtOAc) and then further purified by flash chromatography on a Biotage silica cartridge (c-Hex~20% EtOAc) to give the title compound (535 mg, 1.88 mmol, 58% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.57 (d, J = 5.06 Hz, 1 H), 8.38 (s, 1 H), 7.46 (d, J = 5.06 Hz, 1 H), 5.80 (s, 2 H), 3.57 - 3.64 (m, 2 H), 0.83 (d, J = 8.14 Hz, 2 H), -0.11 (s, 9 H)

[0255] Intermediate 117: 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridazin-4-amine [ka] Intermediate 117 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-amine (Intermediate 30, 90 mg, 0.29 mmol) and 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyridine (Intermediate 116, 99 mg, 0.35 mmol) to afford the title compound (113 mg, 0.20 mmol, 70% yield). LC-MS (ESI): m / z (M+1): 558.4 (Method 2)

[0256] Intermediate 118: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-hydroxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate [ka] Intermediate 118 was prepared according to the method used for the synthesis of intermediate 47 starting from 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}ethan-1-ol (Intermediate 4, 193 mg, 0.63 mmol) and tert-butyl N-(4-bromopyridin-2-yl)carbamate (191 mg, 0.70 mmol) to give the title compound (100 mg, 0.21 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 476.3 (Method 2).

[0257] Intermediate 119: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-amine [ka] Intermediate 119 was prepared according to the method used in the synthesis of Intermediate 7 from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 1.1 g, 3.5 mmol) and (1-methylazetidin-3-yl)methanol (460 mg, 4.55 mmol) starting at 120° C. to afford the title compound (665 mg, 1.75 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 379.2 (Method 1)

[0258] Intermediate 120:6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-amine [ka] In a suitable vial, 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-amine (Intermediate 119, 475 mg, 1.25 mmol), 5-chloro-2-fluorobenzeneboronic acid (284 mg, 1.63 mmol), Na 2 CO 3 (266 mg, 2.51 mmol) and Pd(PPh 3 ) 4 A mixture of (73 mg, 0.06 mmol) was suspended in toluene (5 mL) / ethanol (1.7 mL) / water (1.7 mL). The vial was sealed, evacuated, and N 2 The mixture was back-filled with 5-chloro-2-fluorobenzeneboronic acid (200 mg, 1.15 mmol) and Pd(PPh 3 ) 4 (73 mg, 0.06 mmol) was added again and the mixture was heated for 7 h. The mixture was diluted with EtOAc and washed with Celite. (登録商標) The organic phase was washed with brine, separated, filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 100% EtOAc) to give the title compound (204 mg, 0.43 mmol, 34% yield). LC-MS (ESI): m / z (M+1): 473.2 (Method 1)

[0259] Intermediate 121: 6-(5-chloro-2-fluorophenyl)-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-amine [ka] Intermediate 121 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-amine (Intermediate 120, 144 mg, 0.30 mmol) to give the title compound (95 mg, 0.29 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 323.1 (Method 2).

[0260] Intermediate 122: tert-Butyl N-[2-({4-[(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)amino]-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl}oxy)ethyl]-N-methanesulfonylcarbamate [ka] A solution of tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-hydroxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Intermediate 118, 75 mg, 0.14 mmol) in anhydrous THF (5 mL) was added at RT with 2 Bottom, tert-butyl N-methylsulfonylcarbamate (30 mg, 0.15 mmol) and PPh 3 (40 mg, 0.15 mmol), followed by diisopropyl azodicarboxylate (0.03 mL, 0.15 mmol) were added. The yellow solution was stirred for 1 h at RT and then further tert-butyl N-methylsulfonylcarbamate (30 mg, 0.15 mmol), PPh 3 (40 mg, 0.15 mmol) and diisopropyl azodicarboxylate (0.03 mL, 0.15 mmol) were added. The mixture was heated at 55° C. for 1 h. Further tert-butyl N-methylsulfonylcarbamate (90 mg, 0.45 mmol), PPh 3(120 mg, 0.45 mmol) and diisopropyl azodicarboxylate (0.09 mL, 0.45 mmol) were added and after 1 h at 55° C. the conversion was complete. The mixture was concentrated under reduced pressure and the residue purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 0+0.1%HCOOH to 60%MeCN+0.1%HCOOH) to give the title compound (130 mg, estimated quantitative recovery). LC-MS (ESI): m / z (M+1): 653.3 (Method 1)

[0261] Intermediate 123: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine [ka] Intermediate 123 was prepared according to the method used in the synthesis of Intermediate 7 starting from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 100 mg, 0.32 mmol) and 2,2,2-trifluoroethanol (30 μL, 0.41 mmol) to give the title compound (88 mg, 0.23 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 378.2 (Method 1)

[0262] Intermediate 124: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine [ka] Intermediate 124 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(34 mg, 0.05 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (Intermediate 123, 88 mg, 0.23 mmol) and 5-chloro-2-fluorobenzeneboronic acid (61 mg, 0.31 mmol) to give the title compound (88 mg, 0.19 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 472.2 (Method 1)

[0263] Intermediate 125: 6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine [ka] Intermediate 125 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (Intermediate 124, 88 mg, 0.19 mmol) to afford the title compound (48 mg, 0.15 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 322.1 (Method 1)

[0264] Intermediate 126: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate [ka] Intermediate 126 was prepared according to the method used for the synthesis of Intermediate 47, starting from 6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (Intermediate 125, 48 mg, 0.15 mmol) and tert-butyl N-(4-bromopyridin-2-yl)carbamate (45 mg, 0.16 mmol) to give the title compound (50 mg, 0.10 mmol, 65% yield). LC-MS (ESI): m / z (M+1): 514.2 (Method 1).

[0265] Intermediate 127: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate [ka] Intermediate 127 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-amine (Intermediate 9, 60 mg, 0.20 mmol) and tert-butyl N-(4-bromopyridin-2-yl)carbamate (59 mg, 0.22 mmol) to give the title compound (60 mg, 0.12 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 496.2 (Method 1).

[0266] Intermediate 128: 6-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-amine [ka] Intermediate 128 was prepared according to the method used for the synthesis of Intermediate 109 starting from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 500 mg, 1.06 mmol) and 2-pyrrolidin-1-ylethanol (550 mg, 4.77 mmol) to give the title compound (664 mg, assumed quantitative recovery). LC-MS (ESI): m / z (M+1): 393.2 (Method 2).

[0267] Intermediate 129: 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-amine [ka] Intermediate 129 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (161 mg, 0.22 mmol) starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-amine (Intermediate 128, 664 mg, 1.06 mmol) and 5-chloro-2-fluorobenzeneboronic acid (287 mg, 1.65 mmol) to give the title compound (355 mg, 0.73 mmol, 66% yield). LC-MS (ESI): m / z (M+1): 487.4 (Method 2)

[0268] Intermediate 130: 6-(5-chloro-2-fluorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-amine [ka] Intermediate 130 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-amine (Intermediate 129, 355 mg, 0.73 mmol) to afford the title compound (233 mg, 0.69 mmol, 95% yield). LC-MS (ESI): m / z (M+1): 337.1 (Method 2)

[0269] Intermediate 131: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-yl]amino}pyridin-2-yl)carbamate [ka] Intermediate 131 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-amine (Intermediate 12, 50 mg, 0.15 mmol) and tert-butyl N-(4-bromopyridin-2-yl)carbamate (46 mg, 0.17 mmol) to give the title compound (50 mg, 0.10 mmol, 63% yield). LC-MS (ESI): m / z (M+1): 520.2 (Method 1).

[0270] Intermediates 132 and 133 tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfonylpropoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Int 132) and tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfinylpropoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Int 133) [ka] tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Intermediate 131, 160 mg, 0.30 mmol) was suspended in MeOH (6 mL) and diluted with Oxone® (136 mg, 0.44 mmol) in H 2 A solution of 2 mL of HO was added. The resulting suspension was stirred at RT for 55 min. Saturated NaHCO 3 A solution was added to adjust the pH to 8, then EtOAc was added and the product was extracted with EtOAc three times. The organic phases were collected and evaporated to dryness and the residue was purified by flash chromatography on a Biotage silica cartridge (50% c-Hex to 100% EtOAc, then 30% MeOH in EtOAc). Appropriate fractions were collected to give tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfonylpropoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Int 132, 70 mg, 0.13 mmol, 43% yield) and tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfinylpropoxy)pyridazin-4-yl]amino}pyridin-2-yl)carbamate (Int 133, 75 mg, 0.14 mmol, 47% yield). Int 132:LC-MS (ESI): m / z (M+1): 552.2 (Method 1) Int 133:LC-MS (ESI): m / z (M+1): 536.3 (Method 1)

[0271] Intermediate 134: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide [ka] Intermediate 134 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-amine (Intermediate 26, 110 mg, 0.33 mmol) and N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (Intermediate 112, 91 mg, 0.36 mmol) to afford the title compound (72 mg, 0.15 mmol, 45% yield). LC-MS (ESI): m / z (M+1): 485.2 (Method 1)

[0272] Intermediate 135: 6-Chloro-3-(oxolan-3-yloxy)pyridazin-4-amine [ka] To a solution of oxolan-3-ol (1.48 mL, 18.29 mmol) in DMF (33.3 mL) was added 60% dispersion of NaH in oil (731 mg, 18.29 mmol) and the mixture was stirred at RT for 1.5 h (until gas evolution ceased). 3,6-Dichloropyridazin-4-amine (1 g, 6.1 mmol) dissolved in DMF (13.3 mL) was added and the reaction was warmed to 130 °C for 3 h. The mixture was diluted with EtOAc and saturated NaHCO 3 The aqueous phase was further extracted with EtOAc (3x) and the combined organic layers were filtered through a phase separator and concentrated under reduced pressure. To remove residual DMF, n-heptane was added and the solvent was evaporated under reduced pressure. This was repeated three times. As DMF was still present, the mixture was loaded onto SCX (20 g) and washed with MeOH, then 1N NH 3The mixture was washed with MeOH solution of 100 mg of ethyl acetate. The basic fractions were evaporated and then triturated with DCM to give the first batch of the title compound (100 mg, 0.46 mmol). The methanolic fractions were evaporated to give the crude product (3.88 g) containing the formyl derivative. This material was dissolved in ethanol (12.5 mL), 2N NaOH (2.5 mL, 5 mmol) was added and the mixture was heated at 65° C. for 30 min. The ethanol was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 50% EtOAc) and the appropriate fractions were collected, combined with the first batch and evaporated to give the title compound (655 mg, 3.03 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 216.0 (Method 1)

[0273] Intermediate 136: 6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-amine [ka] Intermediate 136 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (441 mg, 0.60 mmol) starting from 6-chloro-3-(oxolan-3-yloxy)pyridazin-4-amine (Intermediate 135, 650 mg, 3.01 mmol) and 5-chloro-2-fluorobenzeneboronic acid (788 mg, 4.52 mmol) to give the title compound (562 mg, 1.82 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 310.1 (Method 2)

[0274] Intermediate 137: tert-Butyl 4-{[(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate [ka] Intermediate 137 was prepared according to the method used for the synthesis of Intermediate 47, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (Intermediate 39, 110 mg, 0.27 mmol) to give the title compound (130 mg, 0.18 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 732.4 (Method 2).

[0275] Intermediate 138: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate [ka] Intermediate 138 was prepared according to the method used for the synthesis of intermediate 39 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 600 mg, 2.40 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (722 mg, 3.60 mmol) to afford the title compound (740 mg, 1.79 mmol, 74% yield). LC-MS (ESI): m / z (M+1): 414.3 (Method 2)

[0276] Intermediate 139: tert-Butyl 4-{[(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate [ka] Intermediate 139 was prepared according to the method used for the synthesis of Intermediate 47, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate (Intermediate 138, 110 mg, 0.27 mmol) to give the title compound (106 mg, 0.14 mmol, 59% yield). LC-MS (ESI): m / z (M+1): 746.4 (Method 2).

[0277] Intermediate 140: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate [ka] Intermediate 140 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-amine (Intermediate 50, 100 mg, 0.37 mmol) and tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate (Intermediate 57, 169 mg, 0.41 mmol) to afford the title compound (110 mg, 0.18 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 602.3 (Method 2)

[0278] Intermediate 141: N-(4-bromopyridin-2-yl)-2-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide [ka] Intermediate 141 was prepared according to the method used for the synthesis of Intermediate 72 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 300 mg, 1.20 mmol) and (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (289 mg, 1.53 mmol) to give the title compound (282 mg, 0.87 mmol, 72% yield). LC-MS (ESI): m / z (M+1): 325.1 (Method 2).

[0279] Intermediate 142: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide [ka] Intermediate 142 was prepared according to the method used for the synthesis of intermediate 47, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and N-(4-bromopyridin-2-yl)-2-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide (Intermediate 141, 86 mg, 0.27 mmol) to give the title compound (55 mg, 0.08 mmol, 35% yield). LC-MS (ESI): m / z (M+1): 658.4 (Method 2).

[0280] Intermediate 143: N-(4-bromopyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide [ka] Intermediate 143 was prepared according to the method used for the synthesis of intermediate 72 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 300 mg, 1.20 mmol) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane hydrobromide (424 mg, 1.55 mmol) to give the title compound (280 mg, 0.86 mmol, 72% yield). LC-MS (ESI): m / z (M+1): 325.1 (Method 2).

[0281] Intermediate 144: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide [ka] Intermediate 144 was prepared according to the method used for the synthesis of intermediate 47, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and N-(4-bromopyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide (Intermediate 143, 86 mg, 0.27 mmol) to give the title compound (91 mg, 0.14 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 658.4 (Method 2).

[0282] Intermediate 145: 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}ethan-1-ol [ka] Process 1 2-(Methylamino)ethanol (0.16 mL, 2.01 mmol), K 2 CO 3 (557 mg, 4.03 mmol) and 3,6-dichloropyridazin-4-amine (330 mg, 2.01 mmol) were mixed in DMF (3 mL) and heated at 110° C. for 2 days. The mixture was loaded onto an SCX, washed with MeOH and diluted with 1N NH 3 in MeOH. Evaporation of the basic fractions gave the crude material containing 24% a / a of 2-[(4-amino-6-chloro-pyridazin-3-yl)-methyl-amino]ethanol which was used directly in the next step.

[0283] Process 2 In a suitable vial, 2-[(4-amino-6-chloro-pyridazin-3-yl)-methyl-amino]ethanol (2 mmol), 5-chloro-2-fluorobenzeneboronic acid (697 mg, 4 mmol), K 2 CO 3 (829 mg, 6 mmol) in a mixture of 1,2-dimethoxyethane (9.6 mL) and H 2 Degas the solution (vacuum / N) with 2.39 mL of O. 2 ), followed by Pd(dppf)Cl 2 (293 mg, 0.40 mmol) was added. The vial was sealed and heated at 110 °C for 1 h. Additional Pd(dppf)Cl 2 (293 mg, 0.40 mmol), K 2 CO 3 (829 mg, 6 mmol) and 5-chloro-2-fluorobenzeneboronic acid (697 mg, 4 mmol) were added and then heated at 110° C. for 1 h. The mixture was filtered through a celite (登録商標) The crude material was purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH~40% MeCN) to give the title compound (30 mg, 0.10 mmol, 5% yield). LC-MS (ESI): m / z (M+1): 297.1 (Method 2)

[0284] Intermediate 146: 6-(5-chloro-2-fluorophenyl)-3-(oxetan-3-yloxy)pyridazin-4-amine [ka] Process 1 3-Oxetanol (0.04 mL, 0.61 mmol) and t-BuOK (75 mg, 0.67 mmol) were mixed in THF (3 mL) and stirred for 10 min, after which 3,6-dichloropyridazin-4-amine (100 mg, 0.61 mmol) was added. The resulting yellow mixture was stirred for 1 h at RT and then heated at 70 °C overnight. The mixture was cooled to RT, loaded onto an SCX, washed with MeOH and purified with 1N NH 3 in MeOH. Evaporation of the basic fractions gave a mixture containing 44% a / a of the title compound (109 mg) which was used as is.

[0285] Process 2 In a suitable vial, 6-chloro-3-(oxetan-3-yloxy)pyridazin-4-amine (109 mg), 5-chloro-2-fluorobenzeneboronic acid (82 mg, 0.47 mmol), K 2 CO 3 (98 mg, 0.71 mmol) and Pd(dppf)Cl 2 (34 mg, 0.05 mmol) in a mixture of 1,2-dimethoxyethane (1.12 mL) and H 2 Degas the solution (vacuum / N) with HO (0.28 mL). 2 ), then heated at 110°C for 1 hour. 2 (34 mg, 0.05 mmol), K 2 CO 3 (98 mg, 0.71 mmol) and 5-chloro-2-fluorobenzeneboronic acid (82 mg, 0.47 mmol) were added, and then the mixture was stirred at 110° C. for 1 h. (登録商標) The crude material was purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2O+0.1%NH 4 OH~40% MeCN) to give the title compound (35 mg, 0.12 mmol, 19% yield). LC-MS (ESI): m / z (M+1): 296.1 (Method 2)

[0286] Intermediate 147: 6-Chloro-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine [ka] Intermediate 147 was prepared according to the method used for the synthesis of Intermediate 9 starting from 6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (Intermediate 123, 454 mg, 1.20 mmol) to give the title compound (236 mg, 1.03 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 228.4 (Method 2).

[0287] Intermediate 148: N-(4-{[6-chloro-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 148 was prepared according to the method used for the synthesis of Intermediate 47 starting from 6-chloro-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (Intermediate 147, 236 mg, 1.03 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 400 mg, 1.23 mmol) to give the title compound (293 mg, 0.62 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 474.4 (Method 2).

[0288] Intermediate 149: 6-Chloro-3-(2-methoxyethoxy)pyridazin-4-amine [ka] Intermediate 149 was prepared according to the method used for the synthesis of intermediate 3, starting from 2-methoxyethan-1-ol (1.392 g, 18.29 mmol). Reverse phase flash chromatography on a Biotage C18 cartridge (H 2 O / MeCN 95:5+0.1%HCOOH~30%MeCN / H 2 Purification with 0.05:5+0.1% HCCOH) gave the title compound (0.5 g, 2.455 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 204.2 (Method 2)

[0289] Intermediate 150: Tert-Butyl (4-((6-chloro-3-(2-methoxyethoxy)pyridazin-4-yl)amino)pyridin-2-yl)carbamate [ka] Intermediate 150 was prepared according to the method used for the synthesis of intermediate 18, starting from intermediate 149 (470 mg, 2.308 mmol) and using tert-butyl (4-bromopyridin-2-yl)carbamate (630 mg, 2.308 mmol). Reverse phase flash chromatography on a Biotage C18 cartridge (H 2 O / MeCN 95:5+0.1%HCOOH~30%MeCN / H 2 Purification with 0.05% HCOOH (95:5 + 0.1% HCCOH) gave the title compound (30 mg, 0.076 mmol, 3.3% yield). LC-MS (ESI): m / z (M+1): 396.3 (Method 2)

[0290] Intermediate 151: 6-Chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)pyridazin-4-amine [ka] Intermediate 151 was prepared following the method used for the synthesis of Intermediate 3, starting from 2-(4-methylpiperazin-1-yl)ethan-1-ol (5.28 g, 36.6 mmol). The reaction was heated to 130° C. and stirred for 18 h. The reaction was cooled and the DMF was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 1M aqueous HCl. The aqueous layer was collected and washed with saturated K 2 CO 3 The mixture was basified with aqueous hexane. The resulting solution was evaporated to dryness. The solid was suspended in EtOH (40 mL), boiled for 30 min, and filtered. The mother liquor was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on a Biotage silica NH cartridge (0-5% EtOH in DCM) to give the title compound (1.5 g, 5.52 mmol, 45% yield). LC-MS (ESI): m / z (M+1): 272.3 (Method 2)

[0291] Intermediate 152: N 4 -(6-chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)pyridazin-4-yl)pyridine-2,4-diamine [ka] Intermediate 152 was prepared according to the method for the synthesis of intermediate 18, starting from intermediate 151 (200 mg, 0.736 mmol) using tert-butyl (4-bromopyridin-2-yl)carbamate (302 mg, 1.104 mmol). The reaction mixture was heated to 110° C. and stirred for 3 h. Then MTBE (20 mL) was added and the organic phase was quenched with 1M aqueous HCl (10 mL). The two phases were separated and the aqueous layer was neutralized by the addition of solid NaOH. The water was evaporated to dryness under reduced pressure to give the title compound, which was used as such in the next step. LC-MS (ESI): m / z (M+1): 364.4 (Method 2)

[0292] Intermediate 151: 6-Chloro-3-(2-methoxyethoxy)pyridazin-4-amine [ka] Intermediate 151 was prepared according to the method used for the synthesis of intermediate 3, starting from 2-methoxyethan-1-ol (1.392 g, 18.29 mmol). Reverse phase flash chromatography on a Biotage C18 cartridge (100% H 2 O / MeCN 95:5+0.1%HCOOH~30%MeCN / H 2 Purification with 0.05:5+0.1% HCCOH) gave the title compound (0.5 g, 2.455 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 204.2 (Method 2)

[0293] Intermediate 152: Tert-Butyl (4-((6-chloro-3-(2-methoxyethoxy)pyridazin-4-yl)amino)pyridin-2-yl)carbamate [ka] Intermediate 152 was prepared according to the method used for the synthesis of intermediate 18, starting from intermediate 151 (470 mg, 2.308 mmol) and using tert-butyl (4-bromopyridin-2-yl)carbamate (630 mg, 2.308 mmol). Reverse phase flash chromatography on a Biotage C18 cartridge (100% H 2 O / MeCN 95:5+0.1%HCOOH~30%MeCN / H 2 Purification with 0.05% HCOOH (95:5 + 0.1% HCCOH) gave the title compound (30 mg, 0.076 mmol, 3.3% yield). LC-MS (ESI): m / z (M+1): 396.3 (Method 2)

[0294] Intermediate 153: Methyl 3-[(tert-butyldimethylsilyl)oxy]cyclobutane-1-carboxylate [ka] Intermediate 153 was prepared according to the method used for the synthesis of intermediate 65 starting from 3-methyl 3-hydroxycyclobutane-1-carboxylate (0.5 g, 3.84 mmol) to afford the title compound (0.85 g, 3.53 mmol, 92% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 4.14 (tt, J = 8.2, 6.7 Hz, 1H), 3.67 (s, 3H), 2.59 - 2.41 (m, 3H), 2.23 - 2.15 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H)

[0295] Intermediate 154: {3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methanol [ka] In a flame-dried two-neck flask, a solution of methyl 3-[(tert-butyldimethylsilyl)oxy]cyclobutane-1-carboxylate (Intermediate 153, 850 mg, 3.53 mmol) in THF (10 mL) was heated with a 2 M solution of lithium aluminum hydride in THF (5.3 mL, 10.61 mmol) at 0 °C under N 2 The mixture was stirred at the same temperature for 30 minutes and then 5 g of Na 2 SO 4 followed by the addition of 20 mL of EtOAc at 0° C. The mixture was stirred for 5 min, then water was added until the mixture was clear. The mixture was filtered, washed with EtOAc, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica cartridge (cHex~50% EtOAc) to give the title compound (536 mg, 2.48 mmol, 70% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 4.15 (quin, J = 7.3 Hz, 1H), 3.60 (t, J = 5.9 Hz, 2H), 2.34 (dtt, J = 9.4, 7.0, 2.6 Hz, 2H), 2.01 - 1.87 (m, 1H), 1.62-1.73 (m, 2H), 1.33 (t, J = 5.7 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 6H)

[0296] Intermediate 155: 3-({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methoxy)-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 155 was prepared according to the method used for the synthesis of Intermediate 7 from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 400 mg, 1.27 mmol) and {3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methanol (Intermediate 154, 0.49 mL, 4.14 mmol) at 110° C. to afford the title compound (478 mg, 0.97 mmol, 76% yield). LC-MS (ESI): m / z (M+1): 494.3 (Method 1)

[0297] Intermediate 156: 3-({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methoxy)-6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 156 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(141 mg, 0.19 mmol) starting from 3-({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methoxy)-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 155, 478 mg, 0.97 mmol) and 5-chloro-2-fluorobenzeneboronic acid (253 mg, 1.45 mmol) to give the title compound (288 mg, 0.49 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 588.4 (Method 1)

[0298] Intermediate 157: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}methyl)cyclobutan-1-ol [ka] Intermediate 157 was prepared according to the method used for the synthesis of Intermediate 64 starting from 3-({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methoxy)-6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 156, 288 mg, 0.49 mmol) to give the title compound (66 mg, 0.20 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 324.1 (Method 1).

[0299] Intermediate 158: 6-Chloro-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridazin-4-amine [ka] Intermediate 158 was prepared according to the method used for the synthesis of intermediate 135 starting from (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2.42 g, 18.3 mmol) and 3,6-dichloropyridazin-4-amine (1 g, 6.20 mmol) to give the title compound (855 mg, 3.30 mmol, 54% yield). LC-MS (ESI): m / z (M+1): 260.1 (Method 1).

[0300] Intermediate 159: 6-(5-chloro-2-fluorophenyl)-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridazin-4-amine [ka] Intermediate 159 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (451 mg, 0.62 mmol) starting from 6-chloro-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridazin-4-amine (Intermediate 158, 800 mg, 3.08 mmol) and 5-chloro-2-fluorobenzeneboronic acid (806 mg, 4.62 mmol) to give the title compound (510 mg, 1.44 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 354.1 (Method 2)

[0301] Intermediate 160: 3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutan-1-one [ka] Intermediate 160 was prepared following the method used for the synthesis of intermediate 65 starting from 3-(hydroxymethyl)cyclobutan-1-one (2 g, 20 mmol) to afford the title compound (3.6 g, 16.8 mmol, 84% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 3.74 (s, 2H), 3.07 - 3.01 (m, 2H), 2.92 (t, J = 3.0 Hz, 2H), 2.65 - 2.50 (m, 1H), 0.90 (s, 9H), 0.07 (s, 6H)

[0302] Intermediate 161: 3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutan-1-ol [ka] In a flame-dried flask, a solution of 3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutan-1-one (Intermediate 160, 500 mg, 2.33 mmol) in THF (23.3 mL) was added to a 1 M solution of L-Selectride® in THF (3.5 mL, 3.5 mmol) at −78 °C with N 2 The mixture was stirred at -78 °C for 1 h, then warmed to RT and stirred for 30 min. The reaction was diluted with 2.5 mL of saturated NaHCO 3 The mixture was quenched by the addition of aqueous 30% (w / w) hydrogen peroxide, then cooled using an ice bath, followed by careful addition of 30% (w / w) hydrogen peroxide. 2 A solution of 2,4-dichlorophenyl ether (0.4 mL, 3.92 mmol) was added. The mixture was warmed to RT and stirred for 15 min. The mixture was extracted with EtOAc and washed with water. The organic phase was washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica cartridge (cHex to 25% EtOAc) to give the title compound (472 mg, 2.18 mmol, 93% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm δ ppm 4.07 - 4.23 (m, 1 H), 3.58 (d, J = 4.9 Hz, 2 H), 2.31 - 2.47 (m, 2 H), 1.93 - 2.09 (m, 2 H), 1.63 - 1.78 (m, 2 H), 0.86 - 0.96 (m, 9 H), 0.07 (s, 5 H)

[0303] Intermediate 162: 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutoxy)-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 162 was prepared according to the method used for the synthesis of Intermediate 7 from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 400 mg, 1.27 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutan-1-ol (Intermediate 161, 358 mg, 1.65 mmol) starting at 120° C. to afford the title compound (210 mg, 0.42 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 494.4 (Method 1)

[0304] Intermediate 163: 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutoxy)-6-(5-chloro-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine [ka] Intermediate 163 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (62 mg, 0.09 mmol) starting from 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}cyclobutoxy)-6-chloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 162, 210 mg, 0.43 mmol) and 5-chloro-2-fluorobenzeneboronic acid (111 mg, 0.64 mmol) to give the title compound (110 mg, 0.19 mmol, 44% yield). LC-MS (ESI): m / z (M+1): 588.4 (Method 1)

[0305] Intermediate 164: (3-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}cyclobutyl)methanol [ka] Intermediate 164 was prepared starting from intermediate 163 (110 mg, 0.19 mmol) according to the method used for the synthesis of intermediate 64 to give the title compound (40 mg, 0.12 mmol, 63% yield). LC-MS (ESI): m / z (M+1): 324.1 (Method 1).

[0306] Intermediate 165: 3-{[(4-amino-6-chloropyridazin-3-yl)oxy]methyl}phenol [ka] To a solution of 3-hydroxybenzyl alcohol (454 mg, 3.66 mmol) in DMF (6.7 mL) was added 60% dispersion of NaH in oil (293 mg, 7.32 mmol) and the mixture was stirred at RT for 30 min (until gas evolution ceased). 3,6-Dichloropyridazin-4-amine (200 mg, 1.22 mmol) dissolved in DMF (2.7 mL) was added and the reaction was warmed to 90° C. for 12 h. The mixture was diluted with EtOAc and saturated NaHCO 3 Washed with aqueous solution (3x) and brine (1x). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM and the resulting precipitate was collected by filtration to give the title compound (100 mg, 0.4 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 252.1 (Method 1).

[0307] Intermediate 166: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}methyl)phenol [ka] Intermediate 166 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(41 mg, 0.06 mmol) starting from 3-{[(4-amino-6-chloropyridazin-3-yl)oxy]methyl}phenol (Intermediate 165, 70 mg, 0.28 mmol) and 5-chloro-2-fluorobenzeneboronic acid (72 mg, 0.42 mmol) to give the title compound (34 mg, 0.10 mmol, 35% yield). LC-MS (ESI): m / z (M+1): 346.1 (Method 2)

[0308] Intermediate 167: tert-Butyl 3-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate [ka] Intermediate 167 was prepared according to the method used for the synthesis of Intermediate 72 starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 33, 330 mg, 1.32 mmol) and tert-butyl 3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (359 mg, 1.59 mmol) to afford the title compound (460 mg, 1.05 mmol, 79% yield). LC-MS (ESI): m / z (M+1): 439.2 (Method 1)

[0309] Intermediate 168: N-(4-bromopyridin-2-yl)-2-{3,6-diazabicyclo[3.2.2]nonan-3-yl}acetamide [ka] Intermediate 168 was prepared according to the method used for the synthesis of Intermediate 40 starting from tert-butyl 3-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (Intermediate 167, 460 mg, 1.05 mmol) to give the title compound (355 mg, 1.05 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 339.1 (Method 2)

[0310] Intermediate 169: N-(4-bromopyridin-2-yl)-2-{6-methyl-3,6-diazabicyclo[3.2.2]nonan-3-yl}acetamide [ka] Intermediate 169 was prepared according to the method used for the synthesis of Intermediate 31 starting from N-(4-bromopyridin-2-yl)-2-{3,6-diazabicyclo[3.2.2]nonan-3-yl}acetamide (Intermediate 168, 355 mg, 1.05 mmol) and 37% w / w aqueous formaldehyde (0.12 mL, 1.57 mmol) to give the title compound (350 mg, 0.99 mmol, 95% yield). LC-MS (ESI): m / z (M+1): 353.1 (Method 2).

[0311] Intermediate 170: Ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate [ka] 1-Methylpiperazine (0.55 mL, 5 mmol) and ethyl 3-oxocyclobutane-1-carboxylate (950 mg, 6.7 mmol) were mixed in DCM (30 mL) and stirred for 15 min at RT. Sodium triacetoxyborohydride (2.12 g, 10 mmol) was added portionwise and the resulting reaction mixture was stirred overnight at RT. MeOH (30 mL) was carefully added and the mixture was stirred for 30 min and then concentrated under reduced pressure. The crude material was dissolved in MeOH and the solution was loaded onto SCX, washed with MeOH and diluted with 1N NH 3in MeOH. Evaporation of the basic fractions gave the crude material which was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex ~ 30% EtOAc) to give the title compound (927 mg, 4.1 mmol, 82% yield) as an irresolvable mixture of diastereoisomers in a 9 / 1 ratio cis / trans. LC-MS (ESI): m / z (M+1): 227.3 (Method 2)

[0312] Intermediate 171: N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide [ka] A stirred solution of 4-bromopyridin-2-amine (1.15 g, 6.63 mmol) in THF (28 mL) was added to a 2 mL flask at −78 °C with N 2 Under reduced pressure, 1.6N n-butyllithium in hexane (3.55 mL, 5.68 mmol) was added portionwise over 10 min, and the reaction mixture was then stirred at -78 °C for 1 h. Ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate (Intermediate 170, 600 mg, 2.65 mmol) in THF (12 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 overnight at RT. The mixture was diluted with MeOH and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex ~ 40% EtOAc) to give the title compound (410 mg, 1.16 mmol, 44% yield) as an irresolvable mixture of diastereoisomers in a cis / trans 9 / 1 ratio. LC-MS (ESI): m / z (M+1): 355.1 (Method 2)

[0313] Intermediate 172:Cis N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide [ka] Intermediate 172 was prepared according to the method used for the synthesis of intermediate 47, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Intermediate 171, 102.7 mg, 0.29 mmol) to give the title compound (60 mg, 0.09 mmol, 36% yield). Only the major cis isomer was isolated. LC-MS (ESI): m / z (M+1): 686.4 (Method 2)

[0314] Intermediate 173: N-(4-bromopyridin-2-yl)-3-(4-methyl-1,4-diazepan-1-yl)propanamide [ka] Intermediate 173 was prepared according to the method used for the synthesis of Intermediate 2, starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 1, 350 mg, 1.54 mmol) and 1-methyl-1,4-diazepane (238 mg, 2.08 mmol) to give the title compound (434 mg, 1.27 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 341.1 (Method 2).

[0315] Intermediate 174:N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-1,4-diazepan-1-yl)propanamide [ka] Intermediate 174 was prepared according to the method used for the synthesis of Intermediate 47 starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methyl-1,4-diazepan-1-yl)propanamide (Intermediate 173, 90.7 mg, 0.27 mmol) to give the title compound (94 mg, 0.14 mmol, 58% yield). LC-MS (ESI): m / z (M+1): 674.4 (Method 2)

[0316] Intermediate 175: (2,2-Dimethyl-1,3-dioxolan-4-yl)methanethiol [ka] Pyridinium p-toluenesulfonate (232 mg, 0.92 mmol) was added to a stirred mixture of 3-mercapto-1,2-propanediol (1 g, 9.25 mmol) and magnesium sulfate (1.7 g, 13.87 mmol) in acetone (15 mL) at RT. After 3 days, the solids were filtered, the solvent removed under reduced pressure, and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~10% EtOAc) to give the title compound (650 mg, 4.38 mmol, 47% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 4.23 (dq, J = 6.70, 5.95 Hz, 1H), 4.13 (dd, J = 8.27, 6.10 Hz, 1H), 3.79 (dd, J = 8.28, 5.95 Hz, 1H), 2.76 (ddd, J = 13.44, 7.92, 5.47 Hz, 1H), 2.63 (ddd, J = 13.48, 9.04, 6.72 Hz, 1H), 1.47 (dd, J = 11.38, 0.94 Hz, 4H), 1.38 (q, J = 0.70 Hz, 3H)

[0317] Intermediate 176: 6-Chloro-3-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}pyridazin-4-amine [ka] To an ice-cold solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanethiol (Intermediate 175, 678 mg, 4.57 mmol) in DMF (10 mL) was added 60% dispersion of NaH in oil (183 mg, 4.57 mmol) and the mixture was stirred at RT for 1 h (until gas evolution ceased). The mixture was cooled in an ice bath and 3,6-dichloropyridazin-4-amine (500 mg, 3.05 mmol) dissolved in DMF (2 mL) was added and the reaction was allowed to warm and stir at RT for 3 h. The mixture was poured into ice water and extracted with EtOAc. The organic phase was separated and Na 2 SO 4 The residue was purified by flash chromatography on a Biotage silica cartridge (cHex to 50% EtOAc) to give the title compound (550 mg, 1.99 mmol, 65% yield). LC-MS (ESI): m / z (M+1): 276.1 (Method 1)

[0318] Intermediate 177:6-(5-chloro-2-fluorophenyl)-3-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}pyridazin-4-amine [ka] Intermediate 177 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (146 mg, 1.99 mmol) starting from 6-chloro-3-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}pyridazin-4-amine (Intermediate 176, 550 mg, 1.99 mmol) and 5-chloro-2-fluorobenzeneboronic acid (522 mg, 2.99 mmol) to give the title compound (220 mg, 0.59 mmol, 30% yield). LC-MS (ESI): m / z (M+1): 370.1 (Method 2)

[0319] Intermediates 178 and 179: Cis N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide (178) and trans N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide (179) [ka] Process 1 A solution of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (1.06 g, 3.87 mmol), DIPEA (1.53 mL, 8.79 mmol) and ethyl 3-oxocyclobutane-1-carboxylate (500 mg, 3.52 mmol) in DCM (15 mL) was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.49 g, 7.03 mmol) was added portionwise and the resulting reaction mixture was stirred overnight at RT. Methanol (30 mL) was carefully added and the mixture was stirred for 30 min and then concentrated under reduced pressure. The crude material was dissolved in MeOH, loaded onto SCX, washed with MeOH and purified with 1N NH 3 in MeOH. The basic fractions were collected, dried and purified by flash chromatography on a Biotage silica NH cartridge (cHex ~ 15% EtOAc) to give an inseparable mixture of cis / trans ethyl 3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxylate (400 mg, 1.68 mmol, 48% yield) which was used directly in the next step.

[0320] Process 2 A stirred solution of 4-bromopyridin-2-amine (0.73 g, 4.2 mmol) in THF (18.7 mL) was added to a 20 mL flask at −78 °C with N 2Under this condition, 1.6N n-butyllithium in hexane (1.44 mL, 3.6 mmol) was added in portions over 10 min, and the reaction mixture was then stirred at -78°C for 1 h. A solution of cis / trans ethyl 3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxylate (400 mg, 1.68 mmol) in THF (8 mL) was added in portions over 10 min at -78°C. After 5 min, the cooling bath was removed and the resulting reaction mixture was stirred at RT overnight. The mixture was diluted with MeOH and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex ~ 85% EtOAc then EtOAc) to give cis N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide (180 mg, 0.49 mmol, 29% yield) and trans N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide (60 mg, 0.16 mmol, 10% yield). Intermediate 178: LC-MS (ESI): m / z (M+1): 367.0 (Method 2) 11H NMR (400 MHz, chloroform-d) δ ppm 11.80 (br s, 1 H), 8.48 (d, J = 1.1 Hz, 1 H), 8.08 (d, J = 5.4 Hz, 1 H), 7.15 (dd, J = 5.3, 1.5 Hz, 1 H), 3.44 (s, 1 H), 3.31 (br s, 1 H), 3.25 - 3.31 (m, 1 H), 3.08 (tt, J = 8.6, 4.5 Hz, 1 H), 2.98 (d, J = 10.0 Hz, 1 H), 2.93 (d, J = 10.0 Hz, 1 H), 2.69 (dd, J = 10.0, 2.4 Hz, 1 H), 2.64 (dd, J = 9.9, 2.2 Hz, 1 H), 2.49 - 2.63 (m, 2 H), 2.46 (s, 3 H), 2.06 - 2.18 (m, 2 H), 1.94 (br d, J = 9.8 Hz, 1 H), 1.77 (br d, J = 9.9 Hz, 1 H) Intermediate 179: LC-MS (ESI): m / z (M+1): 367.0 (Method 2) 1 1H NMR (400 MHz, chloroform-d) δ ppm 8.52 (s, 1 H), 8.07 (d, J = 5.4 Hz, 1 H), 7.81 (br s, 1 H), 7.20 (dd, J = 5.3, 1.4 Hz, 1 H), 3.40 (quin, J = 6.7 Hz, 1 H), 3.28 (s, 1 H), 3.22 (s, 1 H), 3.13 - 3.21 (m, 1 H), 2.79 (d, J = 9.9 Hz, 1 H), 2.62 - 2.72 (m, 2 H), 2.55 (dd, J = 10.0, 2.4 Hz, 1 H), 2.39 - 2.52 (m, 2 H), 2.38 (s, 3 H), 2.14 - 2.28 (m, 2 H), 1.66 - 1.76 (m, 2 H)

[0321] Intermediate 180:Cis N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide [ka] In a microwave vial, add Xantphos (12 mg, 0.02 mmol), K 3 PO 4 (56 mg, 0.27 mmol), 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 55 mg, 0.13 mmol), cis N-(4-bromo-2-pyridyl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutanecarboxamide (Intermediate 178, 58 mg, 0.16 mmol) and Pd 2 (dba) 3 A solution of the mixture (12 mg, 0.01 mmol) in 1,4-dioxane (2 mL) was degassed (vacuum / N 2 ) and heated at 110° C. under microwave irradiation for 5 hours. The mixture was filtered through Celite (登録商標) It was filtered through a pad, washed with EtOAc and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica NH cartridge (cHex / EtOAc / MeOH 100:0:0 to 0:98:2) to give the title compound (56 mg, 0.08 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 698.5 (Method 2)

[0322] Intermediate 181:Trans N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide [ka] Intermediate 181 was prepared according to the method used for the synthesis of intermediate 180, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 58 mg, 0.14 mmol) and TRANS N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide (Intermediate 179, 55 mg, 0.15 mmol) to give the title compound (50 mg, 0.07 mmol, 52% yield). LC-MS (ESI): m / z (M+1): 698.5 (Method 2).

[0323] Intermediate 182: Ethyl 3-(thiomorpholin-4-yl)cyclobutane-1-carboxylate [ka] Intermediate 182 was prepared according to the method used for the synthesis of intermediate 170 starting from thiomorpholine (0.5 ml, 4.94 mmol) and ethyl 3-oxocyclobutane-1-carboxylate (638 mg, 4.49 mmol) to give the title compound (950 mg, 4.14 mmol, 92% yield) as an irresolvable mixture of diastereoisomers in a cis / trans 85 / 15 ratio. LC-MS (ESI): m / z (M+1): 230.3 (Method 2)

[0324] Intermediate 183:Cis N-(4-bromopyridin-2-yl)-3-(thiomorpholin-4-yl)cyclobutane-1-carboxamide [ka] Intermediate 183 was prepared according to the method used for the synthesis of Intermediate 171 starting from 4-bromopyridin-2-amine (1.79 g, 10.36 mmol) and ethyl 3-(thiomorpholin-4-yl)cyclobutane-1-carboxylate (Intermediate 182, 950 mg, 4.14 mmol) to give the title compound (565 mg, 1.59 mmol, 38% yield). Only the major cis isomer was isolated. LC-MS (ESI): m / z (M+1): 356.0 (Method 2)

[0325] Intermediate 184: Cis N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(thiomorpholin-4-yl)cyclobutane-1-carboxamide [ka] Intermediate 184 was prepared according to the method used for the synthesis of intermediate 180, starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 100 mg, 0.24 mmol) and cis N-(4-bromopyridin-2-yl)-3-(thiomorpholin-4-yl)cyclobutane-1-carboxamide (Intermediate 183, 103 mg, 0.29 mmol) to give the title compound (140 mg, 0.20 mmol, 84% yield). LC-MS (ESI): m / z (M+1): 689.4 (Method 2).

[0326] Intermediate 185: Cis tert-butyl 7-[3-(ethoxycarbonyl)cyclobutyl]-4,7-diazaspiro[2.5]octane-4-carboxylate [ka] Intermediate 185 was prepared according to the method used for the synthesis of intermediate 170 starting from tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1.15 g, 5.42 mmol) and ethyl 3-oxocyclobutane-1-carboxylate (700 mg, 4.92 mmol) to give the title compound (1.03 g, 3.05 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 340.0 (Method 2) 1 H NMR (400 MHz, chloroform-d) δ ppm 4.12 (q, J = 7.0 Hz, 2 H), 3.55 (br s, 2 H), 2.71 - 2.81 (m, 1 H), 2.61 - 2.70 (m, 1 H), 2.30 - 2.37 (m, 2 H), 2.23 - 2.32 (m, 2 H), 2.13 - 2.17 (m, 2 H), 2.05 - 2.17 (m, 2 H), 1.46 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.98 (br s, 2 H), 0.74 (s, 2 H)

[0327] Intermediate 186: Cis-ethyl 3-{4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxylate [ka] Intermediate 186 was prepared according to the method used for the synthesis of Intermediate 40 starting from cis tert-butyl 7-[3-(ethoxycarbonyl)cyclobutyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 185, 1.03 g, 3.05 mmol) to give the title compound (724 mg, 3.04 mmol, 99% yield). LC-MS (ESI): m / z (M+1): 239.9 (Method 2).

[0328] Intermediate 187:Cis-ethyl 3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxylate [ka] Intermediate 187 was prepared according to the method used for the synthesis of Intermediate 31 starting from Cis-ethyl 3-{4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxylate (Intermediate 186, 724 mg, 3.04 mmol) and 37% w / w aqueous formaldehyde (0.3 mL, 3.95 mmol) to give the title compound (540 mg, 2.14 mmol, 70% yield). LC-MS (ESI): m / z (M+1): 253.4 (Method 2)

[0329] Intermediate 188: Cis N-(4-bromopyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxamide [ka] Intermediate 188 was prepared according to the method used for the synthesis of intermediate 171 starting from 4-bromopyridin-2-amine (926 mg, 5.35 mmol) and cis ethyl 3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxylate (Intermediate 187, 540 mg, 2.14 mmol) to give the title compound (394 mg, 1.04 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 379.3 (Method 2).

[0330] Intermediate 189: Cis N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxamide [ka] Xantphos (36 mg, 0.06 mmol), K 3 PO 4 (179 mg, 0.83 mmol), 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 172 mg, 0.42 mmol), cisN-(4-bromopyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxamide (Intermediate 188, 205 mg, 0.54 mmol) and Pd 2 (dba) 3 A solution of the mixture (38 mg, 0.04 mmol) in 1,2-dimethoxyethane (4.15 mL) was degassed (vacuum / N 2 ) for 45 min at 105° C. The mixture was filtered through a celite (登録商標) Filter through a pad, wash with EtOAc and saturated NaHCO 3 After washing with aqueous solution, the organic solvent was separated, dried and removed under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica NH cartridge (cHex~100% EtOAc) to give the title compound (79 mg, 0.11 mmol, 27% yield). LC-MS (ESI): m / z (M+1): 712.4 (Method 2)

[0331] Intermediate 190: Cis N-(6-chloropyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide [ka] Intermediate 190 was prepared according to the method used for the synthesis of Intermediate 171 starting from 6-chloro-4-pyrimidinamine (100 mg, 0.77 mmol) and ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate (Intermediate 170, 192 mg, 0.85 mmol) to afford the title compound (19 mg, 0.06 mmol, 7.5% yield). LC-MS (ESI): m / z (M+1): 310.2 (Method 2)

[0332] Intermediate 191: CisN-(6-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide [ka] Intermediate 191 was prepared according to the method used for the synthesis of Intermediate 189 starting from 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 22 mg, 0.05 mmol) and cis N-(6-chloropyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Intermediate 190, 19 mg, 0.06 mmol) to give the title compound (15 mg, 0.02 mmol, 41% yield). LC-MS (ESI): m / z (M+1): 687.4 (Method 2)

[0333] Intermediate 192: 4-Bromo-3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazine [ka] A suspension of 3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 67, 303 mg, 0.72 mmol) in MeCN (3.6 mL) was treated with copper(II) bromide (274 mg, 1.23 mmol) followed by tert-butyl nitrite (0.15 mL, 1.23 mmol) at RT. The mixture was stirred for 2 h and then washed with saturated NaHCO 3 The mixture was quenched by the addition of aqueous H2 The mixture was diluted with O and extracted with EtOAc. The organic phase was washed with Na 2 SO 4 The crude product was purified by flash chromatography on a Biotage silica NH cartridge (cHex~30% EtOAc) to give the title compound (265 mg, 0.55 mmol, 77% yield). LC-MS (ESI): m / z (M+1): 477.1 (Method 1).

[0334] Intermediate 193: Methyl 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylate [ka] In a suitable vial, add methyl 3-iodothiophene-2-carboxylate (1 g, 3.73 mmol), Pd(dppf)Cl 2 (273 mg, 0.37 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.08 g, 4.85 mmol) and Na 2 CO 3 (791 mg, 7.46 mmol) in a mixture of 1,2-dimethoxyethane (9.607 mL) and H 2 O (4.8 mL) solution for 10 min. 2 The mixture was degassed by bubbling with water and then heated at 70° C. for 3 h. (登録商標) The organic phase was washed with saturated NaHCO 3 Wash with aqueous solution and brine, then add Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica cartridge (DCM to 10% MeOH) to give the title compound (693 mg, 2.92 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 238.2 (Method 1)

[0335] Intermediate 194:Methyl 3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate [ka] A mixture of methyl 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylate (Intermediate 193, 580 mg, 2.44 mmol) and 5% w / w Pd / carbon (1.18 g, 0.56 mmol) in MeOH (12 mL) was dissolved in H 2 The mixture was stirred under atmospheric pressure for 20 hours. (登録商標) The mixture was filtered through ethyl acetate, the cake was washed with MeOH, and the solvent was removed under reduced pressure. The residue was redissolved in MeOH (12 mL), treated with 5% w / w Pd on carbon (1.18 g, 0.56 mmol), and diluted with H 2 The mixture was stirred under atmospheric pressure for 4 hours. (登録商標) The mixture was filtered through filtration, the cake was washed with MeOH and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica cartridge (DCM to 75% MeOH) to give the title compound (355 mg, 1.48 mmol, 53% yield). LC-MS (ESI): m / z (M+1): 240.2 (Method 1).

[0336] Intermediate 195: Methyl 5-iodo-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate [ka] A 2.0 M solution of lithium diisopropylamide in THF (0.96 mL, 1.93 mmol) cooled to -78 °C was added to a solution of methyl 3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate (Intermediate 194, 317 mg, 1.28 mmol) in THF (8.5 mL) under nitrogen atmosphere. The mixture was stirred for 2 h at the same temperature and then treated with solid iodine (489 mg, 1.93 mmol) at -78 °C. The reaction was stirred for 1 min and then warmed to RT and saturated NaHCO 3 aqueous solution, followed by saturated Na 2 S 2 O3 The mixture was extracted with DCM and 2 SO 4 The crude product was purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 The collected fractions were purified with saturated NaHCO 3 The solution was treated with aqueous ethyl acetate and extracted with EtOAc. 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave the title compound (235 mg, 0.64 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 366.1 (Method 1)

[0337] Intermediate 196: Methyl 3-(1-methylpiperidin-4-yl)-5-[(4-nitropyridin-2-yl)amino]thiophene-2-carboxylate [ka] Intermediate 196 was prepared according to the method used for the synthesis of Intermediate 189 starting from 2-amino-4-nitropyridine (116 mg, 0.84 mmol) and methyl 5-iodo-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate (Intermediate 195, 235 mg, 0.64 mmol) to afford the title compound (112 mg, 0.30 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 377.3 (Method 1)

[0338] Intermediate 197: Methyl 5-{[(tert-butoxy)carbonyl](4-nitropyridin-2-yl)amino}-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate [ka] A solution of DMAP (84 mg, 0.68 mmol) and methyl 3-(1-methylpiperidin-4-yl)-5-[(4-nitropyridin-2-yl)amino]thiophene-2-carboxylate (Intermediate 196, 112 mg, 0.30 mmol) in DCM (3 mL) was treated with di-tert-butyl dicarbonate (156 mg, 0.71 mmol) and stirred at RT overnight. The reaction was cooled to rt with saturated NaHCO 3 The mixture was quenched by the addition of aqueous solution of Na 2 SO 4 The crude product was purified by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 The collected fractions were purified with saturated NaHCO 3 The organic phase was treated with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave the title compound (88 mg, 0.18 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 477.3 (Method 1)

[0339] Intermediate 198: Methyl 5-[(4-aminopyridin-2-yl)[(tert-butoxy)carbonyl]amino]-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate [ka] A mixture of methyl 5-{[(tert-butoxy)carbonyl](4-nitropyridin-2-yl)amino}-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate (Intermediate 197, 88 mg, 0.18 mmol) and 5% w / w Pd / carbon (79 mg, 0.04 mmol) in MeOH (1.23 mL) was dissolved in H 2 The mixture was stirred overnight under atmospheric pressure. (登録商標)The mixture was filtered through celite, the pad was washed with MeOH and concentrated under reduced pressure. The resulting material was dissolved in MeOH (1.73 mL) and 10% w / w Pd on carbon (37 mg, 0.03 mmol) and ammonium formate (55 mg, 0.86 mmol) were added and the mixture was stirred at reflux for 1 h. The mixture was filtered through celite, (登録商標) The mixture was filtered through ethyl acetate, the pad was washed with MeOH and the solvent was concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 4% MeOH) to give the title compound (39 mg, 0.09 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 447.2 (Method 1).

[0340] Intermediate 199: Methyl 5-{[(tert-butoxy)carbonyl](4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)amino}-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate [ka] Intermediate 199 was prepared according to the method used for the synthesis of Intermediate 180, starting from 4-bromo-3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazine (Intermediate 192, 41 mg, 0.09 mmol) and methyl 5-[(4-aminopyridin-2-yl)[(tert-butoxy)carbonyl]amino]-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate (Intermediate 198, 38 mg, 0.09 mmol) to give the title compound (44 mg, 0.05 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 843.5 (Method 2).

[0341] Intermediate 200: 2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)sulfanyl]-2-methylpropan-1-ol [ka] Intermediate 200 was prepared according to the method used for the synthesis of Intermediate 7 starting from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 700 mg, 2.22 mmol) and 2-methyl-2-sulfanylpropan-1-ol (260 mg, 2.45 mmol) in the presence of Xantphos (154 mg, 0.27 mmol) to give the title compound (472 mg, 1.23 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 384.1 (Method 2).

[0342] Intermediate 201: 2-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]sulfanyl}-2-methylpropan-1-ol [ka] Intermediate 201 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (179 mg, 0.24 mmol) starting from 2-[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)sulfanyl]-2-methylpropan-1-ol (Intermediate 200, 470 mg, 1.22 mmol) and 5-chloro-2-fluorobenzeneboronic acid (320 mg, 1.84 mmol) to give the title compound (233 mg, 0.49 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 478.2 (Method 2)

[0343] Intermediate 202: 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]sulfanyl}-2-methylpropan-1-ol [ka] Intermediate 202 was prepared according to the method used for the synthesis of Intermediate 64 starting from 2-{[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]sulfanyl}-2-methylpropan-1-ol (Intermediate 201, 233 mg, 0.49 mmol) to give the title compound (82 mg, 0.25 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 328.1 (Method 2).

[0344] Intermediate 203: 3-({1-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Intermediate 203 was prepared according to the method used for the synthesis of Intermediate 65 starting from 2-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]sulfanyl}-2-methylpropan-1-ol (Intermediate 202, 35 mg, 0.11 mmol) to give the title compound (44 mg, 0.10 mmol, 93% yield). LC-MS (ESI): m / z (M+1): 442.2 (Method 2).

[0345] Intermediate 204: N-(4-{[3-({1-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 204 was prepared according to the method used for the synthesis of Intermediate 47, starting from 3-({1-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 203, 44 mg, 0.10 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 36 mg, 0.11 mmol) to give the title compound (44 mg, 0.06 mmol, 64% yield). LC-MS (ESI): m / z (M+1): 688.4 (Method 2).

[0346] Intermediate 205: Cis N-(4-{[3-({1-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide [ka] Intermediate 205 was prepared according to the method used for the synthesis of Intermediate 189, starting from 3-({1-[(tert-butyldimethylsilyl)oxy]-2-methylpropan-2-yl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 203, 60 mg, 0.14 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide (Intermediate 171, 56 mg, 0.15 mmol) to give the title compound (60 mg, 0.08 mmol, 61% yield). Only the major cis isomer was isolated. LC-MS (ESI): m / z (M+1): 714.4 (Method 2)

[0347] Intermediate 206: Methyl 6-chloro-3-[3-(hydroxymethyl)azetidin-1-yl]pyridazine-4-carboxylate [ka] Intermediate 206 was prepared according to the method used for the synthesis of Intermediate 94 starting from methyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 93, 100 mg, 0.48 mmol) and (azetidin-3-yl)methanol hydrochloride (60 mg, 0.48 mmol) to afford the title compound (80 mg, 0.31 mmol, 64% yield). LC-MS (ESI): m / z (M+1): 258.2 (Method 1)

[0348] Intermediate 207: Methyl 6-(5-chloro-2-fluorophenyl)-3-[3-(hydroxymethyl)azetidin-1-yl]pyridazine-4-carboxylate [ka] Intermediate 207 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (45 mg, 0.06 mmol) starting from methyl 6-chloro-3-[3-(hydroxymethyl)azetidin-1-yl]pyridazine-4-carboxylate (Intermediate 206, 80 mg, 0.31 mmol) and 5-chloro-2-fluorobenzeneboronic acid (108 mg, 0.62 mmol) to give the title compound (90 mg, 0.26 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 352.1 (Method 1)

[0349] Intermediate 208: Methyl 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazine-4-carboxylate [ka] Intermediate 208 was prepared according to the method used for the synthesis of Intermediate 65, starting from methyl 6-(5-chloro-2-fluorophenyl)-3-[3-(hydroxymethyl)azetidin-1-yl]pyridazine-4-carboxylate (Intermediate 207, 90 mg, 0.26 mmol) to afford the title compound (105 mg, 0.22 mmol, 88% yield). LC-MS (ESI): m / z (M+1): 466.3 (Method 1)

[0350] Intermediate 209: 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazine-4-carboxylic acid [ka] Intermediate 209 was prepared according to the method used for the synthesis of Intermediate 96 starting from methyl 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazine-4-carboxylate (Intermediate 208, 105 mg, 0.22 mmol) to give the title compound (90 mg, 0.20 mmol, 90% yield). LC-MS (ESI): m / z (M+1): 452.2 (Method 1).

[0351] Intermediate 210: 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Intermediate 210 was prepared according to the method used for the synthesis of Intermediate 97 (Method B) starting from 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazine-4-carboxylic acid (Intermediate 209, 70 mg, 0.15 mmol) to give the title compound (23 mg, 0.05 mmol, 35% yield). LC-MS (ESI): m / z (M+1): 452.2 (Method 1).

[0352] Intermediate 211: N-(4-{[3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 211 was prepared according to the method used for the synthesis of Intermediate 47 starting from 3-(3-{[(tert-butyldimethylsilyl)oxy]methyl}azetidin-1-yl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 210, 38 mg, 0.07 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 28 mg, 0.08 mmol) to give the title compound (30 mg, 0.04 mmol, 66% yield). LC-MS (ESI): m / z (M+1): 669.6 (Method 1)

[0353] Intermediate 212: tert-Butyl 3,6-dichloropyridazine-4-carboxylate [ka] Method A A solution of 3,6-dichloro-4-pyridazinecarboxylic acid (4.5 g, 23.32 mmol), DMAP (1.64 g, 13.48 mmol) and 2-methyl-2-propanol (4.14 mL, 43.39 mmol) in DCM (93 mL) was treated with N,N'-dicyclohexylcarbodiimide (11.76 g, 57 mmol) at RT and stirred for 24 h. The mixture was filtered through a Celite pad. (登録商標) The organic phase was concentrated under reduced pressure after filtration through a pad. The residue was dissolved in DCM and filtered through a phase separator. The organic phase was washed with saturated NaHCO 3 aqueous solution, 0.1M HCl aqueous solution and H 2 The organic phase was washed with Na 2 SO 4 The residue was purified by flash chromatography on a Biotage silica cartridge (cHex to 5% EtOAc) followed by reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 The collected fractions were purified with saturated NaHCO 3 The organic phase was treated with Na 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound (2.93 g, 11.76 mmol, 57% yield).

[0354] Method B 3,6-Dichloro-4-pyridazinecarboxylic acid (500 mg, 2.59 mmol), DMAP (158 mg, 1.3 mmol) and di-tert-butyl dicarbonate (650 mg, 2.98 mmol) were suspended in THF (12 mL) and heated at 65° C. until gas evolution ceased (45 min). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, then washed with 5% aqueous HCl (2×), 5% aqueous NaOH and brine. The organic solvent was dried and evaporated to give the title compound (520 mg, 2.09 mmol, 81% yield). LC-MS (ESI): m / z (M+1): 249.1 (Method 1)

[0355] Intermediate 213:tert-Butyl 6-chloro-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylate [ka] Intermediate 213 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 350 mg, 1.41 mmol) and methyl azetidine-3-carboxylate hydrochloride (213 mg, 1.04 mmol) to give the title compound (312 mg, 0.95 mmol, 68% yield). LC-MS (ESI): m / z (M+1): 328.2 (Method 1).

[0356] Intermediate 214: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylate [ka] Intermediate 214 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (70 mg, 0.10 mmol) starting from tert-butyl 6-chloro-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylate (Intermediate 213, 312 mg, 0.95 mmol) and 5-chloro-2-fluorobenzeneboronic acid (249 mg, 1.43 mmol) to afford the title compound (320 mg, 0.76 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 422.3 (Method 1)

[0357] Intermediate 215: 6-(5-chloro-2-fluorophenyl)-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylic acid trifluoroacetate [ka] A mixture of tert-butyl 6-(5-chloro-2-fluorophenyl)-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylate (Intermediate 214, 320 mg, 0.76 mmol) in DCM (12 mL) and TFA (3 mL) was stirred at RT overnight. Toluene (2 mL) was added to the mixture, which was evaporated to dryness to give the title compound (336 mg, 0.70 mmol, 92% yield) as the trifluoroacetate salt. LC-MS (ESI): m / z (M+1): 366.2 (Method 1)

[0358] Intermediate 216: Methyl 1-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]azetidine-3-carboxylate [ka] Intermediate 216 was prepared according to the method used for the synthesis of Intermediate 97 (Method B) starting from 6-(5-chloro-2-fluorophenyl)-3-[3-(methoxycarbonyl)azetidin-1-yl]pyridazine-4-carboxylic acid trifluoroacetate (Intermediate 215, 336 mg, 0.70 mmol) in the presence of TEA (0.21 mL, 1.54 mmol) to give the title compound (124 mg, 0.37 mmol, 53% yield). LC-MS (ESI): m / z (M+1): 337.1 (Method 1)

[0359] Intermediate 217: N-(4-nitropyridin-2-yl)prop-2-enamide [ka] To an ice-cold solution of 4-nitropyridin-2-amine (1.2 g, 8.63 mmol) in dry DCM (50 mL) was added TEA (3.6 mL, 25.83 mmol) and 2-propenoyl chloride (1.05 mL, 13 mmol). The solution was stirred at 0° C. for 30 min, then allowed to reach RT and stirred overnight. Water was added, the phases were separated and the organic phase was dried and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~32% EtOAc) to give the title compound (847 mg, 4.38 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 194.0 (Method 1)

[0360] Intermediate 218: 3-(4-Methylpiperazin-1-yl)-N-(4-nitropyridin-2-yl)propanamide [ka] Intermediate 218 was prepared according to the method used for the synthesis of Intermediate 2, starting from N-(4-nitropyridin-2-yl)prop-2-enamide (Intermediate 217, 500 mg, 2.59 mmol) and 1-methylpiperazine (0.65 mL, 5.86 mmol) to give the title compound (674 mg, 2.30 mmol, 89% yield). LC-MS (ESI): m / z (M+1): 294.2 (Method 2).

[0361] Intermediate 219: N-(4-aminopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Method A A mixture of 3-(4-methylpiperazin-1-yl)-N-(4-nitropyridin-2-yl)propanamide (Intermediate 218, 674 mg, 2.3 mmol) and 10% w / w Pd / carbon (100 mg, 0.94 mmol) in MeOH (60 mL) was dissolved in H 2 The mixture was stirred under atmospheric pressure for 6 hours. (登録商標)The mixture was filtered through ethyl acetate and the filtrate was concentrated under reduced pressure (approximately 25 mL). 10% w / w Pd / carbon (150 mg, 1.41 mmol) was added and the mixture was diluted with H 2 The mixture was stirred under atmospheric pressure for an additional 5 hours. (登録商標) It was filtered through a pad and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 4% MeOH) to give the title compound (120 mg, 0.46 mmol, 20% yield).

[0362] Method B 10% w / w Pd / carbon (117 mg, 0.11 mmol) was added to a stirred solution of 3-(4-methylpiperazin-1-yl)-N-(4-nitropyridin-2-yl)propanamide (Intermediate 218, 945 mg, 3.22 mmol) and ammonium formate (1.04 g, 16.28 mmol) in ethanol (32 mL). The mixture was stirred at reflux for 45 min. The mixture was filtered through a Celite filter. (登録商標) It was filtered through a pad, the cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 4% MeOH) to give the title compound (284 mg, 1.08 mmol, 36% yield). LC-MS (ESI): m / z (M+1): 264.2 (Method 2)

[0363] Intermediate 220: 4-Bromo-6-chloro-N-[(3-methoxyphenyl)methyl]pyridazin-3-amine [ka] To a stirred solution of 3-amino-4-bromo-6-chloropyridazine (500 mg, 2.4 mmol) in THF (7 mL) at 0° C. was added N 2Under reduced pressure, 60% dispersion of NaH in oil (110 mg, 2.75 mmol) was added portionwise. After 5 min, the ice bath was removed and the mixture was stirred at RT for 30 min. 1-(Bromomethyl)-3-methoxybenzene (0.35 mL, 2.52 mmol) was added dropwise and the resulting reaction mixture was then stirred at 40° C. for 6 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex to 25% EtOAc) to give the title compound (352 mg, 1.07 mmol, 45% yield). LC-MS (ESI): m / z (M+1): 328.0 (Method 2)

[0364] Intermediate 221: N-{4-[(6-chloro-3-{[(3-methoxyphenyl)methyl]amino}pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 221 was prepared according to the method used for the synthesis of Intermediate 189 from N-(4-aminopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 219, 134 mg, 0.51 mmol) and 4-bromo-6-chloro-N-[(3-methoxyphenyl)methyl]pyridazin-3-amine (Intermediate 220, 168 mg, 0.51 mmol) starting at 120° C. to afford the title compound (110 mg, 0.21 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 511.3 (Method 2)

[0365] Intermediate 222: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-methoxyphenyl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 222 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (30 mg, 0.04 mmol) starting from N-{4-[(6-chloro-3-{[(3-methoxyphenyl)methyl]amino}pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 221, 103 mg, 0.20 mmol) and 5-chloro-2-fluorobenzeneboronic acid (43 mg, 0.25 mmol) to give the title compound (83 mg, 0.14 mmol, 68% yield). LC-MS (ESI): m / z (M-1): 603.4 (Method 1)

[0366] Intermediate 223: 4-Bromo-6-chloro-N-[(3-methoxyphenyl)methyl]-N-methylpyridazin-3-amine [ka] Dispersed 60% NaH in oil (52 mg, 1.3 mmol) in N 2 To a stirred ice-cold solution of 4-bromo-6-chloro-N-[(3-methoxyphenyl)methyl]pyridazin-3-amine (Intermediate 220, 350 mg, 1.07 mmol) in THF (5 mL) was added portionwise under reduced pressure. After 2 min, the ice bath was removed and the mixture was stirred at RT for 25 min, then iodomethane (0.2 mL, 3.21 mmol) was added dropwise and the resulting reaction mixture was stirred for 5 h at 40° C. The reaction mixture was concentrated under reduced pressure, the residue was diluted with DCM, the solids were filtered and the solution was concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~18% EtOAc) to give the title compound (222 mg, 0.65 mmol, 61% yield). LC-MS (ESI): m / z (M-1): 344.0 (Method 1)

[0367] Intermediate 224:N-{4-[(6-chloro-3-{[(3-methoxyphenyl)methyl](methyl)amino}pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 224 was prepared according to the method used for the synthesis of Intermediate 189 from N-(4-aminopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 219, 142 mg, 0.54 mmol) and 4-bromo-6-chloro-N-[(3-methoxyphenyl)methyl]-N-methylpyridazin-3-amine (Intermediate 223, 212 mg, 0.62 mmol) starting at 120° C. to afford the title compound (186 mg, 0.35 mmol, 66% yield). LC-MS (ESI): m / z (M+1): 525.4 (Method 2)

[0368] Intermediate 225: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-methoxyphenyl)methyl](methyl)amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 225 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (53 mg, 0.07 mmol) starting from intermediate 224 (186 mg, 0.35 mmol) and 5-chloro-2-fluorobenzeneboronic acid (77 mg, 0.44 mmol) to afford the title compound (130 mg, 0.21 mmol, 58% yield). LC-MS (ESI): m / z (M+1): 619.4 (Method 2)

[0369] Intermediate 226: tert-Butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate [ka] tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 7.1 mmol) and NaHCO 3 A solution of the mixture (716 mg, 8.52 mmol) in DCM (35.5 mL) was treated with 3-chloroperbenzoic acid (1.75 g, 7.81 mmol) and stirred at RT overnight. The mixture was diluted with saturated Na 2 S 2 O 3 Quench by addition of aqueous saturated NaHCO 3 The solution was extracted with aqueous solution and DCM. 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica NH cartridge (cHex to 100% EtOAc) to give the title compound (1.55 g, 6.82 mmol, 96% yield). 1 H NMR (500 MHz, chloroform-d) δ ppm 4.42 (s, 2 H), 3.97 (q, J = 9.1 Hz, 4 H), 2.77 (s, 2 H), 1.45 (s, 9 H)

[0370] Intermediate 227: 6-Oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate [ka] Intermediate 227 was prepared according to the method used for the synthesis of Intermediate 40 starting from tert-butyl 7-oxo-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 226, 1.55 g, 6.82 mmol) to give the title compound (2.34 g, assumed quantitative recovery). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.64 (s, 2H), 4.45 (s, 2H), 4.04 (ddd, J = 7.0, 5.6, 1.5 Hz, 4H), 2.91 (s, 2H)

[0371] Intermediate 228: tert-Butyl 6-chloro-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazine-4-carboxylate [ka] Intermediate 228 was prepared from intermediate 212 (760 mg, 3.05 mmol) and intermediate 227 (4.59 mmol) according to the method used for the synthesis of intermediate 94, starting at 30° C., to give the title compound (537 mg, 1.58 mmol, 34% yield). LC-MS (ESI): m / z (M+1): 340.1 (Method 1).

[0372] Intermediate 229: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazine-4-carboxylate [ka] Intermediate 229 was prepared according to the method used for the synthesis of Intermediate 16 from tert-butyl 6-chloro-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazine-4-carboxylate (Intermediate 228, 537 mg, 1.58 mmol) and 5-chloro-2-fluorobenzeneboronic acid (965 mg, 5.53 mmol) starting at 100° C. to give the title compound (343 mg, 0.79 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 434.3 (Method 1).

[0373] Intermediate 230: 6-(5-chloro-2-fluorophenyl)-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 230 was prepared according to the method used for the synthesis of Intermediate 215 starting from tert-butyl 6-(5-chloro-2-fluorophenyl)-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazine-4-carboxylate (Intermediate 229, 310 mg, 0.71 mmol) to afford the title compound (335 mg, 0.68 mmol, 95% yield) as the trifluoroacetate salt. LC-MS (ESI): m / z (M+1): 378.1 (Method 1)

[0374] Intermediate 231: 2-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]-6-oxa-2-azaspiro[3.4]octan-7-one [ka] A solution of intermediate 230 (335 mg, 0.68 mmol) and TEA (0.3 mL, 2.18 mmol) in tert-butanol (4.54 mL) was treated with diphenylphosphoryl azide (0.19 mL, 0.89 mmol). The mixture was stirred at 60° C. for 5 h. The mixture was diluted with EtOAc and saturated NaHCO 3 The organic phase was washed with aqueous solution and brine. 2 SO 4 This material was dissolved in DCM (4.54 mL), TFA (1.56 mL, 20.43 mmol) was added and the mixture was stirred at RT overnight. The mixture was concentrated under reduced pressure and then diluted with DCM. The organic phase was washed with saturated NaHCO 3 Wash with aqueous solution of Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 75% EtOAc) to give the title compound (86 mg, 0.25 mmol, 36% yield). LC-MS (ESI): m / z (M+1): 349.1 (Method 2)

[0375] Intermediate 232: tert-Butyl 6-chloro-3-[(oxolan-3-yl)amino]pyridazine-4-carboxylate [ka] Intermediate 232 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 500 mg, 2.01 mmol) and 3-aminotetrahydrofuran (184 mg, 2.11 mmol) to afford the title compound (356 mg, 1.19 mmol, 59% yield). LC-MS (ESI): m / z (M+1): 300.2 (Method 1)

[0376] Intermediate 233: tert-Butyl 6-chloro-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylate [ka] Intermediate 233 was prepared according to the method used for the synthesis of Intermediate 223 starting from tert-butyl 6-chloro-3-[(oxolan-3-yl)amino]pyridazine-4-carboxylate (Intermediate 232, 356 mg, 1.19 mmol) to give the title compound (220 mg, 0.70 mmol, 59% yield). LC-MS (ESI): m / z (M+1): 314.1 (Method 1).

[0377] Intermediate 234: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylate [ka] Intermediate 234 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2(103 mg, 0.14 mmol) starting from tert-butyl 6-chloro-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylate (Intermediate 233, 220 mg, 0.70 mmol) and 5-chloro-2-fluorobenzeneboronic acid (245 mg, 1.41 mmol) to afford the title compound (230 mg, 0.56 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 408.3 (Method 1)

[0378] Intermediate 235: 6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 235 was prepared according to the method used for the synthesis of Intermediate 215 starting from tert-butyl 6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylate (Intermediate 234, 230 mg, 0.56 mmol) to afford the title compound (260 mg, 0.56 mmol, 99% yield) as the trifluoroacetate salt. LC-MS (ESI): m / z (M+1): 352.2 (Method 1)

[0379] Intermediate 236: 6-(5-chloro-2-fluorophenyl)-N3-methyl-N3-(oxolan-3-yl)pyridazine-3,4-diamine [ka] Intermediate 236 was prepared according to the method used for the synthesis of Intermediate 231 starting from 6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazine-4-carboxylic acid trifluoroacetate (Intermediate 235, 260 mg, 0.56 mmol) to afford the title compound (76 mg, 0.23 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 323.2 (Method 1)

[0380] Intermediate 237: 3-[(Methylamino)methyl]oxolan-2-one [ka] A 2M solution of methylamine in THF (3.82 mL, 7.65 mmol) was added to a solution of α-methylene-γ-butyrolactone (0.22 mL, 2.55 mmol) in THF (1 mL). The mixture was stirred at RT overnight and then the volatiles were removed under reduced pressure to give the title compound (350 mg, recovery assumed quantitative) which was used directly in the next step. LC-MS (ESI): m / z (M+1): 129.9 (Method 1)

[0381] Intermediate 238: tert-Butyl 6-chloro-3-{methyl[(2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylate [ka] Intermediate 238 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 200 mg, 0.80 mmol) and 3-[(methylamino)methyl]oxolan-2-one (Intermediate 237, 207 mg, 1.71 mmol) to give the title compound (170 mg, 0.50 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 342.2 (Method 1).

[0382] Intermediate 239: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-{methyl[(2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylate [ka] Intermediate 239 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (71 mg, 0.10 mmol) starting from intermediate 238 (170 mg, 0.49 mmol) and 5-chloro-2-fluorobenzeneboronic acid (170 mg, 0.98 mmol) to afford the title compound (120 mg, 0.27 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 436.3 (Method 1)

[0383] Intermediate 240: 6-(5-chloro-2-fluorophenyl)-3-{methyl[(2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 240 was prepared following the method used for the synthesis of intermediate 215 starting from intermediate 239 (120 mg, 0.27 mmol) to afford the title compound (134 mg, 0.27 mmol, 99% yield) as the trifluoroacetate salt. LC-MS (ESI): m / z (M+1): 380.2 (Method 1)

[0384] Intermediate 241: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}methyl)oxolan-2-one [ka] Intermediate 241 was prepared starting from intermediate 240 (134 mg, 0.27 mmol) according to the method used for the synthesis of intermediate 231 to give the title compound (60 mg, 0.17 mmol, 63% yield). LC-MS (ESI): m / z (M+1): 351.3 (Method 1).

[0385] Intermediate 242: tert-Butyl N-(4,4,4-trifluoro-3-hydroxybutyl)carbamate [ka] 4-Amino-1,1,1-trifluoro-butan-2-ol (360 mg, 2.52 mmol) was dissolved in DCM (5 mL). TEA (0.39 mL, 2.77 mmol) and di-tert-butyl dicarbonate (604 mg, 2.77 mmol) were subsequently added and the reaction was stirred at RT for 4 h. The mixture was diluted with saturated NH 4 Washing with Cl solution, the organic phase was dried and evaporated to give the title compound (620 mg, 2.52 mmol, quantitative yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 6.85 (br. s., 1 H), 6.11 (d, J = 6.60 Hz, 1 H), 3.87 - 4.02 (m, 1 H), 2.97 - 3.14 (m, 2 H), 1.65 - 1.75 (m, 1 H), 1.49 - 1.60 (m, 1 H), 1.37 (s, 9 H)

[0386] Intermediate 243: 1,1,1-trifluoro-4-(methylamino)butan-2-ol [ka] A 2M solution of lithium aluminum hydride in THF (2.55 mL, 5.1 mmol) was added dropwise to a solution of intermediate 242 (620 mg, 2.52 mmol) in THF (12 mL). The resulting solution was refluxed for 1 h, then the mixture was cooled in an ice bath and Na 2 SO 4 10H 2 O was added portionwise until gas evolution ceased. The mixture was diluted with EtOAc and washed with Celite. (登録商標) Filtered through a pad. Volatiles were removed under reduced pressure to give the title compound (340 mg, 2.16 mmol, 85% yield) which was used directly in the next step. LC-MS (ESI): m / z (M+1): 158.0 (Method 2)

[0387] Intermediate 244:tert-Butyl 6-chloro-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylate [ka] Intermediate 244 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 490 mg, 1.97 mmol) and 1,1,1-trifluoro-4-(methylamino)butan-2-ol (Intermediate 243, 340 mg, 2.16 mmol) to afford the title compound (336 mg, 0.91 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 370.3 (Method 1)

[0388] Intermediate 245: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylate [ka] Pd(PPh 3 ) 4 (157 mg, 0.14 mmol) was dissolved in a 2M NaCl solution of a degassed mixture of tert-butyl 6-chloro-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylate (Intermediate 244, 335 mg, 0.91 mmol) and 5-chloro-2-fluorobenzeneboronic acid (632 mg, 3.62 mmol). 2 CO 3 (4.79 mL, 9.58 mmol) was added to a mixture of toluene (14 mL) and ethanol (9 mL). The mixture was heated at 105° C. for 90 min. The mixture was cooled to RT, diluted with EtOAc and the organic phase was separated, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (c-Hex to 20% EtOAc) to give the title compound (300 mg, 0.65 mmol, 70% yield). LC-MS (ESI): m / z (M+1): 464.3 (Method 1)

[0389] Intermediate 246: 6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 246 was prepared according to the method used for the synthesis of Intermediate 215 starting from tert-butyl 6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylate (Intermediate 245, 265 mg, 0.57 mmol) to afford the title compound (300 mg, 0.57 mmol, quantitative yield) as the trifluoroacetate salt. LC-MS (ESI): m / z (M+1): 408.2 (Method 1)

[0390] Intermediate 247: 4-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}-1,1,1-trifluorobutan-2-ol [ka] Intermediate 247 was prepared according to the method used for the synthesis of Intermediate 231 starting from 6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazine-4-carboxylic acid trifluoroacetate (Intermediate 246, 300 mg, 0.57 mmol) to afford the title compound (98 mg, 0.29 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 379.2 (Method 1)

[0391] Intermediate 248: Ethyl 2,2-dimethyl-2H-1,3-benzodioxole-5-carboxylate [ka] To a stirred solution of ethyl 3,4-dihydroxybenzoate (1.5 g, 8.23 ​​mmol) in acetone (4.23 mL, 57.64 mmol) and toluene (5 mL) at RT was added phosphorus trichloride (0.58 mL, 6.59 mmol) dropwise and the resulting reaction mixture was stirred at RT for 20 h. EtOAc (12 mL) was added followed by saturated NaHCO 3 Aqueous solution was added and the mixture was stirred for 15 min and then extracted with EtOAc. The organic phase was separated, washed with brine and added Na 2 SO 4 The mixture was dried at rt and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (c-Hex~25% EtOAc) to give the title compound (1.04 g, 4.7 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 223.1 (Method 1).

[0392] Intermediate 249: (2,2-Dimethyl-2H-1,3-benzodioxol-5-yl)methanol [ka] Intermediate 249 was prepared according to the method used for the synthesis of Intermediate 154 starting from ethyl 2,2-dimethyl-2H-1,3-benzodioxole-5-carboxylate (Intermediate 248, 1.04 g, 4.7 mmol) to afford the title compound (574 mg, 3.18 mmol, 67% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 6.65 - 6.83 (m, 3 H) 5.03 (t, J = 5.83 Hz, 1 H) 4.36 (d, J = 5.72 Hz, 2 H) 1.55 - 1.71 (m, 6 H)

[0393] Intermediate 250: 6-Chloro-3-[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methoxy]pyridazin-4-amine [ka] Intermediate 250 was prepared according to the method used for the synthesis of Intermediate 10 starting from 3,6-dichloropyridazin-4-amine (173 mg, 1.05 mmol) and (2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methanol (Intermediate 249, 570 mg, 3.16 mmol) to afford the title compound (180 mg, 0.58 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 308.1 (Method 2)

[0394] Intermediate 251: 6-(5-chloro-2-fluorophenyl)-3-[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methoxy]pyridazin-4-amine [ka] Intermediate 251 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (86 mg, 0.12 mmol) starting from 6-chloro-3-[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methoxy]pyridazin-4-amine (Intermediate 250, 180 mg, 0.58 mmol) and 5-chloro-2-fluorobenzeneboronic acid (163 mg, 1.60 mmol) to give the title compound (121 mg, 0.30 mmol, 51% yield). LC-MS (ESI): m / z (M+1): 402.1 (Method 2)

[0395] Intermediate 252: Cis 3-(hydroxymethyl)-1-methylcyclobutan-1-ol [ka] A stirred solution of cis-3-hydroxy-3-methylcyclobutanecarboxylic acid (1.2 g, 9.22 mmol) in THF (18 mL) was added to 10 mL of THF at 0° C. 2Under reduced pressure, a 1M solution of borane tetrahydrofuran complex in THF (18.44 mL, 18.44 mmol) was added dropwise. After 5 min, the ice bath was removed and the resulting reaction mixture was stirred at RT for 2.5 h. The mixture was cooled to 0° C. and quenched by the addition of MeOH. After 5 min, the ice bath was removed and stirred at RT for 30 min. The mixture was then concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex to 80% EtOAc) to give the title compound (1.1 g, 9.47 mmol, quantitative yield).

[0396] Intermediate 253: Cis 3-{[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)oxy]methyl}-1-methylcyclobutan-1-ol [ka] Intermediate 253 was prepared according to the method used for the synthesis of Intermediate 7 from 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]pyridazin-4-amine (Intermediate 6, 2.06 g, 6.56 mmol) and cis 3-(hydroxymethyl)-1-methylcyclobutan-1-ol (Intermediate 252, 1 g, 8.6 mmol) starting at 115° C. to give the title compound (938 mg, 2.38 mmol, 36% yield). LC-MS (ESI): m / z (M+1): 394.3 (Method 1)

[0397] Intermediate 254: Cis 3-({[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]oxy}methyl)-1-methylcyclobutan-1-ol [ka] Intermediate 254 was prepared according to the method used for the synthesis of intermediate 245 starting from cis 3-{[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)oxy]methyl}-1-methylcyclobutan-1-ol (Intermediate 253, 380 mg, 0.96 mmol) and 5-chloro-2-fluorobenzeneboronic acid (674 mg, 3.86 mmol) to give the title compound (406 mg, 0.83 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 488.3 (Method 1)

[0398] Intermediate 255: Cis 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}methyl)-1-methylcyclobutan-1-ol [ka] Intermediate 255 was prepared starting from intermediate 254 (838 mg, 1.72 mmol) according to the method used for the synthesis of intermediate 9 to give the title compound (148 mg, 0.44 mmol, 25% yield). LC-MS (ESI): m / z (M+1): 338.1 (Method 1).

[0399] Intermediate 256: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To an ice-cold solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (3 g, 17.63 mmol) in THF (35.2 mL) was added 1 M borane tetrahydrofuran complex in THF (17.63 mL, 17.63 mmol), the mixture was allowed to slowly reach RT and stirred for 16 h. The mixture was cooled to 0 °C and water was added dropwise, followed by solid K. 2 CO 3(ca. 2 equiv.) and then extracted with EtOAc (3x). The combined organic layers were dried and evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~60% EtOAc) to give the title compound (2.1 g, 13.45 mmol, 76% yield). LC-MS (ESI): m / z (M+1): 157.1 (Method 1)

[0400] Intermediate 257: Methyl 3-{[(6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl)oxy]methyl}bicyclo[1.1.1]pentane-1-carboxylate [ka] Intermediate 257 was prepared according to the method used for the synthesis of Intermediate 7 from Intermediate 6 (658 mg, 2.09 mmol) and methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Intermediate 256, 463 mg, 2.93 mmol) starting at 95° C. to give the title compound (660 mg, 1.52 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 434.4 (Method 1).

[0401] Intermediate 258: Methyl 3-({[6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]oxy}methyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] Intermediate 258 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (23.6 mg, 0.03 mmol) starting from intermediate 257 (70 mg, 0.16 mmol) and 5-chloro-2-fluorobenzeneboronic acid (42.2 mg, 0.24 mmol) to afford the title compound (49 mg, 0.09 mmol, 58% yield). LC-MS (ESI): m / z (M+1): 528.3 (Method 1)

[0402] Intermediate 259: Methyl 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]oxy}methyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] Intermediate 259 was prepared following the method used for the synthesis of intermediate 64, starting from intermediate 258 (330 mg, 0.63 mmol), to afford the title compound (164 mg, 0.43 mmol, 69% yield). LC-MS (ESI): m / z (M+1): 378.3 (Method 2)

[0403] Intermediate 260: 3-{[benzyl(methyl)amino]methyl}oxolan-2-one [ka] N-Methyl-1-phenylmethanamine (0.99 mL, 7.65 mmol) was added to a solution of 3-methylene-2-oxolanone (300 mg, 3.06 mmol) in THF (4 mL), the vial was sealed and stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~40% EtOAc) to give the title compound (552 mg, 2.52 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 220.2 (Method 2)

[0404] Intermediate 261: 3-{[benzyl(methyl)amino]methyl}-3-methyloxolan-2-one [ka] A stirred solution of intermediate 260 (548 mg, 2.5 mmol) in THF (12 mL) was added at −78 °C for 2 h. 2A 1M solution of lithium bis(trimethylsilyl)amide in THF (3 mL, 3 mmol) was added dropwise under reduced pressure. The reaction mixture was stirred at -78 °C for 50 min, then iodomethane (0.35 mL, 5.62 mmol) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 20 min, then slowly allowed to reach RT and stirred at RT overnight. The reaction mixture was diluted with EtOAc and NaHCO 3 A concentrated aqueous solution of was added. The mixture was further extracted with EtOAc and the organic phase was washed with water, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~25% EtOAc) to give the title compound (406 mg, 1.74 mmol, 70% yield). LC-MS (ESI): m / z (M+1): 234.9 (Method 2)

[0405] Intermediate 262: 3-Methyl-3-[(methylamino)methyl]oxolan-2-one [ka] To a solution of 3-{[benzyl(methyl)amino]methyl}-3-methyloxolan-2-one (Intermediate 261, 406 mg, 1.74 mmol) in MeOH (65 mL) at RT was added 10% Pd / C 55-65% wet (200 mg, 1.13 mmol) and the resulting mixture was hydrogenated under atmospheric pressure. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (220 mg, 1.54 mmol, 88% yield) which was used as is. LC-MS (ESI): m / z (M+1): 144.0 (Method 2)

[0406] Intermediate 263: tert-Butyl 6-chloro-3-{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylate [ka] Intermediate 263 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 220 mg, 0.88 mmol) and 3-methyl-3-[(methylamino)methyl]oxolan-2-one (Intermediate 262, 220 mg, 1.74 mmol) to afford the title compound (266 mg, 0.75 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 356.2 (Method 1)

[0407] Intermediate 264: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylate [ka] Intermediate 264 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (110 mg, 0.15 mmol) starting from tert-butyl 6-chloro-3-{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylate (Intermediate 263, 266 mg, 0.75 mmol) and 5-chloro-2-fluorobenzeneboronic acid (261 mg, 1.50 mmol) to give the title compound (265 mg, 0.59 mmol, 79% yield). LC-MS (ESI): m / z (M+1): 450.3 (Method 1)

[0408] Intermediate 265: 6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 265 was prepared starting from intermediate 264 (265 mg, 0.59 mmol) according to the method used for the synthesis of intermediate 215 to give the title compound (302 mg, 0.29 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 394.2 (Method 1).

[0409] Intermediate 266: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}methyl)-3-methyloxolan-2-one [ka] Intermediate 266 was prepared according to the method used for the synthesis of Intermediate 231 starting from 6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxooxolan-3-yl)methyl]amino}pyridazine-4-carboxylic acid trifluoroacetate (Intermediate 265, 299 mg, 0.59 mmol) to give the title compound (153 mg, 0.42 mmol, 71% yield). LC-MS (ESI): m / z (M+1): 365.2 (Method 1).

[0410] Intermediate 267: Methyl 4-{4-[(tert-butoxy)carbonyl]-6-chloropyridazin-3-yl}morpholine-2-carboxylate [ka] Intermediate 267 was prepared according to the method used for the synthesis of Intermediate 94 starting from tert-butyl 3,6-dichloropyridazine-4-carboxylate (Intermediate 212, 500 mg, 2.01 mmol) and methylmorpholine-2-carboxylate hydrochloride (365 mg, 2.01 mmol) to give the title compound (375 mg, 1.05 mmol, 52% yield). LC-MS (ESI): m / z (M+1): 358.1 (Method 1).

[0411] Intermediate 268:Methyl 4-{4-[(tert-butoxy)carbonyl]-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl}morpholine-2-carboxylate [ka] Intermediate 268 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (154 mg, 0.21 mmol) starting from intermediate 267 (375 mg, 1.05 mmol) and 5-chloro-2-fluorobenzeneboronic acid (366 mg, 2.10 mmol) to give the title compound (260 mg, 0.57 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 452.2 (Method 1)

[0412] Intermediate 269: 6-(5-chloro-2-fluorophenyl)-3-[2-(methoxycarbonyl)morpholin-4-yl]pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 269 was prepared following the method used for the synthesis of intermediate 215 starting from intermediate 268 (245 mg, 0.54 mmol) to afford the title compound (0.54 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 396.2 (Method 1)

[0413] Intermediate 270: Methyl 4-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]morpholine-2-carboxylate [ka] Intermediate 270 was prepared starting from intermediate 269 (0.54 mmol) according to the method used for the synthesis of intermediate 231 to give the title compound (150 mg, 0.41 mmol, 76% yield). LC-MS (ESI): m / z (M+1): 367.1 (Method 1).

[0414] Intermediate 271: 3-(4-Methylpiperazin-1-yl)propanamide [ka] 1-Methylpiperazine (1.56 mL, 14.07 mmol) and 2-propenamide (1.0 g, 14.07 mmol) were dissolved in H 2 The mixture was mixed in 12 ml of HO and stirred at 60° C. for 6 hours. 2 The O was removed under reduced pressure to give the title compound (2.4 g, 14.02 mmol, 99% yield).

[0415] Intermediate 272: N-(6-chloropyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)propanamide [ka] Cs 2 CO 3 (3.61 g, 11 mmol), Xantphos (382 mg, 0.66 mmol), 4,6-dichloropyrimidine (820 mg, 5.5 mmol) and 3-(4-methylpiperazin-1-yl)propanamide (Intermediate 271, 942 mg, 5.5 mmol) were mixed in 1,2-dimethoxyethane (39 mL) and N 2 was bubbled for 5 min, then Pd(OAc) 2 (62 mg, 0.28 mmol) was added. The mixture was heated at 75° C. for 1.5 h. The mixture was cooled to RT, filtered through Celite with the aid of EtOAc, and the volatiles were removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage NH cartridge (cHex~100% EtOAc) to give the title compound (659 mg, 2.32 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 284.1 (Method 2)

[0416] Intermediate 273: Ethyl 2,2-dimethyl-3-(2,2,2-trifluoroacetamido)propanoate [ka] Trifluoroacetic anhydride (0.92 mL, 6.61 mmol) was added dropwise to a solution of DIPEA (2.4 mL, 13.76 mmol) and ethyl 3-amino-2,2-dimethylpropanoate hydrochloride (1 g, 5.5 mmol) in DCM (20 mL) at RT. The resulting reaction solution was stirred at the same temperature for 3 h. The mixture was treated with 1N aqueous HCl and the product was extracted with DCM. The phases were separated and the organic phase was washed with Na 2 SO 4 Drying at rt, filtration and evaporation afforded the title compound (5.5 mmol, quantitative yield) which was used directly in the next step.

[0417] Intermediate 274: Ethyl 2,2-dimethyl-3-(2,2,2-trifluoro-N-methylacetamido)propanoate [ka] To a solution of intermediate 273 (5.5 mmol) in THF (22 mL) at 0° C. was added iodomethane (0.6 mL, 9.7 mmol), followed by portionwise addition of 60% NaH dispersion in oil (597 mg, 14.92 mmol) over 10 min. The mixture was stirred overnight at RT. The mixture was cooled in an ice bath and washed with 1N aqueous HCl, followed by Et 2 O was added. The aqueous phase was 2 The combined organic phase was extracted twice with Na 2 SO 4 It was dried at 40° C., filtered and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex to 10% EtOAc) to give the title compound (1.31 g, 5.13 mmol, 93% yield).

[0418] Intermediate 275: Ethyl 2,2-dimethyl-3-(methylamino)propanoate [ka] Ethyl 2,2-dimethyl-3-(2,2,2-trifluoro-N-methylacetamido)propanoate (Intermediate 274, 1.31 g, 5.13 mmol) was dissolved in 7N NH 3 in MeOH (22 mL, 154 mmol) and stirred overnight at RT. Volatiles were removed under reduced pressure to give the title compound and its corresponding methyl ester as a 2:1 mixture (740 mg, 4.65 mmol, 91% yield) which was used without further purification.

[0419] Intermediate 276: tert-Butyl 6-chloro-3-[(3-ethoxy-2,2-dimethyl-3-oxopropyl)(methyl)amino]pyridazine-4-carboxylate [ka] Intermediate 276 was prepared according to the method used for the synthesis of Intermediate 94 starting from Intermediate 212 (300 mg, 1.20 mmol) and ethyl 2,2-dimethyl-3-(methylamino)propanoate (Intermediate 275, 211 mg, 1.33 mmol) to give the title compound (120 mg, 0.32 mmol, 27% yield). LC-MS (ESI): m / z (M+1): 372.4 (Method 1).

[0420] Intermediate 277: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-[(3-ethoxy-2,2-dimethyl-3-oxopropyl)(methyl)amino]pyridazine-4-carboxylate [ka] Intermediate 277 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (47 mg, 0.06 mmol) starting from intermediate 276 (120 mg, 0.32 mmol) and 5-chloro-2-fluorobenzeneboronic acid (113 mg, 0.65 mmol) to afford the title compound (140 mg, 0.30 mmol, 93% yield). LC-MS (ESI): m / z (M+1): 466.2 (Method 1)

[0421] Intermediate 278: 6-(5-chloro-2-fluorophenyl)-3-[(3-ethoxy-2,2-dimethyl-3-oxopropyl)(methyl)amino]pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 278 was prepared starting from intermediate 277 (180 mg, 0.39 mmol) according to the method used for the synthesis of intermediate 215 to give the title compound (0.39 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 410.3 (Method 1).

[0422] Intermediate 279: Ethyl 3-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}-2,2-dimethylpropanoate [ka] Intermediate 279 was prepared starting from intermediate 278 (0.39 mmol) according to the method used for the synthesis of intermediate 231 to give the title compound (70 mg, 0.18 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 381.4 (Method 1).

[0423] Intermediate 280 (Enantiomer 1) and Intermediate 281 (Enantiomer 2) 4-{[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}-1,1,1-trifluorobutan-2-ol [ka] Racemic intermediate 247 (210 mg, 0.2 mmol) was separated into single enantiomers by preparative chiral HPLC. [Table 5]

[0424] Intermediate 280 was obtained as the first eluting enantiomer (76 mg). Rt.=10.9 min, ee 100% LC-MS (ESI): m / z (M+1): 379.5 (Method 2)

[0425] Intermediate 281 was obtained as the second eluting enantiomer (32 mg). Rt.=14.5 min, ee 98.6% LC-MS (ESI): m / z (M+1): 379.5 (Method 2)

[0426] Intermediate 282: tert-Butyl 6-chloro-3-{2-[(propan-2-yloxy)carbonyl]azetidin-1-yl}pyridazine-4-carboxylate [ka] Process 1 A stirred mixture of azetidine-2-carboxylic acid (500 mg, 4.95 mmol) in propan-2-ol (10 mL, 130.8 mmol) was added to a 20 mL flask at 0 °C with N 2 Thionyl dichloride (0.6 mL, 8.23 ​​mmol) was added dropwise under reduced pressure. After 5 min, the ice bath was removed and the resulting reaction mixture was stirred at RT for 2.5 h and then heated at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give propan-2-ylazetidine-2-carboxylate hydrochloride (4.95 mmol, quantitative yield), which was used directly in the next step.

[0427] Process 2 Intermediate 282 was prepared according to the method used for the synthesis of intermediate 94 starting from intermediate 212 (650 mg, 2.61 mmol) and propan-2-ylazetidine-2-carboxylate hydrochloride (from step 1, 4.22 mmol) to give the title compound (764 mg, 2.15 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 356.2 (Method 1).

[0428] Intermediate 283: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-{2-[(propan-2-yloxy)carbonyl]azetidin-1-yl}pyridazine-4-carboxylate [ka] Intermediate 283 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (158 mg, 0.21 mmol) starting from intermediate 282 (764 mg, 2.15 mmol) and 5-chloro-2-fluorobenzeneboronic acid (562 mg, 3.22 mmol) to give the title compound (935 mg, 2.08 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 450.2 (Method 1)

[0429] Intermediate 284: 6-(5-chloro-2-fluorophenyl)-3-{2-[(propan-2-yloxy)carbonyl]azetidin-1-yl}pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 284 was prepared starting from intermediate 283 (935 mg, 2.08 mmol) according to the method used for the synthesis of intermediate 215 to give the title compound (898 mg, 1.77 mmol, 85% yield). LC-MS (ESI): m / z (M+1): 394.1 (Method 1).

[0430] Intermediate 285: Propan-2-yl 1-[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]azetidine-2-carboxylate [ka] Intermediate 285 was prepared starting from intermediate 284 (898 mg, 1.77 mmol) according to the method used for the synthesis of intermediate 231 to give the title compound (360 mg, 0.99 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 365.1 (Method 1).

[0431] Intermediate 286: 3-{[benzyl(methyl)amino]methyl}-3-[(benzyloxy)methyl]oxolan-2-one [ka] Intermediate 286 was prepared according to the method used for the synthesis of intermediate 261, starting from intermediate 260 (3.69 g, 16.83 mmol) and benzyl chloromethyl ether (5.67 ml, 38.7 mmol) to give the title compound (2.71 g, 7.99 mmol, 47% yield). LC-MS (ESI): m / z (M+1): 340.2 (Method 4).

[0432] Intermediate 287: tert-Butyl 6-chloro-3-({[3-(hydroxymethyl)-2-oxooxolan-3-yl]methyl}(methyl)amino)pyridazine-4-carboxylate [ka] Process 1 To a stirred solution of intermediate 286 (2.71 g, 7.99 mmol) in EtOAc (80 mL) at RT was added 10% Pd / carbon 55-65% wet (1.36 g, 0.64 mmol) and the resulting mixture was hydrogenated at atmospheric pressure overnight. The mixture was filtered through Celite and concentrated under reduced pressure to give 3-(hydroxymethyl)-3-[(methylamino)methyl]oxolan-2-one (7.99 mmol, quantitative yield), which was used directly in the next step.

[0433] Process 2 Intermediate 287 was prepared following the method used for the synthesis of intermediate 94, starting from intermediate 212 (803 mg, 3.22 mmol) and 3-(hydroxymethyl)-3-[(methylamino)methyl]oxolan-2-one (from step 1, 1.02 g, 6.45 mmol) to afford the title compound (470 mg, 1.26 mmol, 36% yield). LC-MS (ESI): m / z (M+1): 372.1 (Method 3)

[0434] Intermediate 288: tert-Butyl 6-(5-chloro-2-fluorophenyl)-3-({[3-(hydroxymethyl)-2-oxooxolan-3-yl]methyl}(methyl)amino)pyridazine-4-carboxylate [ka] Intermediate 288 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (186 mg, 0.26 mmol) starting from intermediate 287 (470 mg, 1.26 mmol) and 5-chloro-2-fluorobenzeneboronic acid (441 mg, 2.53 mmol) to afford the title compound (448 mg, 0.96 mmol, 76% yield). LC-MS (ESI): m / z (M+1): 466.2 (Method 3)

[0435] Intermediate 289: 6-(5-chloro-2-fluorophenyl)-3-({[3-(hydroxymethyl)-2-oxooxolan-3-yl]methyl}(methyl)amino)pyridazine-4-carboxylic acid trifluoroacetate [ka] Intermediate 289 was prepared starting from intermediate 288 (448 mg, 0.95 mmol) according to the method used for the synthesis of intermediate 215 to give the title compound (0.95 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 410.1 (Method 3).

[0436] Intermediate 290: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}methyl)-3-(hydroxymethyl)oxolan-2-one [ka] Intermediate 290 was prepared starting from intermediate 289 (0.95 mmol) according to the method used for the synthesis of intermediate 231 to give the title compound (69 mg, 0.19 mmol, 19% yield). LC-MS (ESI): m / z (M+1): 381.1 (Method 3).

[0437] Intermediate 291: 3-({[4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl](methyl)amino}methyl)-3-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one [ka] To a stirred solution of a mixture of intermediate 290 (59 mg, 0.15 mmol) and DMAP (3.8 mg, 0.03 mmol) in DCM (2.81 mL) at RT was added imidazole (18 mg, 0.26 mmol) followed by tert-butyldimethylchlorosilane (35.18 mg, 0.230 mmol) and the resulting reaction mixture was stirred overnight at RT. The mixture was diluted with DCM and added NaHCO 3 and water, and the organic phase was washed with Na 2 SO 4 It was dried at 40° C., filtered and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage NH cartridge (cHex to 30% EtOAc) to give the title compound (32 mg, 0.06 mmol, 42% yield). LC-MS (ESI): m / z (M+1): 495.2 (Method 3)

[0438] Intermediate 292:N-{4-[(3-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-oxooxolan-3-yl)methyl](methyl)amino}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 292 was prepared according to the method used for the synthesis of intermediate 189, starting from intermediate 291 (32 mg, 0.06 mmol) and intermediate 2 (23 mg, 0.07 mmol) to give the title compound (24 mg, 0.03 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 741.5 (Method 4).

[0439] Intermediate 293: tert-Butyl 4-{2-[(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate [ka] Intermediate 293 was prepared according to the method used for the synthesis of intermediate 47, starting from intermediate 57 (88 mg, 0.21 mmol) and intermediate 67 (80 mg, 0.19 mmol) to give the title compound (140 mg, 0.19 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 746.1 (Method 2).

[0440] Intermediate 294: Cis{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl 4-methylbenzene-1-sulfonate [ka] To a solution of cis{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methanol (Intermediate 154, 830 mg, 3.84 mmol) in DCM (19 mL) was added TEA (1.6 mL, 11.51 mmol) followed by tosyl chloride (1.10 g, 5.75 mmol). The mixture was stirred at RT for 4 h. Further tosyl chloride (439 mg, 2.3 mmol) and TEA (0.53 mL, 3.84 mmol) were added and the mixture was stirred for 3 h. The reaction was quenched by the addition of water and the organic phase was separated and washed with brine. The organic phase was washed with NaCl. 2 SO 4 The crude material was purified by flash chromatography on a Biotage Si cartridge (cHex~20% EtOAc) to give the title compound (1.44g, 3.84mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 371.2 (Method 1).

[0441] Intermediate 295: Cis 1-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]ethan-1-one [ka] A mixture of cis{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl 4-methylbenzene-1-sulfonate (Intermediate 294, 1.44 g, 3.84 mmol), potassium thioacetate (888 mg, 7.77 mmol) and sodium iodide (58 mg, 0.39 mmol) in DMF (9.7 mL) was stirred at 50° C. for 6 h. The mixture was cooled to RT and then diluted with EtOAc and saturated NaHCO 3 The organic phase was washed with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage Si cartridge (cHex to 10% EtOAc) to give the title compound (646 mg, 2.35 mmol, 61% yield). LC-MS (ESI): m / z (M+1): 275.2 (Method 1)

[0442] Intermediate 296: Cis 3-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]-6-chloropyridazin-4-amine [ka] Process 1 A mixture of cis 1-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]ethan-1-one (Intermediate 295, 646 mg, 2.35 mmol) in THF (15.7 mL) was heated at 0 °C and N 2 The mixture was stirred at the same temperature for 5 min, then warmed to RT and stirred for 30 min. The reaction was cooled to 0 °C and saturated NaHSO 4 The mixture was quenched by the addition of aqueous solution of 1,2-dichloromethane. The mixture was extracted with EtOAc and washed with water. The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give cis {3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methanethiol (530 mg, 2.28 mmol, 97%) which was used directly in the next step.

[0443] Process 2 Intermediate 296 was prepared according to the method used for the synthesis of Intermediate 176 starting from material (from step 1, 528 mg, 2.27 mmol) and 3,6-dichloropyridazin-4-amine (250 mg, 1.52 mmol) to give the title compound (495 mg, 1.27 mmol, 84% yield). LC-MS (ESI): m / z (M+1): 360.2 (Method 1).

[0444] Intermediate 297:Cis 3-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine [ka] Intermediate 297 was prepared by the synthesis of Pd(dppf)Cl according to the method used for the synthesis of intermediate 8. 2 (187 mg, 0.25 mmol) starting from cis 3-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]-6-chloropyridazin-4-amine (Intermediate 296, 495 mg, 1.27 mmol) and 5-chloro-2-fluorobenzeneboronic acid (333 mg, 1.91 mmol) to give the title compound (226 mg, 0.5 mmol, 39% yield). LC-MS (ESI): m / z (M+1): 454.7 (Method 1)

[0445] Intermediate 298: Cis N-[4-({3-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl}amino)pyridin-2-yl]-3-(4-methylpiperazin-1-yl)propanamide [ka] Intermediate 298 was prepared according to the method used for the synthesis of Intermediate 47 starting from cis 3-[({3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}methyl)sulfanyl]-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 297, 95 mg, 0.21 mmol) and N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 2, 78 mg, 0.23 mmol) to afford the title compound (91 mg, 0.13 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 700.4 (Method 2)

[0446] Intermediate 299: N-(4-bromopyridin-2-yl)-3,3-dimethoxycyclobutane-1-carboxamide [ka] Intermediate 299 was prepared according to the method used for the synthesis of intermediate 171 starting from 4-bromopyridin-2-amine (1.24 g, 7.18 mmol) and 3,3-dimethoxycyclobutane-1-carboxylate methyl ester (500 mg, 2.66 mmol) to give the title compound (480 mg, 1.52 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 315.0 (Method 2).

[0447] Intermediate 300: N-(4-{[3-({2-[(tert-butyldimethylsilyl)oxy]ethyl}sulfanyl)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3,3-dimethoxycyclobutane-1-carboxamide [ka] Intermediate 300 was prepared according to the method used for the synthesis of intermediate 189, starting from intermediate 299 (42 mg, 0.13 mmol) and intermediate 67 (50 mg, 0.12 mmol) to give the title compound (67 mg, 0.10 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 648.3 (Method 2).

[0448] Intermediate 301: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-oxocyclobutane-1-carboxamide [ka] A solution of intermediate 300 (67.0 mg, 0.10 mmol) in THF (1.03 mL) was treated with aqueous HCl (1N) (1.03 mL, 1.03 mmol) at RT and the solution was stirred overnight. The reaction was diluted with saturated NaHCO 3 The mixture was quenched by the addition of aqueous solution of 1,2-dichloromethane and then extracted with EtOAc. The organic phase was separated and 2 SO 4 The crude material was purified by flash chromatography on a Biotage Si cartridge (DCM to 20% MeOH) to give the title compound (30 mg, 0.06 mmol, 59% yield). LC-MS (ESI): m / z (M+1): 488.1 (Method 2).

[0449] Intermediate 302: tert-Butyl 8-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]cyclobutyl}-5,8-diazaspiro[3.5]nonane-5-carboxylate [ka] Intermediate 302 was prepared according to the method used for the synthesis of Intermediate 170 starting from tert-butyl 5,8-diazaspiro[3.5]nonane-5-carboxylate (99 mg, 0.44 mmol) and Intermediate 301 (85 mg, 0.17 mmol) to give the title compound (104 mg, 0.15 mmol, 85% yield) as an inseparable mixture of diastereoisomers cis and trans. LC-MS (ESI): m / z (M+1): 698.5 (Method 2).

[0450] Intermediate 303: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-{5,8-diazaspiro[3.5]nonan-8-yl}cyclobutane-1-carboxamide [ka] Intermediate 303 was prepared starting from intermediate 302 (104 mg, 0.15 mmol) according to the method used for the synthesis of intermediate 40 to give the title compound (0.15 mmol, quantitative yield) as an inseparable mixture of diastereoisomers, cis and trans. LC-MS (ESI): m / z (M+1): 598.4 (Method 2).

[0451] Intermediate 304: tert-Butyl 3-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}py...

Claims

1. General formula (I) 【Chemical 1】 [During the ceremony, A is A1, A2, A3 and A4 【Chemistry 2】 selected from the group consisting of: R １ is selected from the group consisting of aryl and pyridyl, wherein said aryl and pyridyl are unsubstituted or substituted with a halogen atom and -(C １ -C ６ ) alkyl; R ２ Ha-NR ５ C(O)R ６ , -NR ５ R ９ and -NH ２ selected from the group consisting of: X １ is C or CH; X ２ is C, CH or N; R ３ Ha-OR ７ and R ４ is H or -C(O)O-(C １ -C ６ ) alkyl; R ５ is H or -(C １ -C ６ ) alkyl; R ６ is 1 or more -(C １ -C ６ ) alkyl-substituted -(C ３ -C ９ ) heterocycloalkyl; -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-NH-C(O)O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —C(O)O—(C １ -C ６ ) alkyl and -(C ３ -C ６ ) cycloalkyl); -(C １ -C ６ ) Alkylene-NH ２ unsubstituted or one or more -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl and -(C ３ -C ６ )cycloalkyl); and unsubstituted or substituted with one or more groups selected from -(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, —O—(C １ -C ６ ) alkyl, —C(O)OH, —C(O)O—(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, -(C ３ -C ６ ) substituted with one or more groups selected from cycloalkyl and halogen atoms; R ７ Ha-(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein said —(C ３ -C ９ )heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted; R ８ Ha-NR Ａ R Ｂ ;-SH;-S-(C １ -C ６ ) alkyl (wherein the -(C １ -C ６ ) alkyl is unsubstituted or substituted with one or more —OH; —S—(C １ -C ６ ) alkylene-OH; -S-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo); —S—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; -S(O)=NH-(C １ -C ６ ) alkyl; -S(O) ２ -(C １ -C ６ ) alkyl; —S(O)—(C １ -C ６ ) alkyl; —S—(C １ -C ６ ) alkylene-(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ )cycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene substituted with one or more groups selected from -OH and -OH); S-(C １ -C ６ ) alkylene-aryl, wherein the aryl is unsubstituted or —C(O)OH, —C(O)O—(C １ -C ６ ) alkylene-NR Ａ R Ｃ and -C(O)O-(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo); —S—(C １ -C ６ ) alkylene-Si((C １ -C ６ )Alkyl) ３ ;-S-(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkylene-OH; -S-(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or oxo and -(C １ -C ６ ) alkyl); １ -C ６ ) alkylene-NH-C(O)-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or substituted with one or more oxo; —S—(C １ -C ６ ) alkylene-NH-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or substituted with one or more oxo; —O—(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) haloalkyl; —O—(C １ -C ６ ) alkylene-OH (wherein the —O—(C １ -C ６ ) alkylene is substituted with one or more —OH; —O—(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-NR Ａ R Ｂ ; -O-(C １ -C ６ ) Alkylene-N ＋ R Ａ R Ｂ R Ｃ ; -O-(C １ -C ６ ) alkylene-S-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O)-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O) ２ -(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-NH-S(O) ２ -(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ )cycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, —C(O)O—(C １ -C ６ ) substituted with one or more groups selected from alkyl and —OH); —O—(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ )cycloalkyl is unsubstituted or -(C １ -C ６ ) alkylene substituted with one or more groups selected from -OH and -OH); -O-(C １ -C ６ ) alkylene-aryl, wherein the aryl is unsubstituted or substituted with one or more —OH; —O—(C １ -C ６ ) alkylene-aryl (wherein the aryl is —(C ５ -C ６ ) heterocycloalkyl, and the -(C ５ -C ６ )heterocycloalkyl is unsubstituted or oxo and -(C １ -C ６ ) alkyl); ３ -C ９ )heterocycloalkyl; and —O—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; R ９ is unsubstituted or —C(O)O—(C １ -C ６ ) alkyl and -(C ３ -C ９ )heteroaryl substituted with one or more groups selected from the group consisting of -(C ３ -C ９ )heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted; R １０ Ha-NR ５ C(O)R ６ and R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ is H or is unsubstituted or substituted with one or more groups selected from halogen and —OH —(C １ -C ６ ) alkyl; -S(O) ２ -(C １ -C ６ ) alkyl; -(C １ -C ６ ) alkylene-aryl, wherein the aryl is substituted with —OH; —(C １ -C ６ ) alkylene-OH; -(C ３ -C ９ ) heterocycloalkyl; -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl; -(C １ -C ６ ) alkylene-aryl-OCO-(C １ -C ６ ) alkyl; and —(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) substituted with one or more groups selected from haloalkyl and oxo; or R Ａ and R Ｂ are bonded to the nitrogen atom together with -(C ３ -C ６ ) heterocycloalkyl, where —(C ３ -C ６ )Heterocycloalkyl is unsubstituted or —C(O)OH, —(C １ -C ６ ) alkylene-OH, —C(O)O—(C １ -C ６ ) alkyl and oxo or substituted with one or more groups selected from -(C ３ -C ６ ) heterocycloalkyl can be a further fused -(C) heterocycloalkyl, where two adjacent carbon atoms are unsubstituted or substituted and unsubstituted or substituted with oxo. ５ -C ６ ) forming a heterocycloalkyl; R Ｃ Ha-(C １ -C ６ ) alkyl. or a pharmaceutically acceptable salt thereof.

2. A is group A1 【Chemistry 3】 and formula (Ia) 【Chemistry 4】 [During the ceremony, R １ is selected from the group consisting of aryl and pyridyl, wherein said aryl and pyridyl are unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and halogen atoms; R ２ Ga-NR ５ C(O)R ６ , -NR ５ R ９ and -NH ２ selected from the group consisting of: R ５ is H or -(C １ -C ６ ) alkyl; R ６ is 1 or more -(C １ -C ６ ) alkyl-substituted -(C ３ -C ９ ) heterocycloalkyl; -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-NH-C(O)O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, —C(O)O—(C １ -C ６ ) alkyl and -(C ３ -C ６ ) cycloalkyl); -(C １ -C ６ ) Alkylene-NH ２ unsubstituted or one or more -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl and -(C ３ -C ６ )cycloalkyl); and unsubstituted or substituted with one or more groups selected from -(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, —O—(C １ -C ６ ) alkyl, —C(O)OH, —C(O)O—(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, -(C ３ -C ６ ) substituted with one or more groups selected from cycloalkyl and halogen atoms; R ８ Ga-NR Ａ R Ｂ ;-SH;-S-(C １ -C ６ ) alkyl (wherein the -(C １ -C ６ ) alkyl is unsubstituted or substituted with one or more —OH; —S—(C １ -C ６ ) alkylene-OH; -S-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo); —S—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; -S(O)=NH-(C １ -C ６ ) alkyl; -S(O) ２ -(C １ -C ６ ) alkyl; —S(O)—(C １ -C ６ ) alkyl; —S—(C １ -C ６ ) alkylene-(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ ) cycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene substituted with one or more groups selected from -OH and -OH); S-(C １ -C ６ ) alkylene-aryl (wherein the aryl is unsubstituted or —C(O)OH, —C(O)O—(C １ -C ６ ) alkylene-NR Ａ R Ｃ and -C(O)O-(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo); —S—(C １ -C ６ ) alkylene-Si((C １ -C ６ )Alkyl) ３ ;-S-(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkylene-OH; -S-(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or oxo and -(C １ -C ６ ) alkyl); １ -C ６ ) alkylene-NH-C(O)-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ )heterocycloalkyl is unsubstituted or substituted with one or more oxo; —S—(C １ -C ６ ) alkylene-NH-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or substituted with one or more oxo; —O—(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) haloalkyl; —O—(C １ -C ６ ) alkylene-OH (wherein the —O—(C １ -C ６ ) alkylene substituted with one or more —OH; —O—(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-NR Ａ R Ｂ ; -O-(C １ -C ６ ) Alkylene-N ＋ R Ａ R Ｂ R Ｃ ; -O-(C １ -C ６ ) alkylene-S-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O)-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O) ２ -(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-NH-S(O) ２ -(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ ) cycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, —C(O)O—(C １ -C ６ ) substituted with one or more groups selected from alkyl and —OH); —O—(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ６ ) cycloalkyl is unsubstituted or -(C １ -C ６ ) alkylene substituted with one or more groups selected from -OH and -OH); -O-(C １ -C ６ ) alkylene-aryl, wherein the aryl is unsubstituted or substituted with one or more —OH; —O—(C １ -C ６ ) alkylene-aryl (wherein the aryl is -(C ５ -C ６ ) heterocycloalkyl, and the -(C ５ -C ６ )heterocycloalkyl is unsubstituted or oxo and -(C １ -C ６ ) alkyl); ３ -C ９ )heterocycloalkyl; and —O—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; R ９ is unsubstituted or —C(O)O—(C １ -C ６ ) alkyl and -(C ３ -C ９ )heteroaryl substituted with one or more groups selected from the group consisting of -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted; R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ is H or is unsubstituted or substituted with one or more groups selected from halogen and —OH—(C １ -C ６ ) alkyl; -S(O) ２ -(C １ -C ６ ) alkyl; -(C １ -C ６ ) alkylene-aryl, wherein the aryl is substituted with —OH; —(C ３ -C ９ ) heterocycloalkyl; -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl; and —(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-O-(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; or R Ａ and R Ｂ together with the nitrogen atom to which they are attached, -(C ３ -C ６ ) heterocycloalkyl (wherein the -(C ３ -C ６ ) heterocycloalkyl is unsubstituted or -C(O)OH, -(C １ -C ６ ) alkylene-OH, —C(O)O—(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; R Ｃ But-(C １ -C ６ ) alkyl.

2. The compound of formula (I) of claim 1, wherein:

3. A compound of formula (Ia) of claim 2 selected from at least one of the following: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-hydroxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfonylpropoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[3-(2-aminoethoxy)-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-(2-methanesulfonamidoethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Methyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}-1-methylpiperazine-2-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-yl]amino}pyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide; Methyl 2-{[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]oxy}acetate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methanesulfinylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methanesulfonylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[imino(methyl)oxo-λ 6-sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; 3-[4-(2-aminoethyl)piperazin-1-yl]-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-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-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxypropyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylamino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; 2-({4-[(2-aminopyridin-4-yl)amino]-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl}oxy)ethan-1-ol; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(1-methylazetidin-3-yl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-[2-({4-[(2-aminopyridin-4-yl)amino]-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl}oxy)ethyl]methanesulfonamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N4-[6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-yl]pyridine-2,4-diamine; N4-[6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N4-[6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-yl]pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[2-(pyrrolidin-1-yl)ethoxy]pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N4-[6-(5-chloro-2-fluorophenyl)-3-[3-(methylsulfanyl)propoxy]pyridazin-4-yl]pyridine-2,4-diamine; N4-[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfonylpropoxy)pyridazin-4-yl]pyridine-2,4-diamine; N4-[6-(5-chloro-2-fluorophenyl)-3-(3-methanesulfinylpropoxy)pyridazin-4-yl]pyridine-2,4-diamine; (3-{[6-(5-chloro-2-fluorophenyl)-4-[(2-cyclopropanamidopyridin-4-yl)amino]pyridazin-3-yl]oxy}propyl)trimethylazanium chloride; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-(piperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-(1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(methylsulfanyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; N-(4-{[6-(3-fluoro-6-methylpyridin-2-yl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N4-[6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-yl]pyridine-2,4-diamine; N4-[6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-yl]pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(1s,3s)-3-hydroxycyclobutyl]methoxy}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(2,3-dihydroxypropoxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-oxo-1,3-dioxolan-4-yl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(1s,3s)-3-(hydroxymethyl)cyclobutoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxyphenyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-{6-methyl-3,6-diazabicyclo[3.2.2]nonan-3-yl}acetamide; Cis-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-1,4-diazepan-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2,3-dihydroxypropyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Cis-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide; Trans-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(thiomorpholin-4-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}cyclobutane-1-carboxamide; Methyl 5-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)amino]-3-(1-methylpiperidin-4-yl)thiophene-2-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(1-hydroxy-2-methylpropan-2-yl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; (1s,3s)-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(1-hydroxy-2-methylpropan-2-yl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(hydroxymethyl)azetidin-1-yl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Trans-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Methyl 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-3-carboxylate; 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-3-carboxylic acid; Propan-2-yl 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-3-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-hydroxyphenyl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-hydroxyphenyl)methyl](methyl)amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(dimethylamino)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{7-oxo-6-oxa-2-azaspiro[3.4]octan-2-yl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(oxolan-3-yl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Methyl 1-[6-(5-chloro-2-fluorophenyl)-4-[(2-{2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamido}pyridin-4-yl)amino]pyridazin-3-yl]azetidine-3-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(oxolan-3-yloxy)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxycyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxycyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxyphenyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxyphenyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxycyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxycyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxy-3-methylcyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-hydroxy-3-methylcyclobutyl)methoxy]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Methyl 3-({[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]oxy}methyl)bicyclo[1.1.1]pentane-1-carboxylate; Cismethyl 3-({[6-(5-chloro-2-fluorophenyl)-4-({2-[-3-(4-methylpiperazin-1-yl)cyclobutanamido]pyridin-4-yl}amino)pyridazin-3-yl]oxy}methyl)bicyclo[1.1.1]pentane-1-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]acetamide; Methyl 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]morpholine-2-carboxylate 4-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]morpholine-2-carboxylate lithium salt; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-((6-(5-chloro-2-fluorophenyl)-3-(methyl((3-methyl-2-oxoxolan-3-yl)methyl)amino)pyridazin-4-yl)amino)pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-((6-(5-chloro-2-fluorophenyl)-3-(methyl((3-methyl-2-oxoxolan-3-yl)methyl)amino)pyridazin-4-yl)amino)pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; Ethyl 3-{[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl](methyl)amino}-2,2-dimethylpropanoate; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[methyl(4,4,4-trifluoro-3-hydroxybutyl)amino]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; Propan-2-yl 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-2-carboxylate; Ammonium 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-2-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({[3-(hydroxymethyl)-2-oxoxolan-3-yl]methyl}(methyl)amino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-hydroxycyclobutyl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-1,4-diazepan-1-yl)cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(propan-2-yl)piperazin-1-yl]cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(propan-2-yl)piperazin-1-yl]cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-ethylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-ethylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-cyclopropylpiperazin-1-yl)cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methoxypiperidin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methoxypiperidin-1-yl)cyclobutane-1-carboxamide; Trans ethyl 1-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]cyclobutyl}piperidine-4-carboxylate; Cisethyl 1-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]cyclobutyl}piperidine-4-carboxylate; Cis 1-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]cyclobutyl}piperidine-4-carboxylic acid; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperidin-1-yl)cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperidin-1-yl)cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl]cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl]cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[3-(2-fluoroethyl)-4-methylpiperazin-1-yl]cyclobutane-1-carboxamide; Trans N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-{5-methyl-5,8-diazaspiro[3.5]nonan-8-yl}cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-{5-methyl-5,8-diazaspiro[3.5]nonan-8-yl}cyclobutane-1-carboxamide; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(3,5-dimethylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-sulfanylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[(4-methylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[(4-cyclopropylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; Propan-2-yl 1-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(3,5-dimethylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]azetidine-2-carboxylate; Cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclopentane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-[(3,5-dimethylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(3-methyl-2-oxoxolan-3-yl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyridin-2-yl)-2-(3,5-dimethylpiperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[2-(2-hydroxyethoxy)ethyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; 3-({[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]sulfanyl}methyl)benzoic acid; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(3-methyl-2-oxoxolan-3-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({[3-(methoxymethyl)-2-oxoxolan-3-yl]methyl}(methyl)amino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({[3-(methoxymethyl)-2-oxoxolan-3-yl]methyl}(methyl)amino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-({[3-(methoxymethyl)-2-oxoxolan-3-yl]methyl}(methyl)amino)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-{[(6-oxooxan-2-yl)methyl]sulfanyl}pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(2-{[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]sulfanyl}ethyl)-5-oxoxolane-3-carboxamide.

4. A is group A2 【Chemistry 5】 and formula (Ib) 【Chemistry 6】 [During the ceremony, X １ is C or CH; R ３ Ga-OR ７ and R ７ But-(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein said —(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted; R ８ Ga-NR Ａ R Ｂ , -O-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) haloalkyl, —O—(C １ -C ６ ) alkylene-OH (wherein the —O—(C １ -C ６ ) alkylene substituted with one or more —OH), —O—(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-NR Ａ R Ｂ , -O-(C １ -C ６ ) Alkylene-N ＋ R Ａ R Ｂ R Ｃ , -O-(C １ -C ６ ) alkylene-S-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-S(O)-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-S(O) ２ -(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-NH-S(O) ２ -(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl and —O—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) substituted with alkyl; R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ is J or -(C １ -C ６ ) alkyl, —S(O) ２ -(C １ -C ６ ) alkyl; R Ｃ But-(C １ -C ６ ) alkyl.

2. The compound of formula (I) of claim 1, wherein:

5. A is A2a 【Chemistry 7】 and formula (Iba) 【Chemistry 8】 [During the ceremony, R ３ Ga-OR ７ and R ７ But-(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein said —(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted; R ８ Ga-NR Ａ R Ｂ , -S-(C １ -C ６ ) alkyl, —S—(C １ -C ６ ) alkylene-OH, -S(O)=NH-(C １ -C ６ ) alkyl, —S(O) ２ -(C １ -C ６ ) alkyl, —S(O)—(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) haloalkyl, —O—(C １ -C ６ ) alkylene-OH (wherein the —O—(C １ -C ６ ) alkylene substituted with one or more —OH), —O—(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-NR Ａ R Ｂ , -O-(C １ -C ６ ) Alkylene-N ＋ R Ａ R Ｂ R Ｃ , -O-(C １ -C ６ ) alkylene-S-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-S(O)-(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-S(O) ２ -(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-NH-S(O) ２ -(C １ -C ６ ) alkyl, —O—(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl and —O—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) substituted with alkyl; R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ is J or -(C １ -C ６ ) alkyl, —S(O) ２ -(C １ -C ６ ) alkyl; R Ｃ But-(C １ -C ６ ) alkyl.

5. The compound of formula (Ib) of claim 4, wherein:

6. The compound of formula (Iba) of claim 2 selected from at least one of the following: 2-{[6-(5-chloro-2-fluorophenyl)-4-({7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl}amino)pyridazin-3-yl]oxy}ethan-1-ol; N-[6-(5-chloro-2-fluorophenyl)-3-(2,2-difluoroethoxy)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-[3-(2-aminoethoxy)-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-(2-{[6-(5-chloro-2-fluorophenyl)-4-({7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl}amino)pyridazin-3-yl]oxy}ethyl)methanesulfonamide; N-[6-(5-chloro-2-fluorophenyl)-3-(2-methoxyethoxy)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-4-yl]-7-methoxyquinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]pyridazin-4-yl]-7-methoxyquinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)-3-methoxypyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine.

7. A is A3 【Chemistry 9】 and formula (Ic) 【Chemistry 10】 [During the ceremony, R １ is selected from the group consisting of aryl and pyridyl, wherein said aryl and pyridyl are unsubstituted or substituted with one or more halogen atoms; X ２ is C, CH or N; R ４ is H or -C(O)O-(C １ -C ６ ) alkyl; R ８ Ga-NR Ａ R Ｂ ;-S-(C １ -C ６ ) alkylene-aryl, wherein the aryl is unsubstituted or —C(O)O—(C １ -C ６ ) alkylene-NR Ａ R Ｃ and -C(O)O-(C １ -C ６ ) alkylene-(C ３ -C ９ )heterocycloalkyl, wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo); —O—(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) haloalkyl; —O—(C １ -C ６ ) alkylene-OH (wherein the —O—(C １ -C ６ ) alkylene substituted with one or more —OH; —O—(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-NR Ａ R Ｂ ; -O-(C １ -C ６ ) Alkylene-N ＋ R Ａ R Ｂ R Ｃ ; -O-(C １ -C ６ ) alkylene-S-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O)-(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-S(O) ２ -(C １ -C ６ ) alkyl; —O—(C １ -C ６ ) alkylene-O-(C １ -C ６ ) alkyl and —O—(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) substituted with alkyl; R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ is J or -(C １ -C ６ ) alkyl, —S(O) ２ -(C １ -C ６ ) alkyl; R Ｃ But-(C １ -C ６ ) alkyl.

2. The compound of formula (I) of claim 1, wherein:

8. The compound of formula (Ic) of claim 7, selected from at least one of the following: Methyl 4-{[6-(5-chloro-2-fluorophenyl)-3-[3-(dimethylamino)propoxy]pyridazin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate; (3-{[6-(5-chloro-2-fluorophenyl)-4-{[2-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}pyridazin-3-yl]oxy}propyl)trimethylazanium chloride; 6-(5-chloro-2-fluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethoxy]-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridazin-4-amine; 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridazin-4-amine; 6-(5-chloro-2-fluorophenyl)-3-[2-(dimethylamino)ethoxy]-N-{1H-pyrazolo[3,4-b]pyridin-4-yl}pyridazin-4-amine; (1-methylpiperidin-4-yl)methyl 3-({[6-(5-chloro-2-fluorophenyl)-4-({1H-pyrrolo[2,3-b]pyridin-4-yl}amino)pyridazin-3-yl]sulfanyl}methyl)benzoate; 2-(Dimethylamino)ethyl 3-({[6-(5-chloro-2-fluorophenyl)-4-({1H-pyrrolo[2,3-b]pyridin-4-yl}amino)pyridazin-3-yl]sulfanyl}methyl)benzoate.

9. A is A4 【Chemistry 11】 and formula (Id) 【Chemistry 12】 [During the ceremony, R １ is aryl that is unsubstituted or substituted with one or more halogen atoms; R １０ Ga-NR ５ C(O)R ６ and R ５ is H; R ６ is 1 or more -(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) alkyl and -(C ３ -C ６ ) cycloalkyl); -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl); and unsubstituted or substituted with one or more -(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl-substituted -(C ３ -C ６ ) cycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) substituted with alkyl; R ８ Ga-NR Ａ R Ｂ ;-S-(C １ -C ６ ) alkyl (wherein the -(C １ -C ６ ) alkyl is unsubstituted or substituted with one or more —OH; —S—(C １ -C ６ ) alkylene-OH (wherein the -(C １ -C ６ ) alkylene is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted); -S-(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or has one or more —(C １ -C ６ ) alkyl substituted); -S(O)=NH-(C １ -C ６ ) alkyl; -S(O) ２ -(C １ -C ６ ) alkyl; —S(O)—(C １ -C ６ ) alkyl; —S—(C １ -C ６ ) alkylene-Si((C １ -C ６ )Alkyl) ３ selected from the group consisting of: R Ａ is H or -(C １ -C ６ ) alkyl; R Ｂ But-(C １ -C ６ ) alkylene-(C ３ -C ９ ) heterocycloalkyl (wherein the -(C ３ -C ９ ) heterocycloalkyl is unsubstituted or -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; or R Ａ and R Ｂ together with the nitrogen atom to which they are bonded - (C ３ -C ６ ) heterocycloalkyl, where —(C ３ -C ６ ) heterocycloalkyl is unsubstituted or -C(O)OH, -(C １ -C ６ ) alkylene-OH, —C(O)O—(C １ -C ６ ) alkyl and oxo or substituted with one or more groups selected from -(C ３ -C ６ ) heterocycloalkyl may be further fused -(C ５ -C ６ ) forms a heterocycloalkyl.

2. The compound of formula (I) of claim 1, wherein:

10. The compound of formula (Id) of claim 9 selected from at least one of the following: Cis N-(6-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)propanamide; Enantiomer 1 N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)propanamide; Enantiomer 2 N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; Cis N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(3,5-dimethylpiperazin-1-yl)propanamide; Cis N-(6-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(4-cyclopropylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-[(2-hydroxyethyl)sulfanyl]pyridazin-4-yl]amino}pyrimidin-4-yl)-3-[(4-methylpiperazin-1-yl)methyl]bicyclo[1.1.1]pentane-1-carboxamide; Trans N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(3,5-dimethylpiperazin-1-yl)cyclobutane-1-carboxamide; Cis N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(3,5-dimethylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{[2-(trimethylsilyl)ethyl]sulfanyl}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(3,5-dimethylpiperazin-1-yl)propanamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-3-(3,5-dimethylpiperazin-1-yl)propanamide; N-(6-{[6-(5-chloro-2-fluorophenyl)-3-{methyl[(3-methyl-2-oxoxolan-3-yl)methyl]amino}pyridazin-4-yl]amino}pyrimidin-4-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carriers or excipients.

12. 12. The pharmaceutical composition of claim 11 for inhaled administration.

13. 13. The pharmaceutical composition of claim 11 or 12 for use in the prevention and / or treatment of a disease, disorder or condition mediated by the ALK5 signaling pathway in a mammal.

14. 13. The pharmaceutical composition of claim 11 or 12 for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

15. 15. The pharmaceutical composition of claim 14 for use in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

16. 16. The pharmaceutical composition of claim 15 for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

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