Pyridazinylamino derivatives as ALK5 inhibitors

Abstract

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

Description

Technical field

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

[0002] Compounds of the invention may be useful, for example, in treating a number of diseases, disorders or conditions associated with the ALK5 signaling pathway. [Background technology]

[0003] Background of the Invention Transforming growth factor beta (TGFβ) is a protein belonging to the TGFβ superfamily.

[0004] It is involved in several processes, both cellular processes such as proliferation, migration and differentiation, and biological processes including wound healing, immunosuppression, carcinogenesis and extracellular matrix production.

[0005] The TGFβ superfamily also contains, among other members, another member known as activin (Act) (see eg Hinck AP, FEBS Letters 586 (2012); 1860-1870).

[0006] Peptide binding 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). .

[0007] TGFβR1 / ALK5 is recruited and activated by phosphorylation of its intracellular domain by TGFβR2, which in turn phosphorylates the activating receptor (R)-Smad family, leading to activation of target gene transcription ( See, e.g., Sheppard D., Proc Am Thorac Soc. (2006);(3):413-417).

[0008] Similar to TGFβ signaling, the activin type I receptor, ALK4, activates target gene transcription (see, e.g., Heldin CH et al., Cold Spring Harb Perspect Biol. (2016) Aug 1;8(8)). .

[0009] Several studies have linked TGFβ hyperactivity and / or dysregulation to many diseases, including cancer and fibrosis (eg 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, an important role of TGFβ has been demonstrated in organs such as lung, heart, liver and kidney (see, e.g., Alhamad EH, J Thorac Dis. (2015);7(3):386-93). ). In particular, TGFβ expression is increased in fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic inflammatory conditions such as chronic obstructive pulmonary disease and asthma (e.g. Thomas BJ et al., Am J Respir Cell Mol Biol (2016); (55):759-766).

[0010] In the lung, TGFβ is expressed on several cell types including epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts.

[0011] These cell populations can produce excess TGFβ in IPF human lung tissue. In addition, high levels of TGFβ have been detected in lung tissue and BAL of IPF patients (see, eg, Bergeron A et al., Eur Respir J (2003);22:69-76).

[0012] TGFβ gene expression and TGFβ protein production have been observed to increase in various animal models of bleomycin, silica, asbestos and radiation-induced pulmonary fibrosis (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); It has been reported that TGFβ expression is sufficient to induce progressive fibrosis in rodents (eg Sime PJ et al., J Clin Invest (1997); 100:768-776; Kim KK et al. .reference).

[0013] Conversely, inhibition of TGFβ signaling obtained by using knockout (KO) animals can inhibit fibrosis progression through TGFβ-associated mechanisms (eg Bonniaud P et al., Am J Respir Crit Care Med (2005); 171:889-898; 34).

[0014] Similar results have been achieved with TGFβR1 inhibition in a mouse bleomycin disease model (see, eg, Wei Y et al., J Clin Invest. (2017); 127(10): 3675-3688).

[0015] Activin signaling dysregulation, analogous to TGFβ, is associated with fibroblast proliferation, myofibroblast differentiation and extracellular matrix (ECM) accumulation (e.g. Yamashita et al., J. Am. Soc. Nephrol. 2004) 15, 91-101). Furthermore, overexpression of activin is associated with liver (see, for example, Patella et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2006) 290, G137-G144), kidney (see, for example, 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). associated with pathology and fibrosis development in various organs such as

[0016] Taken together, these data suggest the importance of targeting ALK5 for pharmacologically treating the above diseases associated with dysregulated TGF signaling pathways.

[0017] TGFβ signaling is strongly associated with cardiovascular homeostasis (see, eg, van Meeteren LA et al., Springer (2013)). Several studies in humans and mice have shown a major role for TGFβ in angiogenesis and vascular morphogenesis. In addition, TGFβ has an important role in heart valve development and functionality. Therefore, the importance of selectively regulating the TGFβ pathway to target pathological effects while avoiding suppression of signaling required for correct homeostasis is evident.

[0018] An answer to this critical point may be addressed through the use of inhaled routes to deliver anti-TGFβ drugs.

[0019] The inhalation route allows treatment of diseased lung compartments while bypassing cardiac exposure concerns.

[0020] Various compounds have been described in the literature as ALK5 and / or ALK4 receptor inhibitors.

[0021] WO2008 / 006583, WO2009 / 087212, WO2009 / 087224, WO2009 / 087225, WO2009 / 133070, WO2009 / 013335 and WO2009 / 050183 (Novartis) each describe inflammatory or obstructive airway disease, pulmonary hypertension and pulmonary fibrosis. Disclosed are pyrimidines, pyridines, imidazopyridines, pyrrolopyrimidines and pyrrolopyridine, imidazopyridazines, imidazopyridine derivatives useful for the treatment of ALK4 or ALK5 mediated diseases.

[0022] WO00 / 61576 and US2003 / 0149277 (Smithkline Beecham Corp) address renal disease, wound healing, kidney disease, congestive heart failure, ulcers, neurological dysfunction and fibrosis as major factors, among others. Disclosed are triarylimidazole derivatives as ALK5 inhibitors useful for the treatment of any disease.

[0023] WO01 / 62756 (Smithkline Beecham P.L.C.), inter alia, for all diseases in which renal disease, wound healing, kidney disease, congestive heart failure, ulcers, neurological dysfunction and fibrosis are major components. Disclosed are pyridinylimidazole derivatives as ALK5 inhibitors useful in treatment.

[0024] WO03 / 087304 (Biogen Inc.) treats inter alia idiopathic pulmonary fibrosis, diabetic nephropathy, liver fibrosis, pulmonary fibrosis, acute lung injury, post-infarct cardiac fibrosis, fibrous carcinoma and fibroma Disclosed are trisubstituted heteroaryls as ALK5 and / or ALK4 inhibitors useful for

[0025] WO2013 / 009140 (SK Chemicals Co) discloses 2-pyridyl substituted imidazole derivatives as ALK5 and / or ALK4 receptor inhibitors useful inter alia for the treatment of renal, hepatic or pulmonary fibrosis.

[0026] Pyridazinylamino derivatives have been disclosed in the literature, but not as ALK5 inhibitors.

[0027] WO2005 / 033105 (Amgen) discloses, among other compounds, pyridazinylamino derivatives as vanilloid receptor ligands for the treatment of numerous diseases and disorders, not including fibrosis.

[0028] WO2002 / 022605 and WO2002 / 022602 (Vertex) disclose pyridazine compounds as protein kinase inhibitors useful in the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia, among others.

[0029] WO02 / 24681 (Ortho-McNeil Pharmaceutical Inc.) discloses pyridazine compounds as tyrosine kinase inhibitors useful as antitumor agents and for the treatment of diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.

[0030] Of note, inhibition of the ALK5 receptor may be useful in treating fibrosis and diseases, disorders and conditions resulting from fibrosis.

[0031] Several efforts have been made in the last 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. [Outline of the Invention] [Problems to be solved by the invention]

[0032] However, there remains the potential to develop receptor ALK5 inhibitors characterized by good potency that are useful for the treatment of diseases or conditions associated with dysregulation of the ALK5 signaling pathway, particularly fibrosis.

[0033] In particular, administered by the inhalation route and characterized by good pulmonary activity, good pulmonary retention and a good inhalation profile corresponding to low metabolic stability to minimize systemic exposure and associated safety issues, There remains the potential to develop inhibitors of the receptor ALK5 useful for the treatment of diseases or conditions associated with dysregulation of ALK5 signaling in the respiratory field, particularly idiopathic pulmonary fibrosis (IPF).

[0034] In this direction, potent inhibition of the ALK5 receptor for administration by inhalation, showing at the same time a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability and good selectivity over kynomes. We have surprisingly discovered a novel series of compounds of general formula (I) which solves the problem of providing agents. [Means for solving the problem]

[0035] SUMMARY OF THE INVENTION In a first aspect, the invention provides a compound of formula (I) [formation] [In the formula, R. 1 is optionally a halogen atom, -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) aryl substituted with one or more groups selected from haloalkyl; A is A1, A2 and A3 [formation] is selected from the group consisting of; R. 2 Ha-NR 5 C(O)R 6 and -NR 5 R. 6 is selected from the group consisting of; X 1 is C, CH or N; R. 3 is -C(O)NR 5 R. 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , -NR 5 C(O)R 7 and -OC(O)NR 5 R. 7 is selected from the group consisting of; R. 3’ is H or -(C 1 -C 6 )alkoxy, -OH, -C(O)O-(C 1 -C 6 )alkyl and -C(O)NH-heterocycloalkyl, wherein said heterocycloalkyl is a single -(C 1 -C 6 ) substituted with alkyl; R. 4 is -C(O)NR 5 R. 7 and -C(O)heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 6 is-(C 1 -C 6 )alkylene-NR A R. B ;-NH-(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); optionally -(C 1 -C 6 )alkylene-NR A R. C and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); heteroaryl substituted with one or more groups selected from; 1 -C 6 )alkylene-NR C -(C 1 -C 6 )alkylene-NR A R. C ;-(C 1 -C 6 )alkylene-NR A -C(O)O-(C 1 -C 6 )alkyl; optionally heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 )alkyl substituted with); optionally one or more -(C 1 -C 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-N-oxide-heterocycloalkyl; and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -OH, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 )alkylene-C(O)O-R C , -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 ) alkylene-SO 2 -(C1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo); R. 7 teeth: - (C 1 -C 6 )alkylene-NR A R. B ; - In some cases -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 ) alkylene-heterocycloalkyl substituted with one or more groups, wherein each of said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); - -(C 1 -C 6 )alkylene-C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); and - -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1 -C 6 )alkylene-NR C -Both (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl) selected from; R. A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, cycloalkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl, -cycloalkyl-C(O)O-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) haloalkyl. ] and pharmaceutically acceptable salts thereof.

[0036] In a second aspect, the invention relates to pharmaceutical compositions comprising a compound of formula (I) and pharmaceutically acceptable salts thereof admixed with one or more pharmaceutically acceptable carriers or excipients.

[0037] In a third aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt or a medicament comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof for use as a medicament Regarding the composition.

[0038] In a further aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of diseases, disorders or conditions mediated by the ALK5 receptor in mammals. or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof.

[0039] In a further aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis. or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof.

[0040] In a further aspect, the invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof or a compound of formula (I) for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF). and pharmaceutically acceptable salts thereof. [Mode for carrying out the invention]

[0041] 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 pharmaceutically acceptable salts or solvates thereof.

[0042] As used herein, the term "pharmaceutically acceptable salt" means that, if the parent compound is present, either the free acid or the basic group is any salt that is conventionally intended to be pharmaceutically acceptable. Refers to derivatives of the compounds of formula (I) which are appropriately modified by converting them into the corresponding addition salts with bases or acids.

[0043] Suitable examples of such salts may thus include inorganic or organic acid addition salts of basic residues such as amino groups and inorganic or organic basic addition salts of acid residues such as carboxylic acid groups.

[0044] Cations of inorganic bases which may be suitably used in preparing salts include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0045] Those obtained by reaction of the principal compounds functioning as bases with inorganic or organic acids to form salts, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, camphorsulphonic acid, acetic acid , oxalic, maleic, fumaric, succinic and citric acid salts.

[0046] The term "solvate" means a physical association of a compound of the invention with one or more organic or inorganic solvent molecules. This physical association involves hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent molecules.

[0047] The term "stereoisomer" refers to isomers of the same structure that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0048] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0049] The term "diastereomer" refers to stereoisomers that are not mirror images.

[0050] The terms "racemate" or "racemic mixture" refer to a composition that consists of equimolar amounts of two enantiomeric species and lacks optical activity.

[0051] The symbols "R" and "S" represent the placement of substituents around the chiral carbon atom. The isomeric descriptors 'R' and 'S' are used herein as descriptors to denote the atomic arrangement relative to the core molecule and are described in the literature ((IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996) ) is intended to be used as defined in

[0052] The term "tautomer" refers to each of two or more isomers of a compound that exist in equilibrium with each other and are readily exchanged for one another by movement of atoms or groups within the molecule.

[0053] The term "halogen" or "halogen atom" or "halo" as used herein includes fluorine, chlorine, bromine and iodine atoms.

[0054] The term "(C x -C y )alkyl" (where x and y are integers) refers to a straight or branched chain alkyl group having x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the terms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n - contains hexyl.

[0055] The term "(C x -C y )Alkoxy" (where x and y are integers) refers to a straight or branched chain hydrocarbon attached to the remainder of the molecule through an oxygen bridge, with the indicated number of carbons.

[0056] The term "(C x -C y ) alkylene” (where x and y are integers) is a C x -C y Refers to an alkyl group.

[0057] The expression "(C x -C y )haloalkyl” (where x and y are integers) is defined above as “C x -C y Refers to an "alkyl" group.

[0058] Therefore, the "(C x -C y Examples of )haloalkyl" groups can include halogenated, polyhalogenated and fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl.

[0059] 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.

[0060] 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, eg, phenyl.

[0061] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N and O and two such heteroaryl groups fused through a common bond. Includes groups having monocyclic rings or having one such monocyclic ring and one monocyclic aryl ring.

[0062] The term "(C x -C y )heterocycloalkyl" (wherein x and y are integers) has at least one ring carbon atom replaced by at least one heteroatom (e.g. N, S or O) or -oxo( =O) substituents which may be saturated or partially unsaturated monocyclic or bicyclic (C x -C y ) refers to a cycloalkyl group. The heterocycloalkyl may be further optionally substituted at any available ring position, ie, a carbon or heteroatom available for substitution. Substitution can be on a carbon atom, including spiro-disubstitution, in which two heterocyclic rings or a heterocycloalkyl and a cycloalkyl ring are joined through a single carbon atom to form a bicyclic ring system. Substitutions can also be on two adjacent carbon atoms to form a fused 5-6 membered heterocycloalkyl ring. Additionally, the heterocycloalkyl can be a diazabicyclo ring.

[0063] The term "-(C x -C y )alkylene-heterocycloalkyl" means -(C x -C y ) refers to a heterocycloalkyl ring attached to an alkylene group.

[0064] The term "N-oxide-heterocycloalkyl" refers to a heterocycloalkyl containing one nitrogen atom with an oxygen atom as a substituent.

[0065] Throughout this specification, the use of an asterisk "*" in structural formulas indicates the point of attachment of the radical group to the rest of the molecule.

[0066] A dash (“-”) that is not between two letters or symbols is intended to represent a point of attachment for a substituent.

[0067] A carbonyl group is preferably represented herein as -C(O)- as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0068] In general, bracketed groups are side groups not included in the chain, and to help disambiguate linear chemical formulas, brackets are used when considered useful; for example, the sulfonyl group -SO 2 - is, for example, -S(O) to disambiguate with the sulphine group -S(O)O- 2 Also represented as -.

[0069] The present invention relates to novel compounds that differ in structure from those disclosed in the literature, at least for common novel core scaffolds. Indeed, the present invention provides compounds that are [pyridazin-4-yl]amino derivatives that are inhibitors of the receptor ALK5, which have therapeutically desirable characteristics and are particularly promising for certain fibrosis diseases, including idiopathic pulmonary fibrosis (IPF). Regarding.

[0070] The compounds of the present invention are active as inhibitors of the ALK5 receptor, are potent, and exhibit properties such as good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability and good selectivity across kynomes. exhibit improved properties.

[0071] In this regard, the common general knowledge does not describe or suggest the pyridazinylamino derivative of general formula (I) of the present invention having receptor ALK5 inhibitory activity that solves the above needs.

[0072] Amgen describes, 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 describes the compounds as vanilloid receptor ligands for the treatment of numerous diseases and disorders. Amgen does not disclose the compound as an ALK5 inhibitor nor for the treatment of fibrosis.

[0073] Vertex describes, inter alia, pyridazine derivatives. The compounds of formula (I) of the present invention differ from those of Vertex at least in the presence of a pyridyl or pyridyl fused group attached to the amino linker carrying the pyridazine ring rather than a triazole group. Vertex compounds have been described as protein kinase inhibitors useful in the treatment of cancer, diabetes, Alzheimer's disease and schizophrenia. Vertex does not list the compound as an ALK5 inhibitor or for treating fibrosis.

[0074] Ortho-McNeil describes pyridazine compounds. The compounds of formula (I) of the present invention differ from those of Ortho-McNeil in the positions of at least two nitrogen atoms in the pyridazine ring. Ortho-McNeil compounds are described as anti-tumor agents and as tyrosine kinase inhibitors useful in the treatment of diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis. Ortho-McNeil does not disclose compounds as ALK5 inhibitors or for treating fibrosis.

[0075] More particularly, the present invention relates to a series of compounds represented by general formula (I), further detailed below, which have inhibitory activity at the receptor ALK5 receptor.

[0076] Advantageously, an inhibitory effect on the receptor ALK5 may be effective in treating diseases in which these receptors have a substantial role in the etiology, such as fibrosis and diseases, disorders and conditions from fibrosis.

[0077] Unlike the analogous compounds of the prior art, the compounds of formula (I) of the present invention are appreciated by those skilled in the art when searching for suitable and effective compounds useful in the treatment of fibrosis, especially idiopathic pulmonary fibrosis. can act as an antagonist of the ALK5 receptor.

[0078] As shown in the experimental part, particularly Table 4, the compounds of formula (I) of the present invention exhibit remarkable potency, less than about 10 nM, in terms of inhibitory activity against the receptor ALK5 and are involved in fibrosis and fibrosis-induced diseases. It is confirmed that it can inhibit the ALK5 receptor that

[0079] In contrast to compounds C1 and C2 which are characterized by no pyridinyl or pyridinyl condensing group attached to the amino group bearing the pyridazine ring, as shown in the experimental part, comparative examples, especially Table 4, the pyridazine in the compounds of the invention The presence of a pyridinyl or pyridinyl fused group attached to the ring-bearing amino group is shown to unexpectedly and significantly determine the associated increase in inhibitory activity against the ALK5 receptor.

[0080] Furthermore, as also shown in Table 4, NH on the pyridine ring 2 The presence of certain substituents on the pyridine ring described herein unexpectedly and exceptionally favors the ALK5 receptor, contrary to compound C3, which is characterized by a group and falls within the scope of Amgen's general formula. It is shown to determine the associated increase in inhibitory activity.

[0081] Advantageously, the compounds of the present invention have significantly higher potency and can be administered to humans at lower doses than prior art compounds, reducing adverse events typically associated with administration of high doses of drugs.

[0082] In addition to its particularly potent inhibitory activity against the receptor ALK5, the compounds of the invention allow efficient action in the lung compartment while at the same time presenting drawbacks associated with systemic exposure such as safety and tolerability issues. It is also characterized by a good inhalation profile with low metabolic stability that allows minimization of .

[0083] Therefore, the compounds of the present invention are particularly suitable for administration by the inhalation route, with good pulmonary activity, good pulmonary retention and good inhalational stability corresponding to low metabolic stability which minimizes systemic exposure and associated safety issues. It is appreciated by those skilled in the art when searching for suitable and effective compounds useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, characterized by profile.

[0084] Thus, in one aspect, the present invention provides a compound of general formula (I) [formation] [In the formula, R. 1 is optionally a halogen atom, -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) aryl substituted with one or more groups selected from haloalkyl; A is A1, A2 and A3 [formation] is selected from the group consisting of; R. 2 Ha-NR 5 C(O)R 6 and -NR 5 R. 6 is selected from the group consisting of; X 1 is C, CH or N; R. 3 is -C(O)NR 5 R. 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , -NR 5 C(O)R 7 and -OC(O)NR 5 R. 7 is selected from the group consisting of; R. 3’ is H or -(C 1 -C 6 )alkoxy, -OH, -C(O)O-(C 1 -C 6 )alkyl and -C(O)NH-heterocycloalkyl, wherein said heterocycloalkyl is a single -(C 1 -C 6 ) substituted with alkyl; R. 4 is -C(O)NR 5 R. 7 and -C(O)heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 6 is-(C 1 -C 6 )alkylene-NR A R. B ;-NH-(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); optionally -(C 1 -C 6 )alkylene-NR A R. C and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); heteroaryl substituted with one or more groups selected from; 1 -C 6 )alkylene-NR C -(C 1 -C 6 )alkylene-NR A R. C ;-(C 1 -C 6 )alkylene-NR A -C(O)O-(C 1 -C 6 )alkyl; optionally heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 )alkyl substituted with); optionally one or more -(C 1 -C 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-N-oxide-heterocycloalkyl; and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -OH, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 )alkylene-C(O)O-R C , -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo); R. 7 teeth - (C 1 -C 6 )alkylene-NR A R. B ; - In some cases -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 ) alkylene-heterocycloalkyl substituted with one or more groups, wherein each of said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); - -(C 1 -C 6 )alkylene-C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); and - -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1 -C 6 )alkylene-NR C -Both (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl) is selected from the group consisting of; R. A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, cycloalkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl, -cycloalkyl-C(O)O-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) haloalkyl. ] and pharmaceutically acceptable salts thereof.

[0085] In another aspect, the present invention provides a [formation] [In the formula, R. 1 is aryl optionally substituted with one or more halogen atoms; A is A1, A2 and A3 [formation] is selected from the group consisting of; R. 2 Ha-NR 5 C(O)R 6 and -NR 5 R. 6 is selected from the group consisting of; X 1 is C, CH or N; R. 3 is -C(O)NR 5 R. 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , -NR 5 C(O)R 7 and -OC(O)NR 5 R. 7 is selected from the group consisting of; R. 4 is -C(O)NR 5 R. 7 and -C(O)heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 6 is-(C 1- C. 6 )alkylene-NR A R. B , cycloalkyl, one or more -(C 1- C. 6 )alkyl substituted heterocycloalkyl and -(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1- C. 6 ) alkyl, -SO 2 -(C 1- C. 6 ) substituted with one or more groups selected from alkyl and oxo); R. 7 teeth - (C 1- C. 6 )alkylene-NR A R. B , - 1 or more -(C 1- C. 6 ) heterocycloalkyl substituted with alkyl, - -(C 1- C. 6 )alkylene-C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl) and - -(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl and -C(O)-(C 1- C. 6 ) substituted with one or more groups selected from alkyl) is selected from the group consisting of; R. A is-(C 1- C. 6 ) is an alkyl; R. B is heterocycloalkyl; R. 8 is H or -(C 1 -C 6 ) alkyl. ] and pharmaceutically acceptable salts thereof.

[0086] In a more preferred embodiment, the invention relates to compounds of formula (I), wherein R 1 is phenyl substituted with one or more groups selected from phenyl.

[0087] In another preferred embodiment, R 5 is H or -CH 3 is.

[0088] In a particularly preferred embodiment, the present invention provides a compound of formula (Ia) [formation] where A is A1 [formation] A compound of formula (I) which is R. 1 is optionally a halogen atom, -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) aryl substituted with one or more groups selected from haloalkyl; R. 2 is-NR 5 C(O)R 6 and -NR 5 R. 6 is selected from the group consisting of; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 6 is-(C 1 -C 6 )alkylene-NR A R. B ;-NH-(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) alkyl), optionally -(C 1 -C 6 )alkylene-NR A R. C and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); heteroaryl substituted with one or more groups selected from; 1 -C 6 )alkylene-NR C -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-NR A -C(O)O-(C 1 -C 6 )alkyl; optionally heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 )alkyl substituted with); optionally one or more -(C 1 -C 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-N-oxide-heterocycloalkyl; and -(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -OH, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1- C. 6 ) alkyl, -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 )alkylene-C(O)O-R C , -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo); R. A is-(C 1- C. 6 ) is an alkyl; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, cycloalkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl, -cycloalkyl-C(O)O-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of haloalkyl; It relates to compounds and their pharmaceutically acceptable salts.

[0089] In an even more preferred embodiment, the present invention provides a compound of formula (Iaa) [formation] A represented by A1a [formation] A compound of formula (I) which is R. 1 is optionally a halogen atom, -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) aryl substituted with one or more groups selected from haloalkyl; R. 2 is-NR 5 C(O)R 6 and -NR 5 R. 6 is selected from the group consisting of; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 6 is-(C 1 -C 6 )alkylene-NR A R. B ;-NH-(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); optionally -(C 1 -C 6 )alkylene-NR A R. C and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); heteroaryl substituted with one or more groups selected from; 1 -C 6 )alkylene-NR C -(C 1 -C 6 )alkylene-NR A R. C ;-(C 1 -C 6 )alkylene-NR A -C(O)O-(C 1 -C 6 )alkyl; optionally heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 )alkyl substituted with); optionally one or more -(C 1 -C 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-N-oxide-heterocycloalkyl; and -(C 1- C. 6) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -OH, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1- C. 6 ) alkyl, -C(O)OH, -C(O)O-(C 1 -C 6 ) alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 )alkylene-C(O)O-R C , -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo); R. A is-(C 1- C. 6 ) is an alkyl; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, cycloalkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl, -cycloalkyl-C(O)O-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of haloalkyl; It relates to compounds and their pharmaceutically acceptable salts.

[0090] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iaa) listed in Table 1 below and pharmaceutically acceptable salts thereof.

[0091] [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]

[0092] In an even more preferred embodiment, the invention is a compound of formula (Iaa), wherein R 2 is -NHC(O)R 6 is; R 6is cyclopropyl, 1-ethylpiperazine, 4-ethylmorpholine, 1-ethyl-4-methylpiperazine, (4-acetylpiperazin-1-yl)ethyl, 4-propylmorpholine, -(3-methyl-1,3- diazinan-1-yl)ethyl, -(3-methanesulfonyl-1,3-diazinan-1-yl)ethyl, 4-methylmorpholine, N-ethyl-N-methyloxetan-3-amine, 1-methylpiperidine, -1-ethyl-(4-methyl-2-oxopiperazin-1-yl), -4-ethyl-(1-methyl-2-oxopiperazin-1-yl), -(4-methanesulfonylpiperazine-1- yl)ethyl, -(3-acetyl-1,3-diazinan-1-yl)ethyl, -(3-methanesulfonyl-1,3-diazinan-1-yl)ethyl, -[4-(2,2, 2-Trifluoroethyl)piperazin-1-yl]ethyl, -[3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]ethyl, -1-propyl-4-methyl Piperazine, -[4-(2-aminoethyl)piperazin-1-yl]ethyl, -[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]ethyl, -[4-(2-hydroxyethyl) piperazin-1-yl]ethyl, methyl(2-(4-ethylpiperazin-1-yl)ethyl)carbamate, -[4-(2-methanesulfonylethyl)piperazin-1-yl]ethyl, -[4-( 2-Cyanoethyl)piperazin-1-yl]ethyl, 4-methylpiperazine, methyl 4-ethyl-piperazine-2-carboxylate, 4-ethyl-piperazine-2-carboxylic acid, -[2-(methylamino)ethyl] amino-ethyl, methyl 4-ethyl-1-methylpiperazine-2-carboxylate, 4-ethyl-1-methylpiperazine-2-carboxylic acid, methyl 2-(4-methylpiperazin-1-yl)acetate, methyl 2 -(4-ethylpiperazin-2-yl)acetate, methyl 2-(4-ethyl-1-methylpiperazin-2-yl)acetate, methyl 1-ethyl-4-methylpiperazine-2-carboxylate, methyl 2- (1-ethyl-4-methylpiperazin-2-yl)acetate, methyl 2-(1-ethyl-piperazin-2-yl)acetate, -4-[2-(methylamino)ethyl]piperazin-1-yl- Ethyl, methyl(2-(4-ethylpiperazin-1-yl)ethyl)-N-methylcarbamate, -4-[2-(methylamino)ethyl]piperazin-1-yl-methyl, methyl(2-(4 -methylpiperazin-1-yl)ethyl)-N-methylcarbamate, -[4-(2-aminoethyl)piperazin-1-yl]methyl, methyl(2-(4-methylpiperazin-1-yl)ethyl) carbamate, -4-ethyl-1,1-dimethylpiperazin-1-ium, -[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-ethyl, methyl 1 -isopropyl-4-ethylpiperazine-2-carboxylate, 4-ethylthiomorpholine, -(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-ethyl, ethyl-4-ethyl-1 -methylpiperazine-2-carboxylate, 4-methylmorpholine 4-oxide, propan-2-yl 4-ethyl-1-methylpiperazine-2-carboxylate, cyclopropyl 4-ethyl-1-methylpiperazine-2-carboxylate Lato, Oxetan-3-yl 4-ethyl-1-methylpiperazine-2-carboxylate, -(1-oxo-thiomorpholin-4-yl)ethyl, -[4-(2,2,2-trifluoroethyl )piperazin-1-yl]methyl, -(1,1-dioxo-thiomorpholin-4-yl)ethyl, -(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)ethyl, -[ 4-(2-methanesulfonamidoethyl)piperazin-1-yl]ethyl, -{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}ethyl, -(4,4-difluoropiperidine-1 -yl)ethyl, -(4-hydroxypiperidin-1-yl)ethyl, -2-(4-methylpiperazin-1-yl)ethan-1-amine, -(1-methylpiperidin-4-yl)methanamine, -{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}methyl, -(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)methyl, -(3,4- dimethylpiperazin-1-yl)ethyl, -{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}ethyl, -{2-methyl-5-oxa-2,8-diazaspiro[3.5 ]nonan-8-yl}ethyl, -2-methyl-2,7-diazaspiro[3.5]nonane, -2-methyl-2,8-diazaspiro[4.5]decane, -2-(1,4-diazepane-1 -yl)methyl, -{1-[2-(methylamino)ethyl]-1H-pyrazole}, -{1-[2-(dimethylamino)ethyl]-1H-pyrazole}-(1-methylpiperidine-4 -yl)methyl, -1-propyl-1,4-diazepane, -1-methyl-4-propyl-1,4-diazepane, -[2-(hydroxymethyl)-4-methylpiperazin-1-yl]ethyl , -(4-methylpiperazin-1-yl)cyclobutyl, -2-(piperazin-1-yl)methyl, -1-methyl-4-methyl-1,4-diazepane, -[3-(hydroxymethyl)- 4-methylpiperazin-1-yl]ethyl and -1-methyl-4-methylpiperazine.

[0093] In a further preferred embodiment, the invention is a compound of formula (Iaa), wherein R 2 is-NR 5 R. 6 is; R 6 is selected from the group consisting of -4-(1-methylpiperazine)propyl and -[(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl.

[0094] In an equally preferred embodiment, the present invention provides a compound of formula (Ib) [formation] where A is A2 [formation] A compound of formula (I) which is R. 1 is optionally a halogen atom and -(C 1 -C 6 ) aryl substituted with one or more groups selected from alkyl; X 1 is C, CH or N; R. 3 is-C(O)NR 5 R. 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , -NR 5 C(O)R 7 and -OC(O)NR 5 R. 7 is selected from the group consisting of; R. 3’ is H or -(C 1 -C 6 )alkoxy, -OH, -C(O)O-(C 1 -C 6 )alkyl and -C(O)NH-heterocycloalkyl, wherein said heterocycloalkyl is a single -(C 1 -C 6 ) substituted with alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 7 but - (C 1- C. 6 )alkylene-NR A R. B ; - In some cases -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 ) alkylene-heterocycloalkyl substituted with one or more groups, wherein each of said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); - -(C 1 -C 6 )alkylene-C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); and - -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1 -C 6 )alkylene-NR C Common (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl) is selected from the group consisting of; R. A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-OH and -(C 1 -C 6 ) selected from the group consisting of haloalkyl; It relates to compounds and their pharmaceutically acceptable salts.

[0095] In a more preferred embodiment, the invention relates to compounds of formula (Ib), wherein R 3 is -C(O)OR 7 is; R 3’ is H;R 7 is 4-ethylmorpholine; R 8 is H or -(C 1 -C 6 ) for those that are alkyl.

[0096] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ib) listed in Table 2 below and pharmaceutically acceptable salts thereof.

[0097] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0098] In a particularly preferred embodiment, the present invention provides a compound of formula (Iba) [formation] where A is A2a [formation] A compound of formula (Ib) which is R. 1 is optionally a halogen atom and -(C 1 -C 6 ) aryl substituted with one or more groups selected from alkyl; R. 3 is-C(O)NR 5 R. 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , -NR 5 C(O)R 7 and -OC(O)NR 5 R. 7 is selected from the group consisting of; R. 3’ is H or -(C 1 -C 6 )alkoxy, -OH and -C(O)O-(C 1 -C 6 ) selected from the group consisting of alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 7 but - (C 1 -C 6 )alkylene-NR A R. B , - In some cases -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 ) alkylene-heterocycloalkyl substituted with one or more groups, wherein each of said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); - -(C 1 -C 6 )alkylene-C(O)-heterocycloalkyl, wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl) and - -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1- C. 6 )alkyl-(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -C(O)-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1- C. 6 )alkylene-NR C Common (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6) alkylene-NHSO 2 -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl) is selected from the group consisting of; R. A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. B is heterocycloalkyl; R. c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) selected from the group consisting of alkylene-OH; R. 8 is H or -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-OH and -(C 1 -C 6 ) selected from the group consisting of haloalkyl; It relates to compounds and their pharmaceutically acceptable salts.

[0099] In a more preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 is -NHC(O)R 7 and R 3’ is H and R 7 is 1-ethyl-4-methylpiperazine.

[0100] In a particularly preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 1 is aryl optionally substituted with one or more halogen atoms; R 3 is-C(O)NHR 7 is; R 3’ is H;R 7 is-(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); R 8 is H or -(C 1 -C 6 ) alkyl; and a pharmaceutically acceptable salt thereof.

[0101] In a more preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 is-C(O)NHR 7 is; R 3’ is H;R 7 is selected from the group consisting of 4-ethylmorpholine, 4-ethylpiperazine, 1-ethyl-4-methylpiperazine and 1-ethyl-4-methylpiperidine;R 8 is H or -(C 1 -C 6 ) alkyl.

[0102] In a more preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 is -C(O)OR 7 is; R 3’ is H;R 7 is selected from the group consisting of 4-ethylmorpholine, N-methylpiperidine and N-methylpyrrolidine;R 8 is H or -(C 1 -C 6 ) alkyl.

[0103] In a further preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 is -OC(O)R 7 is; R 3’ is H;R 7 is sometimes -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2- (C 1- C. 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl and -(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein each of said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl) is heterocycloalkyl substituted with one or more groups from ); A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-OH; R B is heterocycloalkyl; R c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-OH; R 8 is H or -(C 1 -C 6 ) alkyl.

[0104] In a more preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 is -OC(O)R 7 is; R 3’ is H;R 7 is -4-methylpiperazine, -N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl, -N-methyl-N-[2-(1-methylpiperidin-4-yl)ethyl ], -4-(2-methanesulfonylethyl)piperazine, -4-(2-hydroxyethyl)piperazine, -4-[2-(dimethylamino)ethyl]piperazine, -4-[2-(1-methylpiperidine) -4-yl)ethyl]piperazine, -4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine, -4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine, - 4-[(1-methylpiperidin-4-yl)methyl]piperazine, -4-(1-methylpiperidin-4-yl)piperazine, -2,8-diazaspiro[4.5]decane, -2-methyl-2, 7-diazaspiro[3.5]nonane, -7-methyl-2,7-diazaspiro[3.5]nonane, -8-methyl-2,8-diazaspiro[4.5]decane, -2-methyl-2,6-diazaspiro[3.4 ] octane, -(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane, -5-methyl-2,5-diazabicyclo[2.2.1]heptane, -3-(pyrrolidine-1 -yl)azetidine, -4-(azetidin-1-yl)piperidine, -(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane and -3-oxetan-3-yl-4- [2-(1-methylpiperidin-4-yl)ethyl]piperazine-3-carboxylate; R 8 is H or -(C 1 -C 6 ) alkyl.

[0105] In a further preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 GA-OR 7 is; R 3’ is H or -(C 1 -C 6 )alkoxy, -OH and -C(O)O-(C 1 -C 6 ) alkyl; R 7 is-(C 1 -C 6 )alkylene-NR A R. B ; optionally 1 or more -(C 1 -C 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONRA R. C , -(C 1 -C 6 )alkylene-NR C Common (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl and -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl) -NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1 -C 6 )alkylene-NR C Common (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl and -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl); R A is-(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-OH; R B is heterocycloalkyl; R c is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-OH; R 8 is H or -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-OH.

[0106] In a more preferred embodiment, the invention relates to compounds of formula (Iba), wherein R 3 GA-OR 7 is; R 3’ is H or -OCH 3 , -OH and -C(O)O-CH 3 is selected from the group consisting of; R 7 is -2-(morpholin-4-yl)ethyl, -2-(piperazin-1-yl)ethyl, -2-(4-methylpiperazin-1-yl)ethyl, 2-(1-methylpiperidine-4- yl)ethyl, -3-(4-methylpiperazin-1-yl)propyl, -2-(4-ethylpiperazin-1-yl)ethyl, -4-ethyl-1-(piperazin-1-yl)ethane- 1-one, -2-(4-methanesulfonylpiperazin-1-yl)ethyl, -1-(4-methylpiperazin-1-yl)ethan-1-one, -2-[4-(2,2, 2-trifluoroethyl)piperazin-1-yl]ethyl, -2-[methyl(oxetan-3-yl)amino]ethyl, -3-(3-methyl-1,3-diazinan-1-yl)propyl, -2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}ethyl, -1-(3-ethyltetrahydropyrimidin-1(2H)-yl)ethan-1-one, methyl -[4-ethyl-(piperazin-1-yl)]propanoate, -2-(3-methyl-1,3-diazinan-1-yl)ethyl, -3-(4-ethylpiperazin-1-yl)- N-methylpropanamide, -2-[4-(2-aminoethyl)piperazin-1-yl]ethyl, -4-ethyl-[(piperazin-1-yl)ethyl]methanesulfonamide, -4-[2 -(dimethylamino)ethyl]piperazin-1-yl-ethyl, N-(2-(4-ethylpiperazin-1-yl)ethyl)acetamide, -3-(4-ethylpiperazin-1-yl)propanenitrile, -2-(4-ethylpiperazin-1-yl)ethan-1-ol, 1-methylpiperidin-4-yl, -2,2'-((2-(4-ethylpiperazin-1-yl)ethyl) azanediyl)bis(ethan-1-ol), methyl (2-(4-ethylpiperazin-1-yl)ethyl)carbamate, -3-(4-ethylpiperazin-1-yl)pentane-1,5-diol, -(1-methylpiperidin-4-yl)methyl and -2-(3-methylimidazolidin-1-yl)ethyl; R 8 is H or methyl, -CF 3 and -CH 2 is selected from the group consisting of OH;

[0107] According to another preferred embodiment, the present invention provides a compound of formula (Ibb) [formation] where A is A2b [formation] with respect to compounds of formula (I) wherein R 3’ are -(1-methylazetidin-3-yl)-carboxamide and -(1-methylpiperidin-4-yl)-carboxamide.

[0108] According to another preferred embodiment, the present invention provides a compound of formula (Ic) [formation] where A is A3 [formation] A compound of formula (I) which is R. 1 is aryl optionally substituted with one or more halogen atoms; R. 4 is-C(O)NR 5 R. 7 and -C(O)heterocycloalkyl, wherein said heterocycloalkyl optionally comprises one or more -(C 1 -C 6 ) substituted with alkyl; R. 5 is H or -(C 1 -C 6 ) is an alkyl; R. 7 is greater than or equal to 1 -(C 1- C. 6 )alkyl substituted heterocycloalkyl and -(C 1- C. 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is optionally one or more -(C 1 -C 6 ) substituted with alkyl); R. 8 is H or -(C 1 -C 6 ) is alkyl; It relates to compounds and their pharmaceutically acceptable salts.

[0109] According to a preferred embodiment, the present invention relates to compounds of formula (Ic) and pharmaceutically acceptable salts thereof listed in Table 3 below.

[0110] [Table 3-1] [Table 3-2]

[0111] In a particularly preferred embodiment, the present invention provides a compound of formula (Ica) [formation] and A is A3a [formation] For a compound of formula (Ic) which is R. 4 is-C(O)NR 5 R. 7 is; R. 5 is H or methyl; R. 7 is selected from the group consisting of 1-ethyl-4-methylpiperazine and 1-ethyl-4-methylpiperidine; R. 8 is H or methyl.

[0112] In a further preferred embodiment, the invention relates to compounds of formula (I), wherein R 6 is-(C 1 -C 6 )alkylene-NR A R. B ;-NH-(C 1 -C 6) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is one or more -(C 1 -C 6 ) substituted by alkyl);-(C 1 -C 6 )alkylene-NR A R. C and -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is one or more -(C 1 -C 6 ) substituted by alkyl); heteroaryl substituted with one or more groups selected from; 1 -C 6 )alkylene-NR C -(C 1 -C 6 )alkylene-NR A R. C ;-(C 1 -C 6 )alkylene-NR A -C(O)O-(C 1 -C 6 )alkyl; optionally heterocycloalkyl, wherein said heterocycloalkyl is one or more -(C 1 -C 6 ) substituted by) alkyl; one or more -(C 1- C. 6 ) heterocycloalkyl substituted with alkyl;-(C 1 -C 6 ) alkylene-N-oxide-heterocycloalkyl; and -(C 1 -C 6 ) alkylene-heterocycloalkyl (where said heterocycloalkyl is -OH, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -C(O)OH, -C(O)O(C 1 -C 6 ) alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 )alkylene-C(O)O-R C , -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 ) substituted with one or more groups selected from alkyl and oxo).

[0113] In another preferred embodiment, the invention relates to compounds of formula (I), wherein R 7 but: - (C 1 -C 6 )alkylene-NR A R. B ; - -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-NR A R. C , heterocycloalkyl, -C(O)O-heterocycloalkyl, -(C 1 -C 6 ) alkylene-heterocycloalkyl, wherein each heterocycloalkyl is substituted with one or more groups selected from -(C 1 -C 6 ) substituted with alkyl); - -(C 1 -C 6 )alkylene-C(O)-heterocycloalkyl (wherein said heterocycloalkyl is one or more -(C 1 -C 6 ) substituted by alkyl); and - -(C 1 -C 6 ) alkylene-heterocycloalkyl (wherein said heterocycloalkyl is -(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkoxy, -(C 1 -C 6 ) alkylene-OH, -(C 1 -C 6 )alkylene-CN, -(C 1 -C 6 ) haloalkyl, -C(O)-(C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 ) alkyl, -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NH 2 , -(C 1 -C 6 )alkylene-NR A R. C , -(C 1 -C 6 )alkylene-CONR A R. C , -(C 1 -C 6 )alkylene-NR C -Both (C 1 -C 6 ) alkyl, -(C 1 -C 6 )alkylene-NR C -C(O)O-(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) alkylene-NHSO 2 -(C 1 -C 6 ) alkyl, -SO 2 -(C 1 -C 6 )alkyl and -(C 1 -C 6 ) alkylene-SO 2 -(C 1 -C 6 ) substituted with one or more groups from alkyl) selected from the group consisting of

[0114] Compounds of the invention, including all compounds listed above, are readily available starting compounds using the general methods and procedures described below or using slightly modified procedures readily available to those skilled in the art. Can be manufactured from matter. Although specific embodiments of the invention may be shown or described herein, it will be appreciated by those skilled in the art that all embodiments or aspects of the invention may be modified using the methods described herein or otherwise known. Recognizing what can be achieved using the methods, reactants and starting materials. When typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are described, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be readily determined by one skilled in the art by routine optimization procedures.

[0115] Therefore, the steps described below should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0116] In some cases, steps may be necessary to mask or protect sensitive or reactive moieties, and generally protecting groups (PG) may be used in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P.G.M. Wuts).

[0117] It has surprisingly been found that the compounds of formula (I) of the present invention efficiently inhibit the receptor ALK5. Advantageously, inhibition of ALK5 can lead to effective treatment of diseases or conditions involving the ALK5 receptor.

[0118] In this regard, the compounds of formula (I) of the present invention, as shown in the experimental part, have a half maximal inhibitory concentration (IC) of 10 nM or less against ALK5. 50 ) was found to have an inhibitory drug potency.

[0119] Preferably, the compounds of the invention have an IC for ALK5 of 5-10 nM 50 have

[0120] Even more preferably, the compounds of the invention have an IC for ALK5 of less than 1 nM 50 have

[0121] In one aspect, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. The invention therefore preferably relates to compounds of formula (I) in the manufacture of a medicament for use in the prevention and / or treatment of diseases, disorders or conditions associated with the ALK5 signaling pathway.

[0122] In a preferred embodiment, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of diseases, disorders or conditions associated with the ALK5 signaling pathway.

[0123] 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.

[0124] 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 fibroblast recruitment and includes heart, kidney, liver, Includes fibrosis of individual organs or tissues such as joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0125] Preferably, a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) of the present invention is used for pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis , cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0126] More preferably, the compounds of formula (I) of the present invention or pharmaceutical compositions comprising compounds of formula (I) are useful for the treatment of idiopathic pulmonary fibrosis (IPF).

[0127] A "safe and effective amount" as used herein with reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent is sufficient to treat the patient's condition, but not severe. It refers to an amount of compound that is low enough to avoid serious side effects, and yet can be routinely determined by one skilled in the art.

[0128] The compounds of formula (I) may be administered once or according to a dosing regimen in which several doses are administered at varying intervals over a period of time. A typical daily dosage may vary depending on the route of administration chosen.

[0129] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) admixed with at least one or more pharmaceutically acceptable carriers or excipients.

[0130] In certain embodiments, the present invention provides formula ( It relates to pharmaceutical compositions of compounds of I).

[0131] Administration of the compounds of the present invention and pharmaceutical compositions thereof is accomplished, for example, by oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and infusion) and inhalation, depending on the needs of the patient. obtain.

[0132] Preferably, the compounds of the invention are administered orally or by inhalation.

[0133] More preferably, the compounds of the invention are administered by inhalation.

[0134] In certain preferred embodiments, the pharmaceutical composition comprising a compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and mixed powders.

[0135] In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is a tablet.

[0136] Compounds of the present invention alone or in various pharmaceutically acceptable carriers, diluents (eg, sucrose, mannitol, lactose, starch) and suspending agents, solubilizers, buffers, binders, disintegrants, preservatives. It may be administered in combination with known additives including agents, coloring agents, flavoring agents, lubricants and the like.

[0137] In a further embodiment, pharmaceutical compositions comprising a compound of formula (I) are liquid oral dosage forms, 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 preservatives, wetting agents, sweetening agents, flavoring agents and agents for emulsifying and / or suspending the compounds of this invention. Known additives may also be included.

[0138] In a further embodiment, the pharmaceutical composition comprising 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.

[0139] For administration as dry powder, single or multi-dose inhalers known from the prior art can be utilized. In this case the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0140] A diluent or carrier which is chemically inert to the compounds of the invention, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compounds of the invention.

[0141] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the invention in solution or in dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other additives.

[0142] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, using jet or ultrasonic nebulizers or soft sprays known from the prior art. It can be delivered by a mist nebulizer.

[0143] The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0144] The dosage of the compounds of the invention will depend on a variety of factors, including, among others, the particular disease being treated, the severity of the symptoms, the route of administration, and the like.

[0145] The invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention in the form of a single or multidose dry powder inhaler or metered dose inhaler.

[0146] All preferred groups or embodiments described above for the compounds of formula (I) may be combined with each other and applied mutatis mutandis analogously.

[0147] Compounds of the invention, including all compounds listed above, are readily available starting compounds using the general methods and procedures described below or using slightly modified procedures readily available to those skilled in the art. Can be manufactured from matter. Although specific embodiments of the invention may be shown or described herein, it will be appreciated by those skilled in the art that all embodiments or aspects of the invention may be modified using the methods described herein or otherwise known. Recognizing what can be achieved using the methods, reactants and starting materials. When typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are described, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be readily determined by one skilled in the art by routine optimization procedures.

[0148] Therefore, the steps depicted below and in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0149] Compounds of formula (I), including all or at least one of the compounds listed above, may generally be prepared according to the methods detailed in the schemes shown below using generally known methods.

[0150] In a first embodiment of the invention, compounds of formula (I) may be prepared as described in Scheme 1. Scheme 1 [formation] Scheme 1 is A, R 1 and R 8 is as defined above, provides possible synthetic routes for the preparation of compounds of formula (I).

[0151] Compounds of formula (III) may be prepared by reacting commercially available compound (II) in a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst. R. 8A typical Suzuki condition for inserting a group involves combining compound (II) with a suitable boronic acid with Pd(dppf)Cl 2 In the presence of a Pd catalyst such as DCM, in a mixed solvent such as 1,4-dioxane and water at a suitable temperature such as 100°C. Reaction of compounds of formula (III) under cross-coupling conditions such as Suzuki cross-coupling in the presence of a Pd catalyst gave compound (IV). R. 1 Typical Suzuki conditions for inserting groups include a suitable base such as KF and PdCl 2 (PPh 3 ) 2 and reacting compound (III) with a suitable boronic acid in the presence of a Pd catalyst such as MeCN and water at a suitable temperature such as 95°C. Finally, compounds of formula (I) are obtained by reacting compounds of formula (IV) and appropriate halides under standard Buchwald-Hartwig amination conditions. Typical Buchwald-Hartwig conditions include a suitable base such as cesium carbonate, a suitable ligand agent such as Xantphos and Pd(OAc) 2 in a suitable solvent such as 1,4-dioxane and at a suitable temperature such as 100°C.

[0152] Alternatively, di-tert-butyl dicarbonate (Boc anhydride, Boc 2 Nitrogen of compounds of formula (III) as bis-tert-butoxycarbonyl (Boc) using O) gives compounds of formula (V). R to obtain compounds of formula (VI) 1 Introduction of can be accomplished using, for example, a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst. Typical Suzuki conditions are Pd(dppf)Cl 2 Compound (V) and a suitable boronic acid in the presence of a Pd catalyst such as DCM, in a suitable base such as sodium carbonate, in a mixed solvent such as 1,4-dioxane and water at a suitable temperature such as 100°C. including reacting For example, removal of the Boc protecting group under acidic conditions such as TFA solution in DCM at room temperature gave compounds of formula (IV). Finally, reaction of compound (IV) under standard Buchwald-Hartwig amination conditions described above gave compound (I).

[0153] Alternatively, insertion of group A into compounds of formula (III) can typically be accomplished by reaction with a suitable halide under standard Buchwald-Hartwig amination conditions to give compounds of formula (VII). Typical Buchwald-Hartwig conditions include a suitable base such as sodium tert-butoxide, a suitable ligand agent such as Xantphos and Pd 2 (dba) 3 in the presence of a suitable catalyst such as in a suitable solvent such as 1,4-dioxane and at a suitable temperature such as 105°C. Finally, R. 1 can be achieved by reacting compound (VII) under a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst, and a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst can be obtained. can. A typical Suzuki condition is Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 compound (VII) and a suitable boronic acid in the presence of a Pd catalyst such as DCM, in the presence of a base such as potassium carbonate, in a mixed solvent such as 1,2-dimethoxyethane and water, at a suitable temperature such as 90°C. including reacting

[0154] In other embodiments, compounds of formula (I) may be prepared as described in Scheme 2. scheme 2 [formation] Compounds of formula (IX) may be prepared by reacting compound (VIII) in a cross-coupling reaction such as Suzuki cross-coupling under Pd catalysis. R. 1 A typical Suzuki condition for inserting Pd(OAc) 2 In the presence of a Pd catalyst such as dppf, in the presence of a ligand agent such as dppf, in the presence of a base such as cesium carbonate, in a mixed solvent such as 1,4-dioxane and water, at an appropriate temperature such as 60 ° C., compound (VIII) and Including reacting the appropriate boronic acid. Reaction of compound (IX) under Buchwald-Hartwig cross-coupling conditions gave compound (I). Typical Buchwald-Hartwig conditions for inserting group A include a suitable base such as cesium carbonate, a suitable ligand agent such as Xantphos and Pd(OAc) 2 in a suitable solvent such as 1,4-dioxane and at a suitable temperature such as 110°C.

[0155] In other embodiments, compounds of formula (I) may be prepared as described in Scheme 3. Scheme 3 [formation] A compound of formula (IX) is reacted with compound (VIII) in a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst, as described above, to form R 1 It can be prepared by inserting groups. A compound of formula (XI) is converted to a compound of formula (IX) with Teoc-NH under Buchwald-Hartwig cross-coupling conditions. 2 It can be prepared by reacting (X, 2-(trimethylsilyl)ethylcarbamate). Typical Buchwald-Hartwig conditions include a suitable base such as cesium carbonate, a suitable ligand agent such as Xantphos and Pd 2 (dba) 3 in a suitable solvent such as 1,4-dioxane and at a suitable temperature such as 100°C. Cleavage of Teoc(2-(trimethylsilyl)ethoxycarbonyl) using cesium fluoride in DMF gave compound (IV). Finally, reaction of compound (IV) under Buchwald-Hartwig cross-coupling conditions gave compound (I). Typical Buchwald-Hartwig conditions for inserting group A comprise reacting compound (IV) with a suitable halide in the presence of a Pd catalyst, as described above.

[0156] A compound of formula (III) can be obtained from compound (VIII) by nucleophilic aromatic substitution with a nucleophile such as ammonium hydroxide in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 90°C. can be manufactured. Compounds of formula (IV) can be synthesized by reacting compound (III) under Suzuki cross-coupling conditions. R. 1 Typical Suzuki conditions for insertion involve reacting compound (III) with the appropriate boronic acid in the presence of a Pd catalyst, as described above. Finally, as described above, reaction of compound (IV) under Buchwald-Hartwig cross-coupling conditions gave compound (I).

[0157] In a specific embodiment of the invention, compounds of formula (I) may be prepared as described in Scheme 4. scheme 4 [formation] Scheme 4 is the R 8 is-(C 1 -C 6 ) alkylene-OH, such as -CH 2 A potential synthetic route is provided for the preparation of compounds of formula (I) that are OH.

[0158] Compounds of formula (XIII) can be prepared from commercially available compound (XII) in the presence of a suitable base such as N,N-diisopropylethylamine in a suitable solvent such as MeCN, typically at room temperature to give 2,4-dimethoxybenzylamine. (dmb) can be obtained by nucleophilic aromatic substitution (SNAr). R to obtain compounds of formula (XIV) 1 Introduction of can be accomplished using, for example, a cross-coupling reaction such as Suzuki cross-coupling in the presence of a Pd catalyst. Typical Suzuki conditions include a suitable base such as N,N-diisopropylethylamine and Pd(PPh 3 ) 4 and reacting compound (XIII) with a suitable boronic acid in the presence of a Pd catalyst such as in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 110°C. Compound (XV) was obtained by reduction of compound (XIV) with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as THF at a suitable temperature such as 0°C to room temperature. For example, N-deprotection of compound (XV) under acidic conditions, such as TFA solution in DCM at room temperature, gave compounds of formula (XVI). Under standard literature conditions such as reaction with tert-butyl(chloro)dimethylsilane in the presence of a suitable base such as triethylamine and a catalytic amount of DMAP, the reaction is carried out in a suitable solvent such as DCM at room temperature. Protection of (XVI) gave compound (XVII). Reaction of compound (XVII) under Buchwald-Hartwig cross-coupling conditions gave compound (XVIII). Typical Buchwald-Hartwig conditions for inserting group A comprise reacting compound (XVII) with a suitable halide in the presence of a Pd catalyst, as described above. Finally, deprotection of compound (XVIII) under standard literature conditions such as reaction with tetrabutylammonium fluoride in a suitable solvent such as THF at a suitable temperature such as room temperature gives compound (I). rice field.

[0159] In a specific embodiment of the invention, compounds of formula (I) may be prepared as described in Scheme 5. scheme 5 [formation] Scheme 5 is the R 8 is-(C 1 -C 6 ) haloalkyl, -(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl and -cycloalkyl-C(O)O-(C 1 -C 6 ) alkyl to provide potential synthetic routes for the preparation of compounds of formula (I).

[0160] Compounds of formula (XXIII) can be obtained according to two different routes. R. 8 is-(C 1 -C 6 ) haloalkyl, e.g. CF 3 (pathway A), compound (XX) is combined with a trifluoromethylsulfinate (e.g. zinc) and an oxidizing agent such as tert-butyl hydroperoxide (TBHP) in a suitable solvent such as a mixture of dichloromethane and water. , starting from commercially available pyridazine (XIX) under Minisci-like reaction conditions, following the general procedure reported in the literature (Baran and coworkers, Nature 2012, 95-99), using an appropriate temperature, typically 60 °C. and can be manufactured. Compound (XX) can be converted to compound (XXIII) by a cross-coupling reaction such as Suzuki cross-coupling reaction in the presence of a typical Pd catalyst. Typical Suzuki conditions include a suitable base such as potassium carbonate and Pd(dppf)Cl 2 and reacting compound (XX) with a suitable boronic acid in the presence of a Pd catalyst such as, in a suitable solvent such as 1,4-dioxane and water at a suitable temperature such as 110°C.

[0161] R. 8 is-(C 1 -C 6 )alkylene-C(O)O-(C 1 -C 6 )alkyl or -cycloalkyl-C(O)O-(C 1 -C 6 ) alkyl, compound (XXIII) can be obtained by route B, starting from commercially available compound (XIX). Therefore, compound (XIX) is converted to compound (XXI) by a Suzuki cross-coupling reaction under conditions analogous to those described above for compound (XXIII). Then R 8 Radicals are converted to redox in a suitable solvent such as DMSO under a suitable LED lamp, typically blue illumination, as described in the literature (Dhar and coworkers, J. Org. Chem. 2018, 83, 3000-3012). Activated ester (RAE such as N-hydroxyphthalimide ester NHPI) can be introduced by a Minisci-like reaction involving a suitable photocatalyst such as 4CzIPN to give compound (XXIII). Reaction of compound (XXIII) under Buchwald-Hartwig cross-coupling conditions gave compound (I). Typical Buchwald-Hartwig conditions for inserting group A comprise reacting compound (XXIII) with a suitable halide in the presence of a Pd catalyst, as described above.

[0162] Production of intermediates and example compounds Chemical names of compounds were generated using Structure To Name Enterprise 10.0 Cambridge Software.

[0163] All reactants whose synthesis is not described in the experimental section are commercially available or are known compounds or can be prepared from known compounds by methods known to those skilled in the art.

[0164] In the procedures that follow, some of the starting materials are identified by an "Intermediate" or "Example" number, indicating the step number. It is provided merely as an aid to the skilled chemist.

[0165] A "similar" or "similar" method means that such a method may involve minor variations in, for example, reaction temperature, reactant / solvent amounts, reaction time, work-up conditions or chromatographic purification conditions.

[0166] Abbreviations - Meaning Boc=tert-butyloxycarbonyl cHex=cyclohexane Cs 2 CO 3 = cesium carbonate DIC=N,N'-diisopropylcarbodiimide DCM=dichloromethane DIPEA=N,N-diisopropylethylamine DMAP=4-(dimethylamino)pyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide dppf=1,1-ferrocenediyl-bis(diphenylphosphine) EtOAc = ethyl acetate HCOOH = formic acid h = hour HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBr = hydrobromic acid HCl=hydrochloric acid H. 2 O=water KF=potassium fluoride K. 3 P.O. 4 = tripotassium phosphate LC-MS = liquid chromatography / mass spectrometry MeCN=acetonitrile MeOH = methanol MTBE = tert-butyl methyl ether NaI = sodium iodide NaOH = sodium hydroxide Na 2 SO 4 = sodium sulfate NaHCO 3 = sodium bicarbonate NaHSO 4 = sodium bisulfate Na 2 CO 3 = sodium carbonate NH 3 = ammonia NH 4 Cl=ammonium chloride Pd / C=palladium / carbon PdCl 2 (PPh 3 ) 2 = bis(triphenylphosphine)palladium(II) dichloride Pd 2 (dba) 3 = tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl 2 DCM = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed 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 SOCl 2 = thionyl chloride s.s. = saturated solution t-BuOOH=tert-butyl hydroperoxide T3P = propylphosphonic anhydride TEA = triethylamine Teoc=2-(trimethylsilyl)ethylcarbamate TFA = trifluoroacetic acid TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate THF=tetrahydrofuran Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0167] General experimental details and methods Analysis method Apparatus, materials and methods used for analysis 1 H-NMR spectra were analyzed at 400 MHZ (proton Frequency) were acquired on a Varian MR-400 spectrometer or an Agilent VNMRS-500 or Bruker Avance 400 spectrometer. Chemical shifts are given as δ values ​​in ppm relative to trimethylsilane (TMS) as internal standard. Coupling constants (J values) are given in Hertz (Hz) and multiplicities are described using the following abbreviations (s = singlet, d = doublet, t = triplet, q = quartet term, m = multiplet, br. s = broad singlet, nd = undetermined, dd = double doublet, ddd = double doublet, quin = quintet, td = triplet , tt = triplet triplet, qd = quadruplet doublet).

[0168] LC / UV / MS analysis method LC / MS retention times are estimated to be subject to an experimental error of +0.5 minutes. LCMS can be recorded under the following conditions: Diode-array DAD chromatographic traces, mass chromatograms and mass spectra on a Micromass ZQTM or Waters SQD single quadrupole operating in positive and / or negative electrospray ES ionization mode. A UPLC / PDA / MS AcquityTM system coupled with a mass spectrometer and / or a Fractionlynx system for use in analysis coupled with a ZQTM single quadrupole operating in positive and / or negative ES ionization mode. The quality control methods used were operated under low or high pH conditions:

[0169] 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. rice field. The flow rate was 1 mL / min. The slope 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.

[0170] 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 NH adjusted to pH=10 with ammonia. 4 HCOs 3 10 mM aqueous solution of , mobile phase solvent B was MeCN. The flow rate was 1 mL / min. The slope 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.

[0171] Production of intermediates Intermediate 1: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-chloropyridazin-4-yl)carbamate 6-Chloropyridazin-4-amine (2.0 g, 15.44 mmol) was dissolved in THF (80 mL) and treated with TEA (3.12 g, 30.88 mmol) and DMAP (0.09 g, 0.77 mmol) followed by di-tert-dicarbonate. Butyl (11.79 g, 54.03 mmol) was added. The mixture was refluxed for 5 hours. The THF was then evaporated and the residue was treated with EtOAc and NH 4 Cl s.s., the organic phase was dried and evaporated, and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex-30% EtOAc) to give intermediate 1 (3.96 g, 12.01 mmol, 78 % yield) was obtained as a white solid. LC-MS (ESI): m / z (M+1): 330.1 (method 1)

[0172] Intermediate 2: tert-Butyl N-[(tert-butoxy)carbonyl]-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]carbamate Intermediate 1 (1.0 g, 3.03 mmol), (5-chloro-2-fluorophenyl)boronic acid (0.58 g, 3.34 mmol) and 2M Na 2 CO 3 (4.55 mL, 9.1 mmol) in 1,4-dioxane (12 mL) in N 2 for 5 min, then Pd(dppf)Cl 2 DCM (248mg, 0.30mmol) was added. The resulting mixture was heated at 100° C. for 1 hour. The reaction was complete so the mixture was evaporated, the residue partitioned between EtOAc and water, the organic phase separated, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (cHex-30% EtOAc) to give Intermediate 2 (1.1 g, 2.6 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 330.1 (method 1)

[0173] Intermediate 3: 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine Method A Intermediate 2 (1.1 g, 2.6 mmol) was dissolved in DCM (10 mL) and TFA (3.0 mL, 39.18 mmol) and the reaction solution was stirred for 5 hours, then another 2 mL of TFA was added and the reaction was allowed to warm overnight at RT. Stirred. 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 treated with 1N NH. 3 in MeOH; the basic fractions were collected to give Intermediate 3 (530 mg, 2.37 mmol, 91% yield) as a white solid.

[0174] Method B 6-chloropyridazin-4-amine (3.0 g, 23.16 mmol), (5-chloro-2-fluorophenyl)boronic acid (5.25 g, 30.1 mmol) and KF (5.25 g, 30.1 mmol) in MeCN (30 mL) / water (23.3 mL) 3.42 g, 57.89 mmol) of N 2 for 2 min, then PdCl 2 (PPh 3 ) 2 (1.63g, 2.32mmol) was added and the mixture was warmed to 95°C. After 7 hours the reaction was not complete so more boronic acid (2 g), catalyst (300 mg) and KF (700 mg) were added and stirred at the same temperature for 24 hours. After cooling, the mixture was evaporated to dryness, the residue was dissolved in large amount of MeOH and some insolubles were filtered. The methanolic solution was concentrated under reduced pressure, dissolved in hot EtOAc and brought to RT. The insolubles were discarded and the solution was evaporated to dryness to give a residue which was crystallized from hot EtOAc. After cooling, the solid was filtered to give a first crop of the title compound (2.2g). Evaporation of the mother liquor and purification by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) gave an additional 500 mg. Two batches were recombined to give intermediate 3 (2.7g, 12.07mmol, 52% yield). LC-MS (ESI): m / z (M+1): 224 (method 2)

[0175] Intermediate 4: Methyl 4-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carboxylate Methyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.5 g, 5.88 mmol) was suspended in THF (20 mL) and N 2 After cooling in an ice bath, 60% dispersion in sodium hydride oil (0.28 g, 11.76 mmol) was added and stirred for 30 minutes at the same temperature, followed by 2-(chloromethoxy)ethyl-trimethylsilane (1.35 mL, 7.64 mmol) was added dropwise. The reaction mixture was brought to RT and stirred for 3 hours. Water and EtOAc were added, the product was extracted several times with EtOAc, the organic phases were collected, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 5% MeOH) to give Intermediate 4 (1.05g, 2.72mmol, 46% yield) as a white wax. LC-MS (ESI): m / z (M+1): 387.0 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 8.15 (d, J = 5.0 Hz, 1 H), 8.13 (s, 1 H), 7.48 (d, J = 5.0 Hz, 1 H), 3.92 (s, 3 H), 5.70 (s, 2 H), 3.56 (dd, J = 8.9, 7.8 Hz, 2 H), 0.88 - 1.01 (m, 2 H), -0.09 - -0.01 (m, 9 H)

[0176] Intermediate 5: Methyl 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate 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 dissolved 60% sodium hydride in oil. % dispersion (0.28 g, 7.12 mmol) was added and the mixture was stirred for 30 minutes before adding 2-(chloromethoxy)ethyl-trimethylsilane (1.09 mL, 6.17 mmol). The reaction mixture was brought to RT and stirred at RT for 3 hours. NH 4 The reaction was quenched with Cl s.s., diluted with EtOAc and washed with brine (1×). The organic phase was dried, concentrated under reduced pressure and the residual solid (yellow) was left overnight at RT. The next day the solid was white in color and UPLC test indicated complete conversion to the stated regioisomer. The residue was purified by flash chromatography on a Biotage silica cartridge (cHex to 10% EtOAc) to give Intermediate 5 (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, 2H), 3.97 (s, 3H), 3.52 - 3.58 (m, 2H), 0.85 - 0.92 (m, 2H), -0.11 - -0.05 (m, 9H)

[0177] Intermediate 6: Lithium 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylate Lithium hydroxide hydrate (116mg, 2.77mmol) Methyl 4-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-3-carboxylate (Intermediate 4, 1.0g, 2.52mmol ) was added to a mixture of THF (12 mL) / MeOH (2 mL) / water (2 mL) and stirred at 50° C. overnight. The next day the volatiles were removed under reduced pressure to give Intermediate 6 (1 g, recovery assumed quantitative) which was used directly in the next step. LC-MS (ESI): m / z (M+1): 373.0 (method 1)

[0178] Intermediate 7: 4-bromo-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3- Carboxamide Intermediate 6 (300 mg, 0.80 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (125 mg, 0.87 mmol) were mixed in MeCN (8 mL) and 1-methylimidazole (0.22 mL, 2.78 mmol). was added, followed by TCFH (268 mg, 0.95 mmol). The resulting solution was stirred at RT for 3 hours and then at 60° C. overnight. The next day the solvent was removed by evaporation, the residue was redissolved in DCM, the solid was filtered off, the liquid was concentrated and purified by flash chromatography on a Biotage silica NH cartridge (DCM to 35% EtOAc) to give an intermediate product. Form 7 (170 mg, 0.34 mmol, 43% yield) was obtained. LC-MS (ESI): m / z (M+1): 518.3 (Method 2)

[0179] Intermediate 8: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxamide 6-(5-Chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 70mg, 0.31mmol), Intermediate 7 (171mg, 0.34mmol), Xantphos (27mg, 0.05mmol) and K 3 P.O. 4 (135 mg, 0.63 mmol) was mixed in 1,4-dioxane (4 mL). N the mixture 2 for 3 min, then Pd 2 (dba) 3 (29 mg, 0.03 mmol) was added and the resulting mixture was heated at 100° C. overnight. The solids were filtered off and the retentate was concentrated and subjected to reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH-MeCN) to give Intermediate 8 (36 mg, 0.06 mmol, 18% yield) which was used as is for the next step. LC-MS (ESI): m / z (M+1): 639.3 (Method 2)

[0180] Intermediate 9: Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b] pyridine-2-carboxylate Methyl 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Intermediate 5, 508mg, 1.48mmol), Cs 2 CO 3 (880 mg, 2.68 mmol), Xantphos (93 mg, 0.16 mmol) and intermediate 3 (300 mg, 1.34 mmol) in 1,4-dioxane (4 mL) and N 2 for 5 min, then Pd(OAc) 2 (15 mg, 0.07 mmol) was added. The resulting reaction mixture was irradiated at MW at 110° C. for 90 minutes. The solids were collected by filtration, washed with EtOAc, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~45% EtOAc) to give intermediate 9 (220 mg, 0.42 mmol , 31% yield) as a yellow foam. LC-MS (ESI): m / z (M): 528.2 (method 1)

[0181] Intermediate 10: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b] pyridine-2-carboxylate Intermediate 9 (30 mg, 0.06 mmol) in THF (1.5 mL) / MeOH (0.50 mL) / H 2 O (0.50 mL) mixture, then lithium hydroxide hydrate (2.62 mg, 0.06 mmol) was added and stirred at 50° C. for 2 hours. Volatiles were removed under reduced pressure to give Intermediate 10 (29 mg, 0.06 mmol, 98% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 373.0 (method 1)

[0182] Intermediate 11: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide 1-(2-Aminoethyl)-4-methylpiperazine (8 mg, 0.06 mmol) was treated with intermediate 10 (29 mg, 0.06 mmol), HATU (25 mg, 0.07 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF ( 2.5 mL) was added to the solution. The mixture was stirred at 50°C for 2 hours, then another 1 equivalent of HATU was added and stirred at 50°C overnight. The mixture was loaded onto SCX, washed with MeOH and 1N NH 3 of MeOH solution. The basic fractions were collected, dried and purified by flash chromatography on a Biotage silica NH cartridge (30% cHex to 10% MeOH in EtOAc) to give intermediate 11 (25 mg, 0.04 mmol, 70% yield). Obtained. LC-MS (ESI): m / z (M+1): 639.2 (method 1)

[0183] Intermediate 12: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide Intermediate 12 was used in the synthesis of intermediate 11 starting from intermediate 10 (29 mg, 0.06 mmol) and 2-(1-methylpiperidin-4-yl)ethan-1-amine (8 mg, 0.06 mmol) The title compound (22 mg, 0.03 mmol, 62% yield) was obtained. LC-MS (ESI): m / z (M+1): 638.3 (method 1)

[0184] Intermediate 13: Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate Intermediate 3 (320 mg, 1.43 mmol), methyl 4-chloroquinoline-7-carboxylate (380 mg, 1.72 mmol) and Cs 2 CO 3 A suspension of (938 mg, 2.86 mmol) in 1,4-dioxane (16 mL) was prepared and N 2 for 2 min, then Pd(OAc) 2(16 mg, 0.07 mmol) and Xantphos (83 mg, 0.14 mmol) were added and the resulting mixture was irradiated at MW (3 hours at 110°C). The mixture was filtered through a pad of Celite®, washed with EtOAc / MeOH, then the organic phase was evaporated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 5% MeOH) to give Intermediate 13 (360 mg, 0.88 mmol, 62% yield). LC-MS (ESI): m / z (M+1): 409.1 (Method 2)

[0185] Intermediate 14: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate Intermediate 14 was prepared following the method used for the synthesis of Intermediate 6 starting from Intermediate 13 (125 mg, 0.31 mmol) to give the title compound (125 mg, 0.31 mmol, quantitative yield) as a yellow solid. Obtained. LC-MS (ESI): m / z (M+1): 395.2 (method 1)

[0186] Intermediate 15: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylic acid Lithium hydroxide hydrate (78 mg, 1.82 mmol) was added to stirring THF (6 mL) and H 2 A mixture of intermediate 13 (500 mg, 1.02 mmol) in O (2 mL) was added at RT. The reaction was warmed to 70° C. for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue is H 2 Treat with O and NaHSO 4 was added until a pH of 6 was reached. Solvent was removed under reduced pressure to give Intermediate 15 (500 mg, recovery assumed quantitative), which was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 395.2 (method 1)

[0187] Intermediate 16: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)formamido]ethyl}piperazine-1-carboxylate Intermediate 14 (65 mg, 0.16 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (45 mg, 0.19 mmol), DIPEA (0.11 mL, 0.65 mmol) and A mixture of HATU (80 mg, 0.21 mmol) was stirred overnight at RT. The mixture was diluted with EtOAc and then washed with water and brine. Na 2 SO 4 Dry with rt, filter and evaporate to give a yellow oil which is subjected to reverse phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH to 55% MeCN) to give Intermediate 16 (48 mg, 0.08 mmol, 49% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 606.4 (method 1)

[0188] Intermediate 17: 4-Chloro-7-[2-(morpholin-4-yl)ethoxy]quinoline 4-chloro-7-hydroxyquinoline (175 mg, 0.97 mmol), 4-(2-hydroxyethyl)morpholine (153 mg, 1.17 mmol) and PPh in dry THF (12 mL) 3 A mixture of (383 mg, 1.46 mmol) was stirred under nitrogen for 2 minutes, then a solution of diisopropyl azodicarboxylate (0.23 mL, 1.17 mmol) in dry THF (3 mL) was added dropwise at 0°C. The resulting mixture was stirred overnight at RT. The mixture was partitioned between EtOAc and brine. The aqueous phase was separated and further extracted with EtOAc. The combined organic layers were washed with brine and Na 2 SO 4 , filtered and evaporated. The residue was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH, and 1N NH 3 in MeOH; the basic fractions were collected to give Intermediate 17 (376 mg, recovery assumed quantitative) as a reddish solid that was not further purified. LC-MS (ESI): m / z (M+1): 293.2 (method 1)

[0189] Intermediate 18: tert-Butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperazine-1-carboxylate The title compound was used in the synthesis of intermediate 17 starting from 4-chloro-7-hydroxyquinoline (300mg, 1.67mmol) and 1-Boc-4-(2-hydroxyethyl)piperazine (423mg, 1.84mmol) The title compound (700 mg, recovery presumed to be quantitative) was prepared according to the method described. LC-MS (ESI): m / z (M+1): 392.3 (method 1)

[0190] Intermediate 19: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazine-1-carboxylate Intermediate 19 was prepared according to the method used for the synthesis of Intermediate 13 starting from Intermediate 18 (159 mg, 0.41 mmol) and Intermediate 3 (70 mg, 0.32 mmol) to give the title compound (30 mg, 0.05 mmol) , 17% yield). LC-MS (ESI): m / z (M+1): 579.3 (method 2)

[0191] Intermediate 20: 4-chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline 4-chloro-7-hydroxyquinoline (150 mg, 0.840 mmol), 3-(4-methylpiperazin-1-yl)propan-1-ol (199 mg, 1.26 mmol) and PPh in THF (5 mL) with stirring 3 (329 mg, 1.25 mmol) at 0 °C with N 2 Under atmosphere, diisopropyl azodicarboxylate (0.25 mL, 1.27 mmol) was added in portions, then the resulting reaction mixture was warmed to 55° C. and stirred for 2 hours. The mixture was concentrated under reduced pressure and the residue was treated with EtOAc and NH 4 Dissolved in a concentrated solution of Cl. The organic phase was washed with water, brine and Na 2 SO 4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) to give Intermediate 20 (172 mg, 0.54 mmol, 64% yield) as an orange oil. LC-MS (ESI): m / z (M+1): 320.1 (method 1)

[0192] Intermediate 21: 4-Chloro-7-[2-(piperazin-1-yl)ethoxy]quinoline Intermediate 18 (534 mg, 1.36 mmol) was dissolved in DCM (3.36 mL), TFA (1.57 mL, 20.44 mmol) was added, then the resulting reaction mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH and treated with 4N NH. 3 in MeOH; the basic fractions were collected to give Intermediate 21 (340 mg, 1.16 mmol, 86% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 292.1 (method 1)

[0193] Intermediate 22: 4-chloro-7-[2-(4-ethylpiperazin-1-yl)ethoxy]quinoline To a stirring solution of intermediate 21 (164 mg, 0.56 mmol) in MeOH (3 mL) was added N 2 Acetic acid (0.32 mL, 5.62 mmol) and acetaldehyde (0.38 mL, 6.74 mmol) were added subsequently. After 5 min sodium cyanoborohydride (174 mg, 2.81 mmol) was added portionwise, the ice bath was removed and the resulting reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure to remove the solvent, then the residue was treated with DCM and NaHCO. 3 dissolved in a concentrated solution of Na 2 SO 4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 4% MeOH) to give Intermediate 22 (74 mg, 0.23 mmol, 41% yield). LC-MS (ESI): m / z (M+1): 320.1 (method 1)

[0194] Intermediate 23: 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline The title compound was used in the synthesis of intermediate 17 starting from 4-chloro-7-hydroxyquinoline (300mg, 1.67mmol) and 1-(2-hydroxyethyl)-4-methylpiperazine (265mg, 1.84mmol) The title compound (200mg, 0.65mmol, 39% yield) was obtained. LC-MS (ESI): m / z (M+1): 306.1 (method 1)

[0195] Intermediate 24: tert-Butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate Starting with intermediate 24 from 4-chloro-7-hydroxyquinoline (250 mg, 1.39 mmol) and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (383 mg, 1.67), intermediate 17 to give the title compound (320 mg, 0.82 mmol, 59% yield). LC-MS (ESI): m / z (M+1): 391.3 (method 1)

[0196] Intermediate 25: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate Intermediate 25 was converted to tert-butyl 4-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 24, 273 mg, 0.70 mmol) and 6-(5- Prepared according to the method used for the synthesis of Intermediate 13 starting from chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 120 mg, 0.54 mmol) to give the title compound (130 mg, 0.22 mmol, 42 % yield). LC-MS (ESI): m / z (M+1): 578.5 (method 1)

[0197] Intermediate 26: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperidin-4-yl)ethoxy]quinolin-4-amine Intermediate 26 was converted to tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperidine Prepared following the method used for the synthesis of Intermediate 21 starting from the -1-carboxylate (Intermediate 25, 130mg, 0.22mmol) to give the title compound (106mg, 0.22mmol, 98% yield) . LC-MS (ESI): m / z (M+1): 478.1 (method 1)

[0198] Intermediate 27: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-methoxyquinolin-4-amine Intermediate 27 was started from 4-chloro-7-methoxyquinoline (484 mg, 2.5 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 3, 480 mg, 2.08 mmol). was prepared according to the method used for the synthesis of intermediate 13 to give the title compound (350mg, 0.92mmol, 44% yield). LC-MS (ESI): m / z (M+1): 381.1 (method 2)

[0199] Intermediate 28: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol A 48% HBr aqueous solution (4 mL, 0.78 mmol) was added to Intermediate 27 (300 mg, 0.78 mmol). The vial was sealed and the mixture was heated at 120° C. for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue was treated with water and the solid was filtered off and dried under reduced pressure to give Intermediate 28 (300 mg, 0.82 mmol, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 367.0 (Method 2)

[0200] Intermediate 29: N-(4-bromopyridin-2-yl)prop-2-enamide A mixture of 4-bromo-2-pyridinamine (1.0 g, 5.78 mmol) and TEA (2.42 mL, 17.34 mmol) in dry DCM (30 mL) was stirred under nitrogen at 0° C. followed by 3-chloropropanoyl chloride. (807 mg, 6.36 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 hours. Add water, separate the organic solution, wash with brine, Na 2 SO 4 and filtered. Evaporation of the solvent gave a red oil, which was purified by flash chromatography on a Biotage silica cartridge (cHex~25% EtOAc) to give intermediate 29 (990 mg, 4.36 mmol, 75% yield). Obtained as a white solid. LC-MS (ESI): m / z (M+1): 228.9 (method 1)

[0201] Intermediate 30: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate Intermediate 29 (150 mg, 0.66 mmol) was dissolved in THF (5 mL), 1-piperazinecarboxylic acid tert-butyl ester (2701 mg, 1.45 mmol) was added and the reaction solution was stirred at 65° C. for 16 hours. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex to EtOAc) to give Intermediate 30 (125 mg, 0.30 mmol, 46% yield) as a foam. . LC-MS (ESI): m / z (M+1): 415.2 (method 1)

[0202] Intermediate 31: tert-Butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate Intermediate 30 (126mg, 0.30mmol), Cs 2 CO 3 (200 mg, 0.61 mmol), Xantphos (21 mg, 0.04 mmol) and intermediate 3 (68 mg, 0.30 mmol) in 1,4-dioxane (4 mL) and N 2 for 5 min, then Pd(OAc) 2 (3.44 mg, 0.02 mmol) was added. The resulting reaction mixture was heated at 100° C. for 12 hours. The solids were collected by filtration, the volatiles were removed under reduced pressure and the residue was subjected to reverse phase flash chromatography (H2O) on a Biotage C18 cartridge. 2 Purification by O+0.1%HCOOH to 50%MeCN+0.1%HCOOH) gave intermediate 31 (70 mg, 0.13 mmol, 41% yield). LC-MS (ESI): m / z (M+1): 556.4 (method 1)

[0203] Intermediate 32: N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide Intermediate 32 was prepared according to the method used for the synthesis of intermediate 30 starting from intermediate 29 (150 mg, 0.66 mmol) and 1-methylpiperazine (330 mg, 3.30 mmol) to give the title compound (220 mg, 0.67 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 327.2 (method 1)

[0204] Intermediate 33: 4-chloro-6-(5-chloro-2-fluorophenyl)-3-methylpyridazine 4,6-dichloro-3-methylpyridazine (630mg, 3.87mmol), (5-chloro-2-fluorophenyl)boronic acid (674mg, 3.87mmol), Cs 2 CO 3 (3.17 g, 9.66 mmol) and dppf (110 mg, 0.190 mmol) were mixed in 1,4-dioxane (15 mL) / water (5 mL). N the mixture 2 for 5 min, then Pd(OAc) 2 (44 mg, 0.190 mmol) was added and the resulting dark mixture was heated at 60° C. for 1 hour. EtOAc and water were added, the product was extracted several times with EtOAc, the organic phases were collected, dried and evaporated. The residue was purified by flash chromatography on a Biotage silica cartridge (cHex~15% EtOAc) to give Intermediate 33 (665 mg, 2.59 mmol, 67% yield) as a white solid. LC-MS (ESI): m / z (M+1): 257.1 (method 1)

[0205] Intermediate 34: N-(4-Nitropyridin-2-yl)prop-2-enamide To an ice-cold solution of 4-nitropyridin-2-amine (300 mg, 2.16 mmol) in dry DCM (12 mL) was added TEA (0.9 mL, 6.47 mmol) and 2-propenoyl chloride (293 mg, 3.23 mmol). rice field. The solution became an orange suspension, which was stirred at 0° C. for 30 minutes. 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 (cHex to 50% EtOAc) on a Biotage silica cartridge to afford Intermediate 34 (150 mg, 0.78 mmol, 36% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 194.1 (method 1)

[0206] Intermediate 35: 3-(4-methylpiperazin-1-yl)-N-(4-nitropyridin-2-yl)propanamide Intermediate 35 was prepared according to the method used for the synthesis of Intermediate 30 starting from Intermediate 34 (150 mg, 0.78 mmol) and 1-methylpiperazine (172 mg, 1.71 mmol) to give the title compound (220 mg, 0.75 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 294.1 (method 1)

[0207] Intermediate 36: N-(4-Aminopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide To a mixture of intermediate 35 (220 mg, 0.75 mmol) and ammonium formate (236 mg, 3.75 mmol) in ethanol (9 mL) was added 10% Pd / C (40 mg, 0.04 mmol) and the mixture was refluxed for 1 hour. The mixture was cooled to RT and filtered through a Celite® pad. The filtrate was concentrated and the residue suspended in DCM and filtered. The filtrate was concentrated under reduced pressure and dried under reduced pressure to give Intermediate 36 (120 mg, 0.46 mmol, 61% yield) as an off-white solid. LC-MS (ESI): m / z (M+1): 264.1 (method 2)

[0208] Intermediate 37: N-(4-bromopyridin-2-yl)-3-(morpholin-4-yl)propanamide Intermediate 37 was prepared according to the method used for the synthesis of intermediate 30 starting from intermediate 29 (60 mg, 0.26 mmol) and morpholine (50 mg, 0.58 mmol) to give the title compound (64 mg, 0.2 mmol, 77 % yield). LC-MS (ESI): m / z (M+1): 314.1 (Method 1)

[0209] Intermediate 38: 3-(4-acetylpiperazin-1-yl)-N-(4-bromopyridin-2-yl)propanamide Intermediate 38 was prepared according to the method used for the synthesis of Intermediate 30 starting from Intermediate 29 (300 mg, 1.1 mmol) and 1-acetylpiperazine (420 mg, 3.29 mmol) to give the title compound (400 mg, 1.1 mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 357.0 (method 1)

[0210] Intermediate 39: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-3-oxopiperazin-1-yl) propanamide Intermediate 39 was prepared according to the method used for the synthesis of Intermediate 30, starting from Intermediate 29 (250 mg, 1 mmol) and 1-methylpiperazin-2-one (252 mg, 2.2 mmol) to give the title compound ( 330 mg, 0.97 mmol, 96% yield). LC-MS (ESI): m / z (M+1): 341.0 (method 1)

[0211] Intermediate 40: N-(4-Bromopyridin-2-yl)-3-[methyl(oxetan-3-yl)amino]propanamide Intermediate 40 was prepared according to the method used for the synthesis of Intermediate 30 starting from Intermediate 29 (150 mg, 0.66 mmol) and N-methyl-3-aminooxetane (173 mg, 1.98 mmol) to give the title compound (205 mg, 0.65 mmol, 99% yield) was obtained. LC-MS (ESI): m / z (M+1): 314.1 (Method 1)

[0212] Intermediate 41: N-(4-bromopyridin-2-yl)-4-chlorobutanamide Intermediate 41 was prepared following the method used to synthesize intermediate 29, starting from 4-bromo-2-pyridinamine (150 mg, 0.87 mmol) and 4-chlorobutyryl chloride (0.11 mL, 0.95 mmol), The title compound (183 mg, 0.66 mmol, 76% yield) was obtained as a white solid. LC-MS (ESI): m / z (M+1): 279.1 (Method 1)

[0213] Intermediate 42: N-(4-bromopyridin-2-yl)-4-(morpholin-4-yl)butanamide A mixture of intermediate 41 (183 mg, 0.65 mmol), morpholine (0.19 mL, 2.22 mmol), TEA (0.16 mL, 1.13 mmol) and NaI (catalytic amount) in dry toluene (10 mL) was stirred at reflux overnight. The mixture was evaporated to dryness, then the crude material was partitioned between EtOAc and brine and the aqueous phase was further extracted with EtOAc. The combined organic layers were washed with brine and Na 2 SO 4 and filtered. Evaporation of the solvent gave intermediate 42 (100 mg, 0.30 mmol, 47% yield). LC-MS (ESI): m / z (M+1): 328.1 (method 1)

[0214] Intermediate 43: N-(4-bromopyridin-2-yl)-3-(4-methyl-2-oxopiperazin-1-yl)propanamide To a solution of intermediate 29 (140 mg, 0.62 mmol) in THF (7 mL) / DMF (0.80 mL) was added sodium hydroxide (210 mg, 5.25 mmol) at RT followed by 4-methyl-2-piperazinone (196 mg, 1.72 mmol). ) was added. The reaction mixture was stirred overnight at RT. The reaction was diluted with water and extracted with EtOAc three times. The organic layer was dried and evaporated under reduced pressure, the residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 70% EtOAc) to give intermediate 43 (96 mg, 0.28 mmol, 71% yield). was obtained as a white solid. LC-MS (ESI): m / z (M+1): 342.9 (method 1)

[0215] Intermediate 44: N-(4-bromopyridin-2-yl)cyclopropanecarboxamide 4-bromo-2-pyridinamine (500 mg, 2.89 mmol) was dissolved in DCM (15 mL) and pyridine (0.7 mL, 8.67 mmol) and the mixture was 2 Stirred at 0° C. under atmosphere, then added cyclopropanecarbonyl chloride (0.31 mL, 3.47 mmol) dropwise. The reaction mixture was stirred at the same temperature for 1 hour. Water was added, the two phases were separated and the organic phase was dried and evaporated. The residue was purified by flash chromatography on a Biotage silica cartridge (DCM to 30% EtOAc) to give Intermediate 44 (220 mg, 0.91 mmol, 32% yield) as a white solid. LC-MS (ESI): m / z (M+1): 241.2 (method 1)

[0216] Intermediate 45: N-(4-bromopyridin-2-yl)-1-methylpiperidine-4-carboxamide Intermediate 45 was prepared according to the method used for the synthesis of intermediate 7 starting from 4-bromo-2-pyridinamine (150mg, 0.87mmol) and 1-methylpiperidine-4-carboxylic acid to give the title compound (118 mg, 0.40 mmol, 46% yield) was obtained as a white solid. LC-MS (ESI): m / z (M+1): 300.0 (method 1)

[0217] Intermediate 46: N-(4-nitropyridin-2-yl)cyclopropanecarboxamide Cyclopropanecarbonyl chloride (0.29 mL, 3.23 mmol) was added to an ice-cooled solution of 2-amino-4-nitropyridine (0.26 mL, 2.16 mmol) in dry pyridine (2.5 mL). The solution was stirred overnight at RT. 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 NH cartridge (cHex~40% EtOAc) to give Intermediate 46 (125 mg, 0.60 mmol, 28% yield). LC-MS (ESI): m / z (M+1): 208.1 (method 1)

[0218] Intermediate 47: N-(4-aminopyridin-2-yl)cyclopropanecarboxamide To a mixture of intermediate 46 (125 mg, 0.60 mmol) and ammonium formate (190 mg, 3.02 mmol) in ethanol (5 mL) was added 10% Pd / C (32 mg, 0.03 mmol) and the mixture was stirred for 30 min at reflux temperature. Stirred. The mixture was cooled to RT and filtered through a Celite® pad. The filtrate was concentrated and the residue suspended in DCM and filtered. The filtrate was concentrated under reduced pressure and dried under reduced pressure to give Intermediate 47 (57 mg, 0.32 mmol, 53% yield) as an off-white solid. LC-MS (ESI): m / z (M+1): 178.1 (method 1)

[0219] Intermediate 48: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)carbamate DPPA (369 mg, 1.34 mmol) was added to a stirring mixture of intermediate 15 (300 mg, 0.74 mmol) and TEA (196 mg, 1.94 mmol) in tert-butanol (4 mL) at RT. 2dripped down. The reaction was warmed to 95° C. for 4 hours. Solvent was removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (DCM to 3% MeOH) to give Intermediate 48 (60 mg, 0.13 mmol, 17% yield). LC-MS (ESI): m / z (M+1): 466.1 (Method 2)

[0220] Intermediate 49: N4-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]quinoline-4,7-diamine A solution of 4N HCl in dioxane (1.0 mL, 32.91 mmol) was added to a stirring solution of intermediate 48 (60 mg, 0.13 mmol) in MeOH at RT. After 3 hours the solvent was removed under reduced pressure. The residue was treated with water and extracted with EtOAc. NH 4 Treated with OH and extracted with DCM. The organic layer was separated, dried and evaporated under reduced pressure to give intermediate 49 (35 mg, 0.1 mmol, 74% yield). LC-MS (ESI): m / z (M+1): 366.1 (Method 2)

[0221] Intermediate 50: 5-{[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino}pyridine-2-carbonitrile 5-amino-2-pyridinecarbonitrile (10 g, 83.95 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (12.1 g, 83.95 mmol) and triethyl orthoformate (80.0 mL, 480.97 mmol) ) was stirred at reflux temperature (145° C., external temperature) for 5 hours. The mixture was brought to RT and filtered. The solid was washed with EtOH and dried under vacuum to give Intermediate 50 (16.32 g, 60 mmol, 71% yield) as a dark yellow solid which was used as is. LC-MS (ESI): m / z (M+1): 274.2 (method 1)

[0222] Intermediate 51: 8-oxo-5,8-dihydro-1,5-naphthyridine-2-carbonitrile In a flask equipped with coolant, add Dowtherm A (90.0 mL, 14.35 mmol) at 220° C. with stirring and N 2 Intermediate 50 (4 g, 14.35 mmol) was added portionwise under atmosphere, then the resulting reaction mixture was stirred at the same temperature for 10 minutes. Bring the mixture to RT and then Et 2 O (80 mL) was added and the mixture so obtained was filtered. The solid was washed with MeOH and filtered. The solids were discarded, the solution was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 3% MeOH) to give Intermediate 51 (331 mg, 1.93 mmol, 13% yield). Obtained. LC-MS (ESI): m / z (M+1): 172.0 (method 1)

[0223] Intermediate 52: 8-bromo-1,5-naphthyridine-2-carbonitrile To a stirring solution of intermediate 51 (425 mg, 2.46 mmol) in DMF (4.52 mL) was added N 2 Below, tribromophosphine (0.3 mL, 3.21 mmol) was added dropwise, then the ice bath was removed and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and MeOH (2 mL) was slowly added followed by 1N aqueous NaOH. The mixture pH was then adjusted to NaHCO 3 to about 8-9 by adding a concentrated solution of The mixture was concentrated under reduced pressure to remove MeOH, then extracted twice with EtOAc. The organic phase is washed with brine and Na 2 SO 4 and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (cHex to 60% EtOAc) on a Biotage silica cartridge to afford Intermediate 52 (415 mg, 1.77 mmol, 72% yield) as a white solid. LC-MS (ESI): m / z (M+1): 236.0 (method 1)

[0224] Intermediate 53: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1,7-naphthyridine-6-carbonitrile Intermediate 3 (340 mg, 1.54 mmol), Intermediate 52 (407 mg, 1.74 mmol), Xantphos (142 mg, 0.24 mmol), Pd 2 (dba) 3 (16 mg, 0.18 mmol) and sodium tert-butoxide (309 mg, 3.2 mmol) was added 1,4-dioxane (8.8 mL) and the vial was sealed and subjected to MW cycle at 140° C. for 45 min. The reaction mixture was concentrated, triturated with MeOH, filtered and the solids discarded; the methanolic solution was concentrated. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 12% MeOH) to give Intermediate 53 (203 mg, 0.54 mmol, 35% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 377.1 (method 1)

[0225] Intermediate 54: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-1,7-naphthyridine-6-carboxylic acid To a solution of intermediate 53 (375 mg, 1 mmol) in MeOH (8 mL) at RT was added aqueous 1N NaOH (8 mL, 8 mmol) and the resulting reaction mixture was stirred at 70° C. for 5 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and 6N aqueous HCl was added until pH ~2-3. The mixture was filtered. The solid was dried under reduced pressure. This material was washed with DCM, the mixture was filtered and the solid was dried under reduced pressure to give Intermediate 54 (278 mg, 0.70 mmol, 71% yield) as a pale yellow solid which was used as is. LC-MS (ESI): m / z (M+1): 396.2 (method 1)

[0226] Intermediate 55: methyl 4-bromoquinoline-6-carboxylate 4-bromoquinoline-6-carboxylic acid (150 mg, 0.60 mmol) was suspended in MeOH (5 mL) and THF (5 mL), then cooled in an ice bath and treated with Et 2 A 2M solution of (trimethylsilyl)diazomethane in O (2 mL, 1.19 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 h, then volatiles were removed under reduced pressure to give intermediate 55 (170 mg, 0.64 mmol, quantitative yield), which was used as is. LC-MS (ESI): m / z (M+1): 268.0 (method 1)

[0227] Intermediate 56: Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate Intermediate 56 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 55 (171 mg, 0.64 mmol) and Intermediate 3 (120 mg, 0.54 mmol) to give the title compound (90 mg, 0.22 mmol). , 41% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 409.2 (method 1)

[0228] Intermediate 57: Lithium 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate Intermediate 57 was prepared following the method used for the synthesis of Intermediate 6 starting from Intermediate 56 (50mg, 0.12mmol) to give the title compound (50mg, 0.12mmol, quantitative yield). LC-MS (ESI): m / z (M+1): 395.3 (method 1)

[0229] Intermediate 58: tert-butyl N-[3-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)propyl]-N-methylcarbamate Intermediate 58 was prepared according to the method used for the synthesis of intermediate 30, starting from intermediate 29 (300 mg, 1.32 mmol) and 3-(N-Boc-N-methylamino)propylamine (622 mg, 3.3 mmol). Worked up to give the title compound (420mg, 1.0mmol, 77% yield). LC-MS (ESI): m / z (M+1): 417.1 (method 1)

[0230] Intermediate 59: tert-butyl N-[3-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)propyl]-N-methylcarbamate Di-tert-butyl dicarbonate (137 mg, 0.63 mmol) was added to a solution of intermediate 58 (200 mg, 0.48 mmol) and TEA (0.1 mL, 0.72 mmol) in DCM (5 mL). Stir at RT for 4 h, then volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~45% EtOAc) to give intermediate 59 (210 mg, 0.41 mmol, 85% yield) was obtained as a white foam. LC-MS (ESI): m / z (M+1): 517.2 (method 1)

[0231] Intermediate 60: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridine-2 -yl)carbamoyl]ethyl})amino}propyl)-N-methylcarbamate Intermediate 60 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 59 (209 mg, 0.41 mmol) and Intermediate 3 (85 mg, 0.37 mmol) to give the title compound (70 mg, 0.11 mmol) , 29% yield). LC-MS (ESI): m / z (M+1): 659.4 (method 1)

[0232] Intermediate 61: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-{[3-(methylamino)propyl]amino}propanamide Intermediate 61 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl] Prepared according to the method used for the synthesis of Intermediate 21 starting from amino}pyridin-2-yl)carbamoyl]ethyl})amino}propyl)-N-methylcarbamate (Intermediate 60, 70 mg, 0.1 mmol) , to give the title compound (60 mg, yield assumed quantitative). LC-MS (ESI): m / z (M+1): 458.1 (method 1)

[0233] Intermediate 62: N-(4-bromopyridin-2-yl)-3-(4-methanesulfonylpiperazin-1-yl)propanamide Intermediate 62, starting from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 1-methylsulfonylpiperazine (289 mg, 1.76 mmol), Prepared according to the method used to synthesize isomer 30 to give the title compound (190 mg, 0.49 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 393.0 (method 1)

[0234] Intermediate 63: 6-[2-fluoro-5-(propan-2-yl)phenyl]pyridazin-4-amine 6-chloropyridazin-4-amine (200 mg, 1.54 mmol), Pd(dppf)Cl in MeCN (8 mL) and water (3 mL) 2 A mixture of DCM (109 mg, 0.15 mmol) and (2-fluoro-5-isopropylphenyl)boronic acid (421 mg, 2.32 mmol) was 2 for 2 min, then KF (228 mg, 3.86 mmol) was added and the mixture was irradiated at MW (110° C., 3 h). After cooling, the mixture was treated with water and extracted with EtOAc. Separate the organic layer and Na 2 SO 4 dried and evaporated. The residue was purified by flash chromatography (100% EtOAc) on a Biotage silica NH cartridge to give Intermediate 63 (290 mg, 1.25 mmol, 81% yield). LC-MS (ESI): m / z (M+1): 232 (Method 1)

[0235] Intermediate 64: 6-(5-chloro-2-fluorophenyl)-N-[2-(4-methylpiperazine-1-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3 -b]pyridin-4-yl]pyridazin-4-amine Intermediate 64 was prepared according to the method used for the synthesis of intermediate 11 starting from intermediate 10 (70 mg, 0.13 mmol) and 1-methylpiperazine (16 mg, 0.16 mmol) to give the title compound (46 mg, 0.08 mmol, 57% yield). LC-MS (ESI): m / z (M+1): 596.3 (method 1)

[0236] Intermediate 66: 2-Hydroxy-1-(4-methylpiperazin-1-yl)ethan-1-one In a suitable flask, 1-methylpiperazine (2.9 mL, 26.15 mmol) was added to a mixture of 2-hydroxyacetic acid ethyl ester (3.09 mL, 32.66 mmol) in 1,4-dioxane (5 mL). The flask was sealed and the reaction mixture was stirred overnight at 120°C. The mixture was brought to RT and concentrated under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 4% MeOH) to afford Intermediate 66 (642 mg, 4.06 mmol, 12% yield) as a thick colorless oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 4.16 (s, 2 H), 3.66 - 3.75 (m, 2 H), 3.25 - 3.34 (m, 2 H), 2.41 (q, J = 5.06 Hz, 4 H), 2.32 (s, 3H)

[0237] Intermediate 67: 2-[(4-Chloroquinolin-7-yl)oxy]-1-(4-methylpiperazin-1-yl)ethan-1-one Intermediate 67 was prepared following the method used for the synthesis of Intermediate 20 starting from 4-chloro-7-hydroxyquinoline (300 mg, 1.67 mmol) and Intermediate 66 (396 mg, 2.5 mmol) to give the title compound (402 mg, 1.26 mmol, 75% yield) was obtained. LC-MS (ESI): m / z (M+1): 320.1 (method 1)

[0238] Intermediate 68: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide Intermediate 68 was used in the synthesis of intermediate 11 starting from intermediate 10 (70 mg, 0.13 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (24 mg, 0.15 mmol) The title compound (60mg, 0.09mmol, 72% yield) was obtained. LC-MS (ESI): m / z (M+1): 653.4 (method 1)

[0239] Intermediate 69: 4-chloro-7-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}quinoline In a vial, to a solution of intermediate 21 (100 mg, 0.34 mmol) in THF (2 mL) at RT, DIPEA (0.18 mL, 1.03 mmol) followed by 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.07 mL, 0.52 mmol) was added. The vial was sealed and shaken overnight at 50°C. The solvent was removed under reduced pressure and the residue was dissolved in MeOH, loaded onto SCX, washed with MeOH and 1N NH. 3 of MeOH solution. Basic fractions were collected and evaporated to give Intermediate 69 (83 mg, 0.22 mmol, 65% yield) as an off-white solid, which was used as is. LC-MS (ESI): m / z (M+1): 374.1 (method 1)

[0240] Intermediate 70: tert-butyl N-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-N-methylcarbamate Synthesis of intermediate 20 starting with intermediate 70 from 4-chloro-7-hydroxyquinoline (300mg, 1.67mmol) and 1,1-dimethylethyl(2-hydroxyethyl)methylcarbamate (450mg, 2.57mmol) to give the title compound (653 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 337.2 (method 1)

[0241] Intermediate 71: {2-[(4-chloroquinolin-7-yl)oxy]ethyl}(methyl)amine Intermediate 71 was prepared following the method used for the synthesis of Intermediate 21 starting from Intermediate 70 (653mg, 1.93mmol) to give the title compound (365mg, 1.54mmol, 79% yield). LC-MS (ESI): m / z (M+1): 237.1 (Method 1)

[0242] Intermediate 72: N-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-N-methyloxetan-3-amine Intermediate 72 was prepared according to the method used for the synthesis of Intermediate 22 starting from Intermediate 71 (180 mg, 0.76 mmol) and 3-oxetane one (165 mg, 2.29 mmol) to give the title compound (168 mg, 0.57 mmol, 75% yield). LC-MS (ESI): m / z (M+1): 293.1 (method 1)

[0243] Intermediate 73: tert-butyl N-(3-acetamidopropyl) carbamate TEA (0.96 mL, 6.89 mmol) and acetic acid acetyl ester (0.59 mL, 6.31 mmol) were added to a solution of tert-butyl N-(3-aminopropyl)carbamate (1.0 g, 5.74 mmol) in DCM (28.7 mL). . The mixture was stirred for 1 hour, then the volatiles were removed under reduced pressure and the residue was treated with EtOAc and NH 4 Cl s.s., phase separation, organic phase NaHCO 3 s.s., then evaporated to give tert-butyl N-(3-acetamidopropyl)carbamate (1.1 g, 5.09 mmol, 89% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 6.24 (br. s., 1 H), 4.91 (br. s., 1 H), 3.30 (q, J = 6.31 Hz, 2 H), 3.13 - 3.24 (m, 2H), 2.01 (s, 3H), 1.63 (quin, J = 6.22 Hz, 2H), 1.43 - 1.46 (s, 9H)

[0244] Intermediate 74: N-(3-Azaniumylpropyl)acetamide chloride A solution of 4N HCl in 1,4-dioxane (11.44 mL, 45.77 mmol) was added dropwise to an ice-cooled solution of intermediate 73 (1.1 g, 5.09 mmol) in 1,4-dioxane (8 mL). The mixture was stirred at RT for 72 h, then the volatiles were removed under reduced pressure to give Intermediate 74 (990 mg, recovery assumed quantitative). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.87 - 8.14 (m, 4 H), 3.09 (q, J = 6.60 Hz, 2 H), 2.71 - 2.84 (m, 2 H), 1.82 (s, 3 H), 1.63 - 1.73 (m, 2H)

[0245] Intermediate 75: N-(4-Bromopyridin-2-yl)-3-[(3-acetamidopropyl)amino]propanamide Intermediate 75 was prepared according to the method used for the synthesis of Intermediate 30 starting from Intermediate 29 (250 mg, 1.10 mmol) and Intermediate 74 (168 mg, 1.10 mmol) to give the title compound (150 mg, 0.44 mmol) , 40% yield). LC-MS (ESI): m / z (M+1): 345.0 (method 1)

[0246] Intermediate 76: tert-butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-acetamidopropyl)carbamate Intermediate 76 was prepared following the method used for the synthesis of Intermediate 59 starting from Intermediate 75 (150mg, 0.44mmol) to give the title compound (100mg, 0.23mmol, 52% yield). LC-MS (ESI): m / z (M+1): 444.2 (method 1)

[0247] Intermediate 77: tert-butyl N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-N-(3- Acetamidopropyl) carbamate Intermediate 77 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 76 (130 mg, 0.29 mmol) and Intermediate 3 (65 mg, 0.29 mmol) to give the title compound (60 mg, 0.10 mmol) , 35% yield). LC-MS (ESI): m / z (M+1): 588.2 (Method 2)

[0248] Intermediate 78: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(3-acetamidopropyl)amino]propanamide Intermediate 78 was prepared following the method used for the synthesis of Intermediate 21 starting from Intermediate 77 (60mg, 0.1mmol) to give the title compound (40mg, 0.08mmol, 80% yield). LC-MS (ESI): m / z (M+1): 486.0 (method 2)

[0249] Intermediate 79: tert-butyl N-(3-methanesulfonamidopropyl) carbamate tert-Butyl N-(3-aminopropyl)carbamate (1.0 g, 5.74 mmol) was dissolved in THF (20 mL), cooled in an ice bath and treated with TEA (1.6 mL, 11.48 mmol) followed by methanesulfonyl chloride (0.58 mL, 7.46 mmol) was added dropwise. A precipitate was observed. The mixture is brought to RT, stirred for 2 hours, water and EtOAc are added, the phases are separated and the organic phase is 4 s.s. of Cl, then NaHCO 3 s.s., dried and evaporated to give intermediate 79 (1.1 g, 4.36 mmol, 76% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 5.31 (br. s., 1 H), 4.74 (br. s., 1 H), 3.28 (q, J = 6.38 Hz, 2 H), 3.15 - 3.22 (m, 2H), 2.94 - 2.99 (m, 3H), 1.73 (quin, J = 6.11 Hz, 2H), 1.41 - 1.49 (m, 9H)

[0250] Intermediate 80: N-(3-Azaniumylpropyl)methanesulfonamide chloride Intermediate 80 was prepared following the method used for the synthesis of Intermediate 74 starting from Intermediate 79 (1.1 g, 4.36 mmol) to give the title compound (910 mg, recovery assumed quantitative). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.07 (br. s., 3 H), 7.16 (t, J = 6.05 Hz, 1 H), 2.97 - 3.08 (m, 2 H), 2.91 (s, 3 H), 2.76 - 2.88 (m , 2H), 1.77 (quin, J = 7.21 Hz, 2H)

[0251] Intermediate 81: N-(4-Bromopyridin-2-yl)-3-[(3-methanesulfonamidopropyl)amino]propanamide Intermediate 81 was prepared according to the method used for the synthesis of Intermediate 30 starting from Intermediate 29 (250 mg, 1.10 mmol) and Intermediate 80 (312 mg, 1.65 mmol) to give the title compound (400 mg, 1.05 mmol) , 95% yield). LC-MS (ESI): m / z (M+1): 381.0 (method 1)

[0252] Intermediate 82: tert-butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-methanesulfonamidopropyl)carbamate Intermediate 82 was prepared following the method used for the synthesis of Intermediate 59 starting from Intermediate 81 (400mg, 1.05mmol) to give the title compound (310mg, 0.65mmol, 61% yield). LC-MS (ESI): m / z (M+1): 481.0 (method 1)

[0253] Intermediate 83: tert-butyl N-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-N-(3- methanesulfonamidopropyl) carbamate Intermediate 83 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 82 (260 mg, 0.54 mmol) and Intermediate 3 (110 mg, 0.49 mmol) to give the title compound (130 mg, 0.21 mmol) , 42% yield). LC-MS (ESI): m / z (M+1): 622.2 (method 2)

[0254] Intermediate 84: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[(3-methanesulfonamidopropyl)amino]propanamide Intermediate 84 was prepared following the method used for the synthesis of Intermediate 21 starting from Intermediate 83 (130mg, 0.21mmol) to give the title compound (80mg, 0.15mmol, 73% yield). LC-MS (ESI): m / z (M+1): 522.2 (method 2)

[0255] Intermediate 85: 4-bromo-N-[3-(4-methylpiperazin-1-yl)propyl]pyridin-2-amine K. 2 CO 33-(4-methylpiperazin-1-yl)propan-1-amine (0.44 mL, 2.56 mmol) and 4-bromo-2-fluoropyridine (300 mg, 5.11 mmol) in DMSO (3 mL). 1.7 mmol) was added to the mixture. The resulting mixture was stirred overnight at 90°C. The next day, bring the mixture to RT, filter off the solids, discard, and purify the crude material by reverse-phase flash chromatography (H2O) on a Biotage C18 cartridge. 2 O+0.1%NH 4 OH-90% MeCN) gave intermediate 85 (320 mg, 1.02 mmol, 60% yield). LC-MS (ESI): m / z (M+1): 315.2 (Method 2)

[0256] Intermediate 86: tert-Butyl N-(4-bromopyridin-2-yl)-N-[3-(4-methylpiperazin-1-yl)propyl]carbamate A solution of 1N lithium bis(trimethylsilyl)amide in THF (1.23 mL, 1.23 mmol) was added to an ice-cooled solution of intermediate 85 (320 mg, 1.02 mmol) in THF (6 mL). 2 dripped down. After stirring for 10 min at the same temperature, di-tert-butyl dicarbonate (268 mg, 1.23 mmol) was added and the reaction was brought to RT and stirred for 5 h. Conversion was not complete so further 1N lithium bis(trimethylsilyl)amide in THF (1.23 mL) was added followed by di-tert-butyl dicarbonate (267 mg) after 5 minutes. The mixture was stirred overnight at RT. The next day the conversion was not complete and further 1N lithium bis(trimethylsilyl)amide in THF (2.46 mL) was added followed by di-tert-butyl dicarbonate (540 mg) after 5 minutes. The reaction mixture was stirred at RT for 24 hours. Water and EtOAc were added and the product was extracted with EtOAc (3x), the organic layers were collected, dried and evaporated. The crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~5% MeOH in EtOAc) to give Intermediate 86 (210 mg, 0.51 mmol, 50% yield).

[0257] Intermediate 87: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-N-[3-(4-methylpiperazine-1- yl)propyl]carbamate Intermediate 87 was prepared according to the method used for the synthesis of Intermediate 13 starting from Intermediate 86 (203 mg, 0.49 mmol) and Intermediate 3 (10 mg, 0.45 mmol) to give the title compound (58 mg, 0.10 mmol) , 23% yield). LC-MS (ESI): m / z (M+1): 556.3 (Method 2)

[0258] Intermediate 88: N-(4-bromopyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide Intermediate 88 was prepared following the procedure used for the synthesis of intermediate 30 starting from intermediate 29 (300 mg, 1.1 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (200 mg, 1.19 mmol). Worked up to give the title compound (220mg, 0.56mmol, 63%). LC-MS (ESI): m / z (M+1): 397.0 (method 1)

[0259] Intermediate 89: 2-(Trimethylsilyl)ethylcarbamate 1,1'-Carbonyldiimidazole (9.9 g, 60.9 mmol) was added to a stirred suspension of 2-(trimethylsilyl)ethanol (6.0 g, 50.7 mmol) in dry toluene (50 mL). The reaction was stirred at RT for 5 hours, then ammonium hydroxide solution (28% NH 4 OH aqueous solution, 10 mL) was added. The mixture was stirred vigorously overnight. The phases were separated and the organic phase was washed with brine, then filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with brine (5x) then filtered and evaporated to give Intermediate 89 (7.5 g, 46.5 mmol, 92% yield) as a colorless oil that solidified on cooling. rice field. 1 H NMR (400 MHz, chloroform-d) δ ppm 4.52 (br. s., 2 H), 4.10 - 4.22 (m, 2 H), 0.93 - 1.07 (m, 2 H), 0.05 (s, 9 H)

[0260] Intermediate 90: 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine Method A Step 1: 4,6-Dichloro-3-methylpyridazine (400 mg, 2.45 mmol) was added to a stirring ammonium hydroxide solution (28% NH 4 Aqueous OH, 3 mL) was added to a solution of 1,4-dioxane (3 mL) at RT. The vial was sealed and the reaction was heated at 90° C. for 40 hours. Solvent was removed under reduced pressure and the residue was purified by flash chromatography (EtOAc) on a Biotage silica NH cartridge to give 6-chloro-3-methylpyridazin-4-amine (210 mg).

[0261] Step 2: MeCN (8 mL) and H 2 PdCl in O (2 mL) 2 (PPh 3 ) 2 A mixture of DCM (50 mg, 0.07 mmol), KF (115 mg, 1.95 mmol) (5-chloro-2-fluorophenyl)boronic acid (170 mg, 0.97 mmol) was 2 for 2 min, then 6-chloro-3-methylpyridazin-4-amine (110 mg, 0.77 mmol) was added and the mixture was irradiated at MW (110° C., 1 h 15 min). After cooling, the mixture was treated with water and extracted with EtOAc. Separate the organic layer and Na 2 SO 4 dried and evaporated. The residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) to give 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (100 mg, 0.42 mmol). , 55% yield).

[0262] Method B In a suitable vial, 4-chloro-6-(5-chloro-2-fluorophenyl)-3-methylpyridazine (Intermediate 33 (500 mg, 1.94 mmol), 2-trimethylsilylethylcarbamate (Intermediate 89, 361 mg, 2.24 mmol), Xantphos (171 mg, 0.30 mmol) and K 3 P.O. 4 (837 mg, 3.89 mmol) were mixed in 1,4-dioxane (15 mL) and N 2 for 2 min, then Pd 2 (dba) 3 (184 mg, 0.20 mmol) was added, then the vial was sealed and irradiated at MW at 100° C. for 5 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~15% EtOAc) to give the Teoc product intermediate (400 mg), which was converted to CsF (297 mg, 1.94 mmol). ) in DMF (5 mL) and heated at 45° C. overnight. Bring to RT, load onto an SCX cartridge (20 g), wash with MeOH, 1N NH 3 of MeOH solution. Basic fractions were collected and evaporated and the residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) to give Intermediate 90 (170 mg, 0.71 mmol, 37% yield). . LC-MS (ESI): m / z (M+1): 228.0 (method 1)

[0263] Intermediate 91: methyl 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2, 3-b]pyridine-2-carboxylate Intermediate 91 was prepared according to the method used for the synthesis of Intermediate 9 starting from Intermediate 5 (284 mg, 0.83 mmol) and Intermediate 90 (210 mg, 0.75 mmol) to give the title compound (100 mg, 0.18 mmol) , 25% yield). LC-MS (ESI): m / z (M+1): 542.2 (method 1)

[0264] Intermediate 92: Lithium 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2, 3-b]pyridine-2-carboxylate Intermediate 92 was prepared following the method used for the synthesis of Intermediate 10 starting from Intermediate 91 (100mg, 0.18mmol) to give the title compound (90mg, 0.17mmol, 94% yield). LC-MS (ESI): m / z (M+1): 528.1 (method 1)

[0265] Intermediate 93:4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2- Intermediate 93 was prepared according to the method used for the synthesis of intermediate 11 starting from intermediate 92 (45 mg, 0.08 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (16 mg, 0.11 mmol) to give the title compound (40 mg, 0.06 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 653.3 (Method 2)

[0266] Intermediate 94: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl] -1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide Intermediate 94 was used in the synthesis of intermediate 11 starting from intermediate 92 (45 mg, 0.08 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (17 mg, 0.11 mmol) The title compound (60 mg, recovery assumed quantitative) was prepared according to the method described. LC-MS (ESI): m / z (M+1): 667.4 (method 1)

[0267] Intermediate for comparison compound Intermediate 95: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(4-chloropyrimidin-2-yl)carbamate 4-Chloro-2-pyrimidinamine (200 mg, 1.54 mmol) with DMAP (38 mg, 0.31 mmol), TEA (0.04 mL, 0.31 mmol) and di-tert-butyl dicarbonate (674 mg, 3.09 mmol) in DCM (8 mL) ) was stirred at RT for 3 h. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~20% EtOAc) to give Intermediate 95 (500 mg, 1.52 mmol, 98% yield) as a white wax. obtained as LC-MS (ESI): m / z (M+1): 330.3 (method 1)

[0268] Intermediate 96: tert-Butyl N-[(tert-butoxy)carbonyl]-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyrimidin-2-yl)carbamate Intermediate 96 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 95 (113 mg, 0.34 mmol) and Intermediate 3 (70 mg, 0.31 mmol) to give the title compound (30 mg, 0.06 mmol) , 18% yield) was obtained as a white solid. LC-MS (ESI): m / z (M+1): 517.4 (Method 1)

[0269] Intermediate 97: 2-Chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine 2-Chloro-1H-imidazo[4,5-b]pyridine (200 mg, 1.3 mmol) in THF (8 mL), N 2 It was suspended 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 temperature for 4 hours. Then it was brought to RT, water and EtOAc were added, the product was extracted several times with EtOAc, 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 Intermediate 97 (180 mg, 0.63 mmol 49% yield) as an oil. LC-MS (ESI): m / z (M+1): 284. 2 (Method 1) 1 H 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)

[0270] Intermediate 98: 6-(5-chloro-2-fluorophenyl)-N-(3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-2-yl)pyridazine-4- Amine Intermediate 98 was prepared according to the method used for the synthesis of Intermediate 31 starting from Intermediate 97 (113 mg, 0.40 mmol) and Intermediate 3 (70 mg, 0.31 mmol) to give the title compound (35 mg, 0.07 mmol) , 24% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 471.4 (method 1)

[0271] Intermediate 99: tert-butyl N-{4-[(6-chloropyridazin-4-yl)amino]pyridin-2-yl}carbamate 6-Chloropyridazin-4-amine (600 mg, 4.63 mmol), tert-butyl 4-bromopyridin-2-ylcarbamate (1.52 g, 5.56 mmol) and sodium tert-butoxide in dry 1,4-dioxane (16 mL) (0.94 g, 9.73 mmol) of the mixture in N 2 for 2 min, then Xantphos (400 mg, 0.69 mmol) and Pd 2 (dba) 3 (0.42 mg, 0.46 mmol) was added. The resulting mixture was irradiated at MW at 105° C. for 1 hour. Conversion was complete so the mixture was suspended in MeOH and the insoluble solid was filtered. The solution was evaporated and purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) to give Intermediate 99 (256 mg, 0.8 mmol, 17% yield). LC-MS (ESI): m / z (M+1): 322.2 (method 1)

[0272] Intermediate 100: Methyl 3-{5-[(2-{[(tert-butoxy)carbonyl]amino}pyridin-4-yl)amino]pyridazin-3-yl}-2-fluorobenzoate K. 2 CO 3 (77 mg, 0.56 mmol) was added to stirring 1,2-dimethoxyethane (4 mL) / H 2 Intermediate 99 (70 mg, 0.21 mmol), Pd(PPh 3 ) 4 (32.3 mg, 0.030 mmol) and (2-fluoro-3-methoxycarbonylphenyl)boronic acid (83 mg, 0.42 mmol). N the mixture 2 degassed with The vial was sealed and heated at 90° C. for 3 hours. After cooling, the solvent was removed under reduced pressure. The residue is H 2 Treated with O and extracted with EtOAc. The organic layer was separated, dried and evaporated. The residue was purified by flash chromatography on a Biotage silica cartridge (DCM to 3% MeOH) to give Intermediate 100 (25 mg, 0.06 mmol, 20% yield). LC-MS (ESI): m / z (M+1): 440.1 (method 2)

[0273] Intermediate 101: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide 48% HBr aqueous solution (10.1 mL, 89.29 mmol) was added to N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-methoxyquinolin-4-amine (Intermediate 27, 850 mg, 2.23 mmol). The vial was sealed and the mixture was stirred at 120° C. for 48 hours. After cooling, the aqueous solution was evaporated to complete dryness, then the residue was suspended in DCM / MeOH and the white solid filtered off to give the first crop. The mother liquor was evaporated, the residue was triturated with DCM and filtered again to obtain a second crop which was combined with the first crop to give 4-{[6-(5-chloro-2- Fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (785 mg, 1.75 mmol, y=79%) was obtained. LC-MS (ESI): m / z (M+1): 367.0 (Method 2)

[0274] Intermediate 102: Ethyl N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate Ethyl chloroformate (470 mg, 4.33 mmol) was mixed with stirring 2-(1-methylpiperidin-4-yl)ethan-1-amine (560 mg, 3.94 mmol) and TEA (0.6 mL, 4.33 mmol) in dry THF ( 10 mL) solution at 0 °C with N 2 dripped down. After 20 minutes the reaction was warmed to RT and stirred for 1 hour, then the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic phase was washed with water. Separate the organic layer and Na 2 SO 4dried and evaporated. The residue was purified by flash chromatography (DCM to 2% MeOH) on a Biotage silica NH cartridge to give ethyl N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate (450 mg, 2.1 mmol, y =53%). LC-MS (ESI): m / z (M+1): 215.1 (method 2)

[0275] Intermediate 103: Methyl[2-(1-methylpiperidin-4-yl)ethyl]amine A solution of ethyl N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate (Intermediate 102, 440 mg, 2.05 mmol) in dry THF (10 mL) was added to stirring 2 M LiAlH in THF. 4 (2.57 mL, 5.13 mmol) solution at RT with N 2 Dripped below. The reaction was stirred at reflux temperature for 3 hours. The mixture was brought to RT and then cooled to 0-5° C. before adding 0.2 ml water in THF followed by 0.3 ml 15% NaOH and 0.2 ml water in THF. The mixture was warmed to RT, stirred for 30 min, then filtered through a pad of Celite®. Removal of the solvent under reduced pressure gave methyl[2-(1-methylpiperidin-4-yl)ethyl]amine (300 mg, 1.92 mmol, y=93%) which was carried on to the next step without further purification. used. LC-MS (ESI): m / z (M+1): 157.1 (method 1)

[0276] Intermediate 104: tert-butyl N-[3-(methanesulfonyloxy)propyl]-N-methylcarbamate Intermediate 104 was prepared following the method used for the synthesis of Intermediate 79 starting from tert-butyl (3-hydroxypropyl)(methyl)carbamate (1 g, 6.28 mmol) to give the title compound (1.32 g, 4.94 mmol, y=93%). LC-MS (ESI): m / z (M+1): 268.1 (method 1)

[0277] Intermediate 105: tert-butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate In a vial, tert-butyl N-[3-(methanesulfonyloxy)propyl]-N-methylcarbamate (Intermediate 104, 650 mg, 2.43 mmol) in MeCN (5 mL) was dissolved in 3-amino-1-propanol (0.93 mL). , 12.16 mmol) was added and the vial was sealed and stirred at 70° C. for 9 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and the organic solution was treated with NaHCO 3 saturated solution, washed with water, Na 2 SO 4 and filtered. Solvent was removed under reduced pressure to give tert-butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate (487 mg, 1.98 mmol, y=81%) as a colorless viscous oil. I got it as a product and used it as is. LC-MS (ESI): m / z (M+1): 247.5 (method 1)

[0278] Intermediate 106: tert-butyl N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)-N-(3-hydroxypropyl)carbamate Intermediate 106 was used for the synthesis of intermediate 59 starting from tert-butyl N-{3-[(3-hydroxypropyl)amino]propyl}-N-methylcarbamate (intermediate 105, 485 mg, 1.97 mmol). Worked up according to the method used to give the title compound (780 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 347.3 (method 1)

[0279] Intermediate 107: tert-butyl N-(3-bromopropyl)-N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)carbamate Stirring tert-butyl N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)-N-(3-hydroxypropyl)carbamate (Intermediate 106, 380mg, 1.1mmol) and PPh 3 (433 mg, 1.65 mmol) in DCM (15 mL), CBr 4 (546 mg, 1.65 mmol) in DCM (3 mL) at 0 °C and N 2 It was added little by little under the atmosphere. The resulting reaction mixture was stirred at 0° C. for 1 hour. The mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~30% EtOAc) to give tert-butyl N-(3-bromopropyl)-N-(3-{[( tert-butoxy)carbonyl](methyl)amino}propyl)carbamate (196 mg, 0.48 mmol, y=44% yield) was obtained as a colorless viscous oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 3.38 - 3.48 (m, 2 H), 3.34 (t, J = 6.93 Hz, 2 H), 3.22 (d, J = 7.04 Hz, 4 H), 2.87 ( s, 3H), 2.06 - 2.20 (m, 2H), 1.71 - 1.85 (m, 2H), 1.43 - 1.54 (m, 18H)

[0280] Intermediate 108: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({3-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7 -yl)oxy]propyl})amino}propyl)-N-methylcarbamate 4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol (Intermediate 28, 320 mg, 0.87 mmol) and K in DMF (8 mL) in a vial 2 CO 3 (274 mg, 1.98 mmol) at RT to tert-butyl N-(3-bromopropyl)-N-(3-{[(tert-butoxy)carbonyl](methyl)amino}propyl)carbamate (intermediate 107, 321 mg, 0.78 mmol) was added. The vial was sealed and stirred at 50° C. for 3 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was further diluted with EtOAc, washed twice with water, and the organic phase was 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 3% MeOH) to give tert-butyl N-(3-{[(tert-butoxy)carbonyl]({3-[(4-{[ 6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]propyl})amino}propyl)-N-methylcarbamate (149 mg, 0.21 mmol, y=27% ) was obtained as a pale yellow foam. LC-MS (ESI): m / z (M+1): 695.3 (method 1)

[0281] Intermediate 109: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-(3-{[3-(methylamino)propyl]amino}propoxy)quinolin-4-amine Intermediate 109 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({3-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl] Prepared according to the method used for the synthesis of Intermediate 21, starting from amino}quinolin-7-yl)oxy]propyl})amino}propyl)-N-methylcarbamate (Intermediate 108, 149 mg, 0.21 mmol) , to give the title compound (121 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 495.2 (method 2)

[0282] Intermediate 110: cis tert-butyl 5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate In a vial, cis-2-boc-hexahydropyrrolo[3,4-c]pyrrole (250 mg, 1.18 mmol) and K in MeCN (3.5 mL) 2 CO 3 To a mixture of (162.76 mg, 1.18 mmol) was added 2-bromoethanol (0.08 mL, 1.18 mmol) at RT and the vial was sealed and stirred at 80° C. overnight. The reaction mixture was filtered and washed with EtOAC. The solution was evaporated under reduced pressure to give cis tert-butyl 5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (320 mg, recovery assumed quantitative). , was used as is. LC-MS (ESI): m / z (M+1): 256.8 (Method 2)

[0283] Intermediate 111: cis tert-butyl 5-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate Intermediate 111 was converted to 4-chloro-7-hydroxyquinoline (150 mg, 0.83 mmol) and cis tert-butyl 5-(2-hydroxyethyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate ( Intermediate 110, 320 mg, 1.18 mmol) was prepared following the method used for the synthesis of intermediate 17 to give the title compound (700 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 418.2 (method 1)

[0284] Intermediate 112: cis tert-butyl 5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-octahydropyrrolo[ 3,4-c]pyrrole-2-carboxylate cis tert-butyl 5-{2-[(4-chloroquinolin-7-yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (intermediate 111, 560 mg, 0.54 mmol), 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 120 mg, 0.54 mmol), Cs 2 CO 3 (356 mg, 1.09 mmol), Xantphos (45 mg, 0.08 mmol) and Pd 2 (dba) 3 (54 mg, 0.06 mmol) was added 1,4-dioxane (4 mL). The vial was sealed and subjected to a MW cycle at 130°C for 50 minutes. The solids were collected by filtration, washed with EtOAc, the filtrate was evaporated under reduced pressure and the crude material was subjected to reverse-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH~70% MeCN) to give cis tert-butyl 5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7- yl)oxy]ethyl}-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (90 mg, 0.15 mmol, 28% yield) was obtained. LC-MS (ESI): m / z (M+1): 605.3 (Method 2)

[0285] Intermediate 113: cis N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{octahydropyrrolo[3,4-c]pyrrol-2-yl}ethoxy)quinoline-4 -Amine Intermediate 113 was converted to cis tert-butyl 5-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl} - starting from octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (Intermediate 112, 90 mg, 0.15 mmol), prepared according to the method used for the synthesis of Intermediate 21 to give the title compound (45 mg , 0.09 mmol, y=60%). LC-MS (ESI): m / z (M+1): 505.2 (method 2)

[0286] Intermediate 114: 4-chloro-7-(2-chloroethoxy)quinoline 4-chloro-7-hydroxyquinoline (200 mg, 1.11 mmol) and K in DMF (3.5 mL) in a vial 2 CO 3 (308 mg, 2.23 mmol) was added 1-bromo-2-chloroethane (0.37 mL, 4.45 mmol) at RT. The vial was sealed and stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate is diluted with water, extracted with EtOAc, the organic phase is washed with water and Na 2 SO 4 and filtered. The solvent was evaporated under reduced pressure to give 4-chloro-7-(2-chloroethoxy)quinoline (229 mg, 0.95 mmol, y=85%) as a pale yellow solid which was used as is. LC-MS (ESI): m / z (M+1): 242.0 (method 1)

[0287] Intermediate 115: tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]carbamate In a vial, a solution of 4-chloro-7-(2-chloroethoxy)quinoline (Intermediate 114, 183 mg, 0.76 mmol) in 1,2-dimethoxyethane (8 mL) was diluted with tert-N-(3-aminopropyl)carbamate. The butyl ester (1.32 g, 7.58 mmol) was added followed by NaI (114 mg, 0.76 mmol) and the vial was sealed and stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on a Biotage silica NH cartridge (cHex-70% EtOAc). Appropriate fractions were repurified by flash chromatography on a Biotage silica cartridge (DCM to 15% MeOH) to give tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy] Ethyl}amino)propyl]carbamate (222 mg, 0.58 mmol, 77% yield) was obtained as a pale orange oil. LC-MS (ESI): m / z (M+1): 380.1 (method 1)

[0288] Intermediate 116: (3-Aminopropyl)({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amine Intermediate 116 was started from tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]carbamate (Intermediate 115, 222 mg, 0.58 mmol). was prepared according to the method used for the synthesis of intermediate 21 to give the title compound (132 mg, 0.47 mmol, 81% yield). LC-MS (ESI): m / z (M+1): 280.0 (method 2)

[0289] Intermediate 117: tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)carbamate Intermediate 117 was prepared starting from (3-aminopropyl)({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amine (intermediate 116, 133 mg, 0.48 mmol) to intermediate 59 to give the title compound (255 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 480.2 (method 1)

[0290] Intermediate 118: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7 -yl)oxy]ethyl})amino}propyl)carbamate Intermediate 118 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)carbamate (intermediate 117, 50 mg, 0.10 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 3, 28 mg, 0.12 mmol), following the procedure used for the synthesis of intermediate 112. Worked up to give the title compound (24mg, 0.04mmol, y=34%). LC-MS (ESI): m / z (M+1): 667.3 (method 1)

[0291] Intermediate 119: 7-{2-[(3-aminopropyl)amino]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine Intermediate 119 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl] Prepared according to the method used for the synthesis of Intermediate 21 starting from amino}quinolin-7-yl)oxy]ethyl})amino}propyl)carbamate (Intermediate 118, 24 mg, 0.04 mmol) to give the title compound ( 21 mg, recovery presumed to be quantitative). LC-MS (ESI): m / z (M+1): 467.2 (Method 2)

[0292] Intermediate 120: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1,3-diazinan-1-yl)ethoxy]quinolin-4-amine In a vial, 7-{2-[(3-aminopropyl)amino]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine (Intermediate 119 , 21 mg, 0.04 mmol) in MeOH (0.8 mL) was added formaldehyde 37% w / w aqueous solution (0.02 mL, 0.22 mmol) at RT. The vial was sealed and stirred at 50° C. for 1.5 hours. The mixture was concentrated under reduced pressure to give N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1,3-diazinan-1-yl)ethoxy]quinoline- The 4-amine (22 mg, recovery assumed quantitative) was obtained as a thick yellow oil and used as is. LC-MS (ESI): m / z (M+1): 479.3 (method 2)

[0293] Intermediate 121:1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine A solution of tert-butyl-chloro-diphenylsilane (2.53 g, 9.22 mmol) in DCM (10 mL) was stirred in 2-(1-piperazinyl)ethanol (1.0 g, 7.68 mmol), pyridine (0.93 mL, 11.52 mmol). and DMAP (93.8 mg, 0.77 mmol) in DCM (20 mL) at 5° C. dropwise. The reaction was warmed to RT and stirred for 10 hours. The mixture was washed with water, the organic layer was separated and Na 2 SO 4 , filtered and evaporated. The residue was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 3% MeOH) to give 1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine (2.2 g, 5.97 mmol, y =77%). LC-MS (ESI): m / z (M+1): 368.7 (Method 2)

[0294] Intermediate 122: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl-4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine-1- carboxylate A solution of 1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}piperazine (Intermediate 121, 413 mg, 1.12 mmol) in THF (5.47 mL) was added to a stirred solution of triphosgene (334.8 mL) in MTBE (5.47 mL). mg, 1.13 mmol) at 0 °C to a mixture of N 2 dripped down. After 1 hour the solvent was evaporated. The solid was treated with MTBE and filtered. The recovered solid was treated with 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (intermediate 101, 200 mg, 0.45 mmol) and K 2 CO 3 (317 mg, 2.29 mmol) was added rapidly to the mixture. The mixture was stirred overnight at RT. The reaction was poured into ice cold water and extracted with EtOAc. Separate the organic layer and Na 2 SO 4 , filtered and evaporated. The residue was subjected to flash chromatography on a Biotage silica NH cartridge (DCM~5%MeOH / 0.5%H 2 O) to give 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-{2-[(tert-butyldiphenylsilyl)oxy ] ethyl}piperazine-1-carboxylate (120 mg, 0.16 mmol, y=35%) was obtained. LC-MS (ESI): m / z (M+1): 761.5 (method 2)

[0295] Intermediate 123: tert-butyl N-{3-[(2,2,2-trifluoroethyl)amino]propyl}carbamate Intermediate 123 was prepared following the method used for the synthesis of Intermediate 69 starting from tert-butyl N-(3-aminopropyl)carbamate (500 mg, 2.87 mmol) to give the title compound (840 mg, recovery quantitative). ) was obtained. LC-MS (ESI): m / z (M+1): 257.1 (method 2)

[0296] Intermediate 124: tert-Butyl N-{3-[N-(2,2,2-trifluoroethyl)acetamido]propyl}carbamate Intermediate 124 was used in the synthesis of intermediate 73 starting from tert-butyl N-{3-[(2,2,2-trifluoroethyl)amino]propyl}carbamate (intermediate 123, 2.87 mmol) to give the title compound (810mg, 2.71mmol, y=94%). LC-MS (ESI): m / z (M+1): 299.1 (Method 2)

[0297] Intermediate 125: (3-Aminopropyl)(2,2,2-trifluoroethyl)amine dihydrochloride DCM (4 mL) of TFA (0.83 mL, 10.86 mmol) tert-butyl N-{3-[N-(2,2,2-trifluoroethyl)acetamido]propyl}carbamate (Intermediate 124, 450 mg, 1.5 mmol) solution and stirred overnight at RT. Volatiles were removed under reduced pressure to give a sticky solid. The residue was dissolved in EtOH (5 mL), 6N HCl (3.0 mL, 18.02 mmol) was added and the resulting mixture was refluxed for 36 hours. Volatiles were removed under reduced pressure and the residue was dried to give (3-aminopropyl)(2,2,2-trifluoroethyl)amine dihydrochloride (230 mg, 1 mmol, y=67%). LC-MS (ESI): m / z (M+1): 157.4 (method 2)

[0298] Intermediate 126: N-(4-Bromopyridin-2-yl)-3-({3-[(2,2,2-trifluoroethyl)amino]propyl}amino)propanamide Intermediate 126 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 228 mg, 1 mmol), (3-aminopropyl)(2,2,2-trifluoroethyl)amine. Prepared according to the method used for the synthesis of Intermediate 30 starting from the dihydrochloride salt (Intermediate 125, 230 mg, 1 mmol) and TEA (0.7 mL, 5 mmol) to give the title compound (230 mg, 0.6 mmol, 60% yield). rate). LC-MS (ESI): m / z (M+1): 383.1 (method 1)

[0299] Intermediate 127: tert-Butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}Propyl)carbamate Intermediate 127 was converted to N-(4-bromopyridin-2-yl)-3-({3-[(2,2,2-trifluoroethyl)amino]propyl}amino)propanamide (Intermediate 126, 200 mg , 0.52 mmol) and prepared according to the method used for the synthesis of intermediate 59 to give the title compound (150 mg, 0.26 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 585.2 (method 1)

[0300] Intermediate 128: tert-Butyl N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)-N-{2-[(4-{[6-(5-chloro -2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}carbamate Intermediate 128 was converted to tert-butyl N-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-N-(3-{[(tert-butoxy)carbonyl](2,2,2- Starting from trifluoroethyl)amino}propyl)carbamate (Intermediate 127, 150mg, 0.26mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 58mg, 0.26mmol). was prepared according to the method used for the synthesis of intermediate 31 to give the title compound (55 mg, 0.08 mmol, 29% yield). LC-MS (ESI): m / z (M+1): 726.2 (method 1)

[0301] Intermediate 129: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-({3-[(2,2,2-trifluoro Ethyl)amino]propyl}amino)propanamide Intermediate 129 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino}propyl)-N-{2-[(4-{[6 Synthesis of Intermediate 21 starting from -(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}carbamate (Intermediate 128, 55mg, 0.08mmol) to give the title compound (40 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 526.3 (Method 2)

[0302] Intermediate 130: 7-(2-bromoethoxy)-4-chloroquinoline Intermediate 130 was prepared following the method used to synthesize intermediate 114, starting with 4-chloro-7-hydroxyquinoline (200 mg, 1.11 mmol) and 1,2-dibromoethane (0.59 mL, 6.85 mmol). to give the title compound (158 mg, 0.55, y=50%). LC-MS (ESI): m / z (M+1): 288.0 (method 1)

[0303] Intermediate 131: tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]-N-methylcarbamate In a vial, 7-(2-bromoethoxy)-4-chloroquinoline (Intermediate 130, 136 mg, 0.47 mmol) and K 2 CO 3To a suspension of (138 mg, 1 mmol) in MeCN (4 mL) was added N-(3-aminopropyl)-n-methylcarbamic acid tert-butyl ester (449 mg, 2.38 mmol), the vial was sealed and incubated at 70 °C for 5 minutes. Stirred for an hour. The reaction mixture was diluted with MeCN and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc. The organic solution was washed twice with water, then with brine, and Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 4% MeOH) to give tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl} Amino)propyl]-N-methylcarbamate (152 mg, 0.39 mmol, y=81%) was obtained as a colorless oil. LC-MS (ESI): m / z (M+1): 394.2 (method 1)

[0304] Intermediate 132: tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate of tert-butyl N-[3-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)propyl]-N-methylcarbamate (Intermediate 131, 152 mg, 0.38 mmol) under stirring. To a solution of DCM (2 mL) was added di-tert-butyl dicarbonate (103 mg, 0.47 mmol) in DCM (1 mL) portionwise at RT, then the resulting mixture was allowed to stand overnight. The mixture was diluted with DCM and NaHCO 3 Wash with saturated solution, Na 2 SO 4 dried at rt, filtered, the solvent removed under reduced pressure and the crude material purified by flash chromatography on a Biotage silica cartridge (cHex~50% EtOAc) to give tert-butyl N-(3-{[(tert- butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate (180mg, 0.36mmol, y=95%) as a colorless dark oil obtained as LC-MS (ESI): m / z (M+1): 495.7 (method 2)

[0305] Intermediate 133: tert-Butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7 -yl)oxy]ethyl})amino}propyl)-N-methylcarbamate Intermediate 133 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}propyl)-N-methyl For the synthesis of intermediate 112 starting from carbamate (intermediate 132, 150 mg, 0.30 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 3, 82 mg, 0.37 mmol) Prepared according to the method used to give the title compound (89 mg, 0.13 mmol, y=43%). LC-MS (ESI): m / z (M+1): 681.5 (Method 2)

[0306] Intermediate 134: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{[3-(methylamino)propyl]amino}ethoxy)quinolin-4-amine Intermediate 134 was converted to tert-butyl N-(3-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl] Prepared according to the method used for the synthesis of Intermediate 21 starting from amino}quinolin-7-yl)oxy]ethyl})amino}propyl)-N-methylcarbamate (Intermediate 133, 89 mg, 0.13 mmol) , to give the title compound (62 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 481.2 (method 2)

[0307] Intermediate 135: tert-Butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate TEA (1.22 mL, 8.72 mmol) and 4-methyl Benzenesulfonyl chloride (1.08 mL, 5.67 mmol) was then added. The mixture was stirred overnight at RT. The mixture was diluted with DCM and NaHCO 3 Washed with a saturated solution (3x), filtered through a phase separator and evaporated under reduced pressure. The crude material was purified by flash chromatography (cHex~40% EtOAc) on a Biotage silica cartridge to give tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate ( 1.60 g, 4.19 mmol, y=96%) as a colorless oil. LC-MS (ESI): m / z (M+1): 384.2 (Method 2)

[0308] Intermediate 136: Benzyl 4-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}ethyl)piperazine-1-carboxylate tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 135, 1.16g, 2.72mmol) and benzylpiperazine-1-carboxylate (500mg, 2.27mmol) ) was dissolved in dry MeCN (22.7 mL), TEA (3.16 mL, 22.7 mmol) was added and the reaction was stirred at 80° C. overnight. Volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (DCM to 10% MeOH) to give benzyl 4-(2-{1-[(tert-butoxy)carbonyl]piperidine- 4-yl}ethyl)piperazine-1-carboxylate (580 mg, 1.34 mmol, y=59%) was obtained. LC-MS (ESI): m / z (M+1): 432.3 (method 2)

[0309] Intermediate 137: Benzyl 4-[2-(piperidin-4-yl)ethyl]piperazine-1-carboxylate Intermediate 137 starting from benzyl 4-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}ethyl)piperazine-1-carboxylate (Intermediate 136, 289 mg, 0.67 mmol) was prepared according to the method used for the synthesis of intermediate 21 to give the title compound (130 mg, 0.39 mmol, y=59%). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.29 - 7.45 (m, 5 H), 5.14 (s, 2 H), 3.47 - 3.56 (m, 4 H), 3.02 - 3.20 (m, 2 H), 2.63 (td, J = 12.27, 2.53Hz, 2H), 2.30 - 2.50 (m, 6H), 1.64 - 1.77 (m, 2H), 1.33 - 1.60 (m, 3H), 1.10 - 1.32 (m , 2H)

[0310] Intermediate 138: Benzyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate Intermediate 138 was treated with benzyl 4-[2-(piperidin-4-yl)ethyl]piperazine-1-carboxylate (Intermediate 137, 250 mg, 0.75 mmol) and formaldehyde 37% w / w aqueous solution (0.41 mL, 9.65 mmol). ) and prepared according to the method used for the synthesis of intermediate 22 to give the title compound (258 mg, 0.75 mmol, recovery assumed quantitative). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.28 - 7.51 (m, 5 H), 5.14 (s, 2 H), 3.46 - 3.56 (m, 4 H), 2.71 - 2.91 (m, 2 H), 2.30 - 2.43 (m, 6H), 2.25 (s, 3H), 1.80 - 1.96 (m, 2H), 1.63 - 1.70 (m, 2H), 1.38 - 1.47 (m, 2H), 1.20 - 1.33 (m, 3H)

[0311] Intermediate 139: 1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine Ammonium formate (282.9 mg, 4.49 mmol) was added to benzyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate (Intermediate 138, 310 mg) in isopropanol (10 mL) with stirring. , 0.90 mmol) and 5% Pd on carbon (191 mg, 0.09 mmol) at RT with N 2 Added below. The reaction was warmed to 80° C. for 1 hour. After cooling, the mixture was filtered through a pad of Celite® and the organic solvent was removed under reduced pressure. The residue was treated with water and NaHCO 3 was added until pH 8. Evaporate the water. The residue was treated with DCM / MeOH, the solid was discarded and the organic solvent was removed under reduced pressure to give 1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine (170 mg, 0.80 mmol, y= 90%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.71 (d, J = 3.08 Hz, 1H), 2.62 - 2.70 (m, 5H), 2.22 (dd, J = 8.72, 6.39 Hz, 5H), 2.11 (s, 3H), 1.78 (td, J = 11.20, 2.35 Hz, 2H), 1.54 - 1.63 (m, 2H), 1.27 - 1.37 (m, 2H), 1.15 (d, J = 2.75 Hz, 1H), 1.04 - 1.14 (m, 2H)

[0312] Intermediate 140: N-(4-bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide of N-(4-bromopyridin-2-yl)-4-chlorobutanamide (Intermediate 41, 100 mg, 0.35 mmol), TEA (0.15 mL, 1.05 mmol) and 1-methylpiperazine (0.38 mL, 3.49 mmol). A THF (5.5 mL) solution was stirred at 70° C. for 24 hours. Volatiles were removed under reduced pressure and the crude material was subjected to reverse flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH~50% MeCN) to give N-(4-bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide (100 mg, 0.29 mmol, y=84%). Obtained as a yellow oil. LC-MS (ESI): m / z (M+1): 343.1 (method 1)

[0313] Intermediate 141: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl} Piperazin-1-yl)ethyl]carbamate 2-(Boc-amino)ethyl bromide (54 mg, 0.24 mmol), N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2- in dry DMF (3 mL) (Piperazin-1-yl)ethoxy]quinolin-4-amine (Example 9, 110 mg, 0.23 mmol) and K 2 CO 3 A mixture of (48 mg, 0.34 mmol) was stirred at 55° C. for 24 hours. Saturate the mixture with NH 4 It was treated with Cl solution and then diluted with brine. The aqueous phase was extracted with EtOAc, then the combined organic phases were washed with brine and Na 2 SO 4 and filtered. Evaporation of the solvent gave an orange oil which was purified by flash chromatography on a Biotage silica cartridge (DCM to 2% MeOH) to give tert-butyl N-[2-(4-{2-[ (4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]carbamate (100 mg, 0.16 mmol, y=70%) was obtained as a red oil. LC-MS (ESI): m / z (M+1): 622.9 (Method 2)

[0314] Intermediate 142: tert-Butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate 1-Methylpiperazine (163 mg, 1.63 mmol) and a catalytic amount of NaI were added to a stirring K 2 CO 3 (346 mg, 2.5 mmol) and tert-butyl 4-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}piperidine-1-carboxylate (Intermediate 135, 480 mg, 1.25 mmol) in dry MeCN (16 mL) added by RT. The reaction was stirred at 70° C. for 10 hours. After cooling, the mixture was poured into cold water and extracted with EtOAc. Separate the organic layer and Na 2 SO 4 , filtered and evaporated. The residue was purified by flash chromatography (DCM to 5% MeOH) on a Biotage silica cartridge to give tert-butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate ( 290 mg, 0.93 mmol, y=74%). LC-MS (ESI): m / z (M+1): 312.3 (Method 1)

[0315] Intermediate 143: 1-Methyl-4-[2-(piperidin-4-yl)ethyl]piperazine Intermediate 143 was prepared starting from tert-butyl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate (Intermediate 142, 290 mg, 0.93 mmol) to give intermediate 49 Prepared according to the method used for synthesis to give the title compound (190mg, 0.9mmol, y=96%). LC-MS (ESI): m / z (M+1): 212.2 (Method 1)

[0316] Intermediate 144: tert-Butyl 4-[(4-chloroquinolin-7-yl)oxy]piperidine-1-carboxylate The title compound was used in the synthesis of intermediate 17 starting from 4-chloro-7-hydroxyquinoline (250mg, 1.39mmol) and 4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (308mg, 1.53mmol) to give the title compound (430mg, 1.19mmol, y=85%). LC-MS (ESI): m / z (M+1): 363.3 (method 1)

[0317] Intermediate 145: tert-Butyl 4-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]piperidine-1-carboxylate Intermediate 145 was converted to tert-butyl 4-[(4-chloroquinolin-7-yl)oxy]piperidine-1-carboxylate (Intermediate 144, 316 mg, 0.67 mmol) and 6-(5-chloro-2-fluoro Prepared according to the method used for the synthesis of Intermediate 9 starting from phenyl)pyridazin-4-amine (Intermediate 3, 150 mg, 0.67 mmol) to give the title compound (230 mg, 0.42 mmol, 62% yield) Obtained. LC-MS (ESI): m / z (M+1): 550.3 (method 1)

[0318] Intermediate 146: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-(piperidin-4-yloxy)quinolin-4-amine Intermediate 146 was converted to tert-butyl 4-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]piperidine-1-carboxylate Prepared following the method used for the synthesis of intermediate 49 starting from (intermediate 145, 230mg, 0.42mmol) to give the title compound (129mg, 0.29mmol, y=69%). LC-MS (ESI): m / z (M+1): 450.2 (method 2)

[0319] Intermediate 147: tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine- 1-carboxylate Intermediate 147 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate (Intermediate 30, 96 mg, 0.23 mmol) and 6-(5- Prepared according to the method used for the synthesis of Intermediate 31 starting from chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 50 mg, 0.21 mmol) to give the title compound (90 mg, 0.16 mmol, 75% yield). LC-MS (ESI): m / z (M+1): 5760.3 (Method 2)

[0320] Intermediate 148: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl) Carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide ( A solution of Example 74, 54 mg, 0.11 mmol) in DMF (0.57 mL) was treated with tert-butyl N-(2-bromoethyl)carbamate (77 mg, 0.34 mmol) and TEA (0.09 mL, 0.69 mmol) at RT. The mixture was stirred for 60 hours at RT. saturated NaHCO 3The reaction was quenched with solution and diluted with brine. The mixture was extracted with EtOAc (x3), filtered using a phase separator and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage silica NH (DCM to 2% MeOH) followed by flash chromatography on Biotage silica (EtOAc to 50% MeOH) to give tert-butyl N-[2-(4 -{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl) Ethyl]carbamate (49 mg, 0.08 mmol, 69% yield) was obtained as an off-white solid. LC-MS (ESI): m / z (M+1): 613.5 (Method 2)

[0321] Intermediate 149: N-(4-Bromopyridin-2-yl)-3-[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]propanamide Intermediate 149 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 233 mg, 1.03 mmol), (3-ethoxyazetidin-3-yl)methanol hydrochloride (206 mg, 1.23 mmol) and TEA (0.29 mL, 2.05 mmol), prepared according to the method used for the synthesis of intermediate 30 to give the title compound (325 mg, 0.91 mmol, 88% yield). LC-MS (ESI): m / z (M+1): 358.1 (method 1)

[0322] Intermediate 150: N-[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-methoxyquinolin-4-amine Intermediate 150 was prepared from 4-chloro-7-methoxyquinoline (139 mg, 0.72 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 150 mg, 0.6 mmol). ) and prepared according to the method used for the synthesis of intermediate 13 to give the title compound (170 mg, 0.43 mmol, 72% yield). LC-MS (ESI): m / z (M+1): 395.1 (method 1)

[0323] Intermediate 151: 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-ol hydrobromide Intermediate 151 was prepared from N-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-methoxyquinolin-4-amine (Intermediate 150, 140 mg, 0.35 mmol). Starting and prepared according to the method used for the synthesis of intermediate 101, the title compound (170 mg, recovery assumed quantitative) was obtained. LC-MS (ESI): m / z (M+1): 381.1 (method 2)

[0324] Intermediate 152: N-(4-Bromopyridin-2-yl)-3-[4-(2-methanesulfonylethyl)piperazin-1-yl]propanamide Intermediate 152 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), 1-(2-methanesulfonylethyl)piperazine dihydrochloride (350 mg, 1.5 mmol) and TEA (0.49 mL, 4 mmol), prepared according to the method used for the synthesis of intermediate 30 to give the title compound (316 mg, 0.65 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 421.0 (method 2)

[0325] Intermediate 153: N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide A solution of 4-bromo-2-pyridinamine (780 mg, 4.51 mmol) and TEA (0.69 mL, 4.96 mmol) in THF (23.1 mL) was treated with 2,2,2-trichloroacetyl chloride (0.48 mL, 4.28 mmol) at 0°C. processed with The mixture was stirred at the same temperature for 10 minutes and then at RT for 4 hours. The mixture was cooled to 0°C and carefully treated with water and then saturated NaHCO. 3 The reaction was quenched with solution. The mixture was extracted with EtOAc and Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (cHex~100% EtOAc) on Biotage silica NH to give N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (1.10 g, 3.45 g). mmol, 77% yield) as a white solid. LC-MS (ESI): m / z (M+1): 318.8 (method 1)

[0326] Intermediate 154: N-(4-bromopyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxamide DMSO (4.2 mL) and Na 2 CO 3 N-(4-Bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 153, 200 mg, 0.63 mmol) in (233 mg, 2.2 mmol), commercially available 2-methyl-2,7- A mixture of diazaspiro[3.5]nonane dihydrochloride (147 mg, 0.69 mmol) was stirred at 100° C. for 2.5 hours. Saturate the mixture with NaHCO 3 Solution and extracted with DCM. Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM to 5% MeOH) on Biotage silica NH to give N-(4-bromopyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane. -7-carboxamide (90 mg, 0.265 mmol, 42% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M+1): 341.1 (method 2)

[0327] Intermediate 155: tert-Butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamate Intermediate 155 was prepared with tert-butyl 4-bromopyridin-2-ylcarbamate (125mg, 0.46mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 100 mg, 0.42 mmol) and prepared according to the method used for the synthesis of intermediate 31 to give the title compound (89 mg, 0.21 mmol, 50% yield). LC-MS (ESI): m / z (M+1): 430.2 (method 1)

[0328] Intermediate 156: N4-[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]pyridine-2,4-diamine Intermediate 156 was converted to tert-butyl N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamate (Intermediate 155 , 89 mg, 0.21 mmol) was prepared following the method used for the synthesis of intermediate 21 to give the title compound (42 mg, 0.13 mmol, y=62%). LC-MS (ESI): m / z (M+1): 330.1 (method 1)

[0329] Intermediate 157: 1,5-dimethyl 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazine -1-yl) pentanedioate N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine (Example 9, 150 mg) in a vial , 0.31 mmol) in MeOH (1.8 mL) was added dimethyl (E)-pent-2-enedioate (0.32 mL, 2.26 mmol) and the vial was sealed and stirred overnight at 70°C. The mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (DCM to 2% MeOH) to yield 1,5-dimethyl 3-(4-{2-[(4-{[ 6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)pentanedioate (85mg, 0.13mmol, y=42%) was obtained as a pale yellow solid. LC-MS (ESI): m / z (M+1): 637.8 (Method 2)

[0330] Intermediate 158: 4-chloro-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline Intermediate 158, starting from 4-chloro-6-methoxyquinolin-7-ol (500 mg, 2.39 mmol) and 1-(2-hydroxyethyl)-4-methylpiperazine (447 mg, 3.1 mmol), was converted to intermediate Prepared according to the method used for the synthesis of 20 to give the title compound (198mg, 0.58mmol, 25% yield). LC-MS (ESI): m / z (M+1): 336.2 (method 1)

[0331] Intermediate 159: N-(4-bromopyridin-2-yl)-2-chloroacetamide 2-Chloroacetyl chloride (0.25 mL, 3.18 mmol) was added to a solution of 4-bromo-2-pyridinamine (500 mg, 2.89 mmol) and TEA (1.21 mL, 8.67 mmol) in dry DCM (14.45 mL) at 0 °C. Dripped. The mixture was stirred at RT for 3 hours. The mixture was diluted with DCM and NaHCO 3 Washed with saturated 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 N-(4-bromopyridin-2-yl)-2-chloroacetamide (470 mg, 1.88 mmol, y=65% ) was obtained as an off-white solid. LC-MS (ESI): m / z (M+1): 249.0 (method 2)

[0332] Intermediate 160: tert-Butyl 4-{[(4-chloroquinolin-7-yl)oxy]methyl}piperidine-1-carboxylate Intermediate 160 starting from 4-chloro-6-methoxyquinolin-7-ol (150mg, 0.83mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (198mg, 0.92mmol) Prepared according to the method used for the synthesis of Intermediate 17 to give the title compound (280mg, 0.74mmol, 89% yield). LC-MS (ESI): m / z (M+1): 377.2 (method 1)

[0333] Intermediate 161: tert-Butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]methyl}piperidine-1-carboxylate Intermediate 161 was converted to tert-butyl 4-{[(4-chloroquinolin-7-yl)oxy]methyl}piperidine-1-carboxylate (Intermediate 161, 241 mg, 0.64 mmol) and 6-(5-chloro- Prepared according to the method used for the synthesis of Intermediate 9 starting from 2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 130 mg, 0.58 mmol) to give the title compound (310 mg, 0.55 mmol, 95% yield). rate). LC-MS (ESI): m / z (M+1): 564.3 (method 1)

[0334] Intermediate 162: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(piperidin-4-yl)methoxy]quinolin-4-amine Intermediate 162 was converted to tert-butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]methyl}piperidine-1 -Carboxylate (Intermediate 161, 282 mg, 0.42 mmol) was prepared following the method used for the synthesis of Intermediate 21 to give the title compound (190 mg, 0.41 mmol, y=96%). LC-MS (ESI): m / z (M+1): 464.2 (Method 2)

[0335] Intermediate 163: tert-butyl N-[2-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)ethyl]-N-methylcarbamate Intermediate 163 was prepared from 7-(2-bromoethoxy)-4-chloroquinoline (Intermediate 130, 100 mg, 0.35 mmol) and N-(2-aminoethyl)-N-methylcarbamic acid tert-butyl ester (305 mg, 1.75 mmol) and prepared according to the method used for the synthesis of intermediate 131 to give the title compound (140 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 380.2 (method 1)

[0336] Intermediate 164: tert-butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate Intermediate 164 was converted to tert-butyl N-[2-({2-[(4-chloroquinolin-7-yl)oxy]ethyl}amino)ethyl]-N-methylcarbamate (Intermediate 163, 140 mg, 0.37 mmol ) and prepared according to the method used for the synthesis of intermediate 132 to give the title compound (18 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 681.5 (Method 2)

[0337] Intermediate 165: tert-Butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7 -yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate Intermediate 165 was converted to tert-butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-chloroquinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methyl For the synthesis of intermediate 112 starting from carbamate (intermediate 164, 176 mg, 0.31 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 3, 67 mg, 0.30 mmol) Prepared according to the method used to give the title compound (135 mg, 0.20 mmol, y=68%). LC-MS (ESI): m / z (M+1): 667.5 (Method 2)

[0338] Intermediate 166: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{[2-(methylamino)ethyl]amino}ethoxy)quinolin-4-amine Intermediate 166 was converted to tert-butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl] Prepared according to the method used for the synthesis of Intermediate 21 starting from amino}quinolin-7-yl)oxy]ethyl})amino}ethyl)-N-methylcarbamate (Intermediate 165, 135 mg, 0.20 mmol) , to give the title compound (100 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 467.3 (method 2)

[0339] Intermediate 167: 1-tert-butyl 2-methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1,2-dicarboxylate Intermediate 167 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.65 mmol) and 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate. Prepared following the method used for the synthesis of intermediate 30 starting from (288mg, 1.18mmol) to give the title compound (248mg, 0.53mmol, 80% yield). LC-MS (ESI): m / z (M+1): 471.1 (method 1)

[0340] Intermediate 168: 1-tert-butyl 2-methyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl ]ethyl}piperazine-1,2-dicarboxylate Intermediate 168 was converted to 1-tert-butyl 2-methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1,2-dicarboxylate (Intermediate 167, 109 mg, 0.23 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 50 mg, 0.21 mmol) following the method used for the synthesis of intermediate 31 to give the title compound (110 mg, 0.17 mmol, 83% yield). LC-MS (ESI): m / z (M+1): 628.4 (Method 2)

[0341] Intermediate 169: tert-Butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)ethyl]-N-methylcarbamate Intermediate 169 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol) and N-(2-aminoethyl)-n-methylcarbamic acid tert-butyl ester. Prepared following the method used for the synthesis of intermediate 30 starting from (288mg, 1.65mmol) to give the title compound (240mg, 0.6mmol, 90% yield). LC-MS (ESI): m / z (M+1): 403.1 (method 1)

[0342] Intermediate 170: tert-butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)ethyl]-N-methylcarbamate Intermediate 170 was converted to tert-butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}amino)ethyl]-N-methylcarbamate (Intermediate 169, 240 mg, 0.60 mmol ) and prepared according to the method used for the synthesis of intermediate 59 to give the title compound (238 mg, 0.47 mmol, y=79%). LC-MS (ESI): m / z (M+1): 503.2 (method 1)

[0343] Intermediate 171: tert-Butyl N-(2-{[(tert-butoxy)carbonyl]({2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino)}pyridin-2-yl)carbamoyl]ethyl})amino}ethyl)-N-methylcarbamate Intermediate 171 was converted to tert-butyl N-[2-({2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}[(tert-butoxy)carbonyl]amino)ethyl]-N-methylcarbamate ( Starting from intermediate 170, 130 mg, 0.26 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 56 mg, 0.24 mmol), intermediate 31 Prepared according to the method used for synthesis to give the title compound (114 mg, 0.17 mmol, 73% yield). LC-MS (ESI): m / z (M+1): 658.4 (method 1)

[0344] Intermediate 172: 1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate Intermediate 172 was used in the synthesis of intermediate 22 starting from methyl-4-boc-piperazine-2-carboxylate (150 mg, 0.61 mmol) and formaldehyde 37% w / w aqueous solution (0.23 mL, 3.07 mmol). to give the title compound (124mg, 0.48mmol, y=78%). LC-MS (ESI): m / z (M+1): 293.1 (method 1)

[0345] Intermediate 173: Methyl 1-methylpiperazine-2-carboxylate hydrochloride 1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (intermediate 172 (124 mg, 0.48 mmol) in 4 M HCl in dioxane (1.2 mL, 4.8 mmol) and MeOH (1.2 mL) was stirred at RT for 2 h Volatiles were removed under reduced pressure to give methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 160 mg, 0.82 mmol, recovery assumed quantitative), It was used in the next step without further purification. LC-MS (ESI): m / z (M+1): 159.1 (Method 2)

[0346] Intermediate 174: Methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate Intermediate 174 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 83 mg, 0.37 mmol), methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 0.47 mmol) and TEA (0.1 mL, 0.73 mmol), prepared according to the method used for the synthesis of intermediate 30 to give the title compound (135 mg, 0.35 mmol, 96% yield). LC-MS (ESI): m / z (M+1): 383.1 (method 1)

[0347] Intermediate 175: N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide N-(4-Bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 200 mg, 0.79 mmol) was added to stirring 1-methyl-1,4-diazepane (181 mg, 1.59 mmol) in dry DMF. (3 mL) was added to the solution at RT. After 3 hours, the mixture was replaced with H 2 Treated with O and extracted with EtOAc. The organic layer is separated, washed with water and Na 2 SO 4 dried, filtered and evaporated to give N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide (180 mg, 0.55 mmol, 69% yield) was obtained. LC-MS (ESI): m / z (M+1): 327.4 (method 2)

[0348] Intermediate 176: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate N-(4-Bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 150 mg, 0.60 mmol), 1-piperazinecarboxylic acid tert-butyl ester (224 mg, 1.2 mmol) in dry DMF (6 mL) and K 2 CO 3 A mixture of (249 mg, 1.8 mmol) was stirred under nitrogen at RT for 18 h. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed several times with brine and Na 2 SO 4 and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~45% EtOAc) to give tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}. Piperazine-1-carboxylate (150 mg, 0.38 mmol, y=62%) was obtained as a white sticky solid. LC-MS (ESI): m / z (M+1): 399.2 (method 1)

[0349] Intermediate 177: N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide Starting with intermediate 177 from tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (intermediate 176, 140 mg, 0.35 mmol), intermediate 21 to give the title compound (104 mg, 0.35 mmol, y=99%). LC-MS (ESI): m / z (M+1): 299.1 (Method 2)

[0350] Intermediate 178: Methyl 2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)acetate In a solution of N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 104 mg, 0.35 mmol) in DMF (3.5 mL), K 2 CO 3 (96 mg, 0.700 mmol) was added followed by 2-bromoacetic acid methyl ester (0.04 mL, 0.38 mmol). The mixture was stirred at RT for 1.5 hours. Saturate the mixture with 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 (DCM to 15% MeOH) on a Biotage silica cartridge. Evaporation of the appropriate fractions under reduced pressure gave methyl 2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)acetate (190 mg, recovery assumed quantitative). Obtained as a white solid. LC-MS (ESI): m / z (M+1): 371.1 (method 1)

[0351] Intermediate 179: Ethyl (2E / Z)-4-[benzyl({2-[(triphenylmethyl)amino]ethyl})amino]but-2-enoate To a solution of N-benzyl-N'-tritylethane-1,2-diamine (1.4 g, 3.57 mmol) in MeCN (10 mL), K 2 CO 3 (0.99 g, 7.13 mmol) and ethyl (2E / Z)-4-bromo-2-butenoate (0.49 mL, 3.57 mmol) were added. The mixture was heated at 50°C for 90 minutes. EtOAc and water were added, the product was extracted with EtOAc (2×), the organic phases were collected, dried, evaporated, and the crude material was purified by flash chromatography (cHex~10% EtOAc) on a Biotage silica cartridge. gave ethyl (E / Z)-4-[benzyl-[2-(tritylamino)ethyl]amino]but-2-enoate (1.57 g, 3.11 mmol, y=87%) as a white wax. . LC-MS (ESI): m / z (M+1): 505.1 (method 1)

[0352] Intermediate 180: Methyl 2-(4-benzylpiperazin-2-yl)acetate Ethyl (2E / Z)-4-[benzyl({2-[(triphenylmethyl)amino]ethyl})amino]but-2-enoate (intermediate 179, 1.57 g, 3.11 mmol) in MeOH (6 mL) and the mixture was refluxed for 1 h. Volatiles were removed under reduced pressure and the residue was loaded onto SCX, washed with MeOH and 1N NH. 3 of MeOH solution. Evaporation of the basic fractions gave methyl 2-(4-benzylpiperazin-2-yl)acetate (560 mg, 2.25 mmol, y=72%) which was used directly in the next step. LC-MS (ESI): m / z (M+1): 248.7 (method 2)

[0353] Intermediate 181: tert-butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate Di-tert-butyl dicarbonate (591 mg, 2.71 mmol) was added to a solution of methyl 2-(4-benzylpiperazin-2-yl)acetate (Intermediate 180, 560 mg, 2.26 mmol) in DCM (6 mL). The solution was stirred at RT for 1 hour. Volatiles were removed under reduced pressure. The crude material was purified by flash chromatography (cHex~15% EtOAc) on a Biotage silica cartridge to give tert-butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (410 mg, 1.2 mmol, y=52%) as a colorless oil. LC-MS (ESI): m / z (M+1): 349.2 (method 1)

[0354] Intermediate 182: tert-Butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate A solution of tert-butyl 4-benzyl-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 181, 410 mg, 1.18 mmol) in MeOH (8 mL) was 2 , followed by the addition of 10% Pd / C (118 mg, 1.18 mmol) and the resulting suspension overnight at RT in H 2 It was stirred under atmosphere. The next day the catalyst was filtered through a pad of Celite®, rinsed with MeOH and the solvent was dried under reduced pressure to give tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (280 mg, 1.08 mmol). , y=92%) as a colorless oil. LC-MS (ESI): m / z (M+1): 259.1 (method 1)

[0355] Intermediate 183: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate Intermediate 183 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1. - Carboxylate (Intermediate 182, 278mg, 1.07mmol) was prepared as described for Intermediate 30 to give the title compound (320mg, 0.53mmol, 75% yield). LC-MS (ESI): m / z (M+1): 487.1 (method 1)

[0356] Intermediate 184: tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-2 -(2-Methoxy-2-oxoethyl)piperazine-1-carboxylate Intermediate 184 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 183 , 157 mg, 0.32 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 70 mg, 0.29 mmol) used in the synthesis of intermediate 31. The title compound (106mg, 0.16mmol, 56% yield) was obtained. LC-MS (ESI): m / z (M+1): 642.3 (Method 2)

[0357] Intermediate 185: Methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate Intermediate 185 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 183 , 100 mg, 0.20 mmol) and prepared according to the method used for the synthesis of intermediate 21 to give the title compound (100 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 387.1 (method 2)

[0358] Intermediate 186: Methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazin-2-yl)acetate Intermediate 186 was treated with methyl 2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate (Intermediate 185, 100 mg, 0.20 mmol) and formaldehyde 37%. Intermediate 22 was prepared as described for intermediate 22 starting from w / w aqueous solution (0.03 mL, 0.39 mmol) to give the title compound (100 mg, 0.25 mmol, 97% yield). LC-MS (ESI): m / z (M+1): 399.1 (method 1)

[0359] Intermediate 187: 1-tert-butyl 2-methyl 4-methylpiperazine-1,2-dicarboxylate Intermediate 187 was prepared starting with 1-tert-butyl 2-methylpiperazine-1,2-dicarboxylate (200 mg, 0.82 mmol) and formaldehyde 37% w / w aqueous solution (0.31 mL, 4.09 mmol) to give intermediate Prepared according to the method used for the synthesis of 22 to give the title compound (173 mg, 0.7 mmol, 82% yield). LC-MS (ESI): m / z (M+1): 259.2 (method 2)

[0360] Intermediate 188: Methyl 4-methylpiperazine-2-carboxylate hydrochloride Intermediate 188 was prepared following the procedure used for the synthesis of intermediate 173 starting from 1-tert-butyl 2-methyl 4-methylpiperazine-1,2-dicarboxylate (Intermediate 187, 170 mg, 0.66 mmol). Worked up to give the title compound (170 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 159.1 (Method 2)

[0361] Intermediate 189: Methyl 1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazine-2-carboxylate Intermediate 189 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 110 mg, 0.48 mmol), methyl 4-methylpiperazine-2-carboxylate hydrochloride (Intermediate 188, 123 mg, 0.63 mmol) and TEA (0.14 mL, 0.97 mmol) was prepared as described for intermediate 30 to give the title compound (82 mg, 0.21 mmol, 44% yield). LC-MS (ESI): m / z (M+1): 385.1 (method 1)

[0362] Intermediate 190: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate Intermediate 190 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 110 mg, 0.48 mmol), commercially available N-4-Boc-2-piperazine acetic acid methyl ester (150 mg, 0.58 mmol) and TEA (0.07 mL, 0.48 mmol) was prepared as described for intermediate 30 to give the title compound (180 mg, 0.37 mmol, 78% yield). LC-MS (ESI): m / z (M+1): 485.0 (method 2)

[0363] Intermediate 191: Methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate Intermediate 191 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 190 , 180 mg, 0.37 mmol) was prepared as described for intermediate 173 to give the title compound (133 mg, 0.34 mmol, 93% yield). LC-MS (ESI): m / z (M+1): 384.8 (method 2)

[0364] Intermediate 192: Methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazin-2-yl)acetate Intermediate 192 was treated with methyl 2-(1-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate (Intermediate 191, 130 mg, 0.34 mmol) and formaldehyde 37%. Intermediate 22 was prepared as described for intermediate 22 starting from w / w aqueous solution (0.04 mL, 0.5 mmol) to give the title compound (135 mg, 0.34 mmol, 99% yield). LC-MS (ESI): m / z (M+1): 399.6 (method 2)

[0365] Intermediate 193: tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-3 -(2-Methoxy-2-oxoethyl)piperazine-1-carboxylate Intermediate 193 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Intermediate 190 , 101 mg, 0.21 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 45 mg, 0.19 mmol) used in the synthesis of intermediate 31. The title compound (79 mg, 0.12 mmol, 65% yield) was obtained. LC-MS (ESI): m / z (M+1): 642.2 (Method 2)

[0366] Intermediate 194: N-(4-bromopyridin-2-yl)-3-piperazin-1-ylpropanamide Intermediate 194 was prepared starting from tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazine-1-carboxylate (Intermediate 30, 650 mg, 1.41 mmol), followed by intermediate Prepared according to the method used to synthesize isomer 21 to give the title compound (488 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 315.0 (Method 2)

[0367] Intermediate 195: tert-Butyl N-[2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate Intermediate 195 was converted to 1N-(4-bromopyridin-2-yl)-3-piperazin-1-ylpropanamide (Intermediate 194, 150 mg, 0.48 mmol) and N-boc-(methylamino)acetaldehyde (124 mg, 0.72 mmol) and prepared according to the method used for the synthesis of intermediate 22 to give the title compound (160 mg, 0.34 mmol, 71% yield). LC-MS (ESI): m / z (M+1): 470.4 (method 2)

[0368] Intermediate 196: tert-Butyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl) Carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate Intermediate 196 was converted to tert-butyl N-[2-(4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate (intermediate 195, 129 mg, 0.27 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 60 mg, 0.25 mmol) for the synthesis of intermediate 31. Prepared according to the method used to give the title compound (103 mg, 0.16 mmol, 66% yield). LC-MS (ESI): m / z (M+1): 627.1 (method 2)

[0369] Intermediate 197: tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate Intermediate 197 was converted to N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 156 mg, 0.53 mmol) and N-Boc-(methylamino)acetaldehyde (138 mg , 0.8 mmol) and prepared according to the method used for the synthesis of intermediate 22 to give the title compound (176 mg, 0.38 mmol, 72% yield). LC-MS (ESI): m / z (M+1): 456.7 (Method 2)

[0370] Intermediate 198: tert-Butyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl] Methyl}piperazin-1-yl)ethyl]-N-methylcarbamate Intermediate 198 was converted to tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 197, 169 mg, 0.37 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (intermediate 90, 80 mg, 0.34 mmol) was used in the synthesis of intermediate 31. Prepared according to the method to give the title compound (110 mg, 0.18 mmol, 53% yield). LC-MS (ESI): m / z (M+1): 627.1 (method 2)

[0371] Intermediate 199: tert-Butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate Intermediate 199 was converted to N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 234mg, 0.78mmol) and tert-butyl N-(2-oxoethyl)carbamate. Prepared following the method used for the synthesis of intermediate 22 starting from (372mg, 2.34mmol) to give the title compound (179mg, 0.4mmol, 52% yield). LC-MS (ESI): m / z (M+1): 442.3 (Method 2)

[0372] Intermediate 200: tert-Butyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl] Methyl}piperazin-1-yl)ethyl]carbamate Intermediate 200 was converted to tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate (Intermediate 199, 174 mg, 0.39 mmol ) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 85 mg, 0.36 mmol) following the procedure used for the synthesis of Intermediate 31. to give the title compound (65 mg, 0.11 mmol, 30% yield). LC-MS (ESI): m / z (M+1): 599.5 (Method 2)

[0373] Intermediate 201: N-(4-{[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)prop-2-enamide N-(4-{[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl) Propanamide (Example 16, 140 mg, 0.29 mmol) in MeOH (2.43 mL) and H 2 A solution of O (0.80 mL) was treated with Oxone® (195 mg, 0.64 mmol) and stirred at RT for 2 h. The mixture was diluted with water and extracted with EtOAc and saturated NaHCO. 3 solution. Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Biotage silica cartridge (DCM to 60% MeOH) to give N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazine-4 -yl]amino}pyridin-2-yl)prop-2-enamide (21 mg, 0.05 mmol, 19% yield) was obtained as an off-white solid. LC-MS (ESI): m / z (M+1): 384.7 (method 2)

[0374] Intermediate 202: tert-Butyl (1S,4S)-5-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Intermediate 202 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.89 mmol), commercially available tert-butyl(1S,4S)-2,5-diazabicyclo[ 2.2.1]Prepared as described for Intermediate 30 starting from heptane-2-carboxylate (209 mg, 1.05 mmol) and TEA (0.12 mL, 0.99 mmol) to give the title compound (380 mg, 0.89 mmol, quantitative yield) was obtained. LC-MS (ESI): m / z (M+1): 425.3 (Method 2)

[0375] Intermediate 203: N-(4-Bromopyridin-2-yl)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide Intermediate 203 was converted to tert-butyl(1S,4S)-5-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxy Prepared according to the method used for the synthesis of intermediate 173 starting from lat (intermediate 202, 380 mg, 0.89 mmol) to give the title compound (260 mg, 0.80 mmol, y=89%). LC-MS (ESI): m / z (M+1): 325.3 (Method 2)

[0376] Intermediate 204: N-(4-bromopyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide Intermediate 204 was converted to N-(4-bromopyridin-2-yl)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide (Intermediate 203, 260 mg, 0.80 mmol) and formaldehyde 37% w / w aqueous solution (0.30 mL, 4 mmol), prepared according to the method used for the synthesis of intermediate 22 to give the title compound (215 mg, 0.63 mmol, y=79% ). LC-MS (ESI): m / z (M+1): 340.9 (method 2)

[0377] Intermediate 205: 8-tert-butyl 2-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)2,8-diazaspiro[4.5]decane-2, 8-dicarboxylate DIPEA (0.15 mL, 0.87 mmol) was added to stirring tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (105 mg, 0.44 mmol) and -{in DCM (10 mL) and DMSO (1 mL). Added to a mixture of [6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (Intermediate 101, 150mg, 0.29mmol) at RT. After 5 minutes the mixture was cooled to 5° C. and 4-nitrophenyl chloroformate (88 mg, 0.44 mmol) was added. After 30 min the reaction was warmed to RT. After 4 hours, the mixture was diluted with DCM, water and NaHCO. 3 Washed with aqueous solution. Separate the organic layer and Na 2 SO 4 , filtered and evaporated. The residue was subjected to flash chromatography on a Biotage silica NH cartridge (DCM~3%MeOH / 0.3%H 2 O) to give 8-tert-butyl 2-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)2,8-diazaspiro [4.5]Decane-2,8-dicarboxylate (120 mg, 0.19 mmol, y=65%) was obtained. LC-MS (ESI): m / z (M+1): 633.4 (method 2)

[0378] Intermediate 206: 1-tert-butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate Methyl-4-Boc-piperazine-2-carboxylate (300 mg, 1.23 mmol) and K in a suitable vial while stirring. 2 CO 3 To a suspension of (271 mg, 1.96 mmol) in MeCN (2 mL) was added 2-iodopropane (0.16 mL, 1.6 mmol). The vial was capped and heated at 85° C. (external temperature) overnight. Furthermore K 2 CO 3 (271 mg, 1.96 mmol) and 2-iodopropane (0.16 mL, 1.6 mmol) were added again and heated at the same temperature for a further 8 hours. The mixture was diluted with DCM and the solid filtered off and washed with more DCM. The filtrate was evaporated under reduced pressure. The crude material was purified by flash chromatography (DCM to 5% MeOH) on a Biotage silica cartridge to give 1-tert-butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate ( 292 mg, 1.02 mmol, y=83%) as a pale yellow oil. LC-MS (ESI): m / z (M+1): 287.6 (method 2)

[0379] Intermediate 207: Methyl 1-(propan-2-yl)piperazine-2-carboxylate dihydrochloride Intermediate 207 was prepared starting from 1-tert-butyl 3-methyl 4-(propan-2-yl)piperazine-1,3-dicarboxylate (Intermediate 206, 290 mg, 1.01 mmol) to give intermediate 173 Prepared according to the method used for synthesis to give the title compound (400 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 187.0 (Method 2)

[0380] Intermediate 208: Methyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-1-(propan-2-yl)piperazine-2-carboxylate Intermediate 208 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200mg, 0.89mmol), methyl 1-(propan-2-yl)piperazine-2-carboxylate Prepared as described for Intermediate 30 starting from the hydrochloride salt (Intermediate 207, 1.06mmol) and TEA (0.25mL, 1.76mmol) to give the title compound (211mg, 0.51mmol, y=58%) rice field. LC-MS (ESI): m / z (M+1): 413.4 (method 2)

[0381] Intermediate 209: tert-butyl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate Intermediate 209 was prepared starting from tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (327mg, 1.44mmol) and formaldehyde 37% w / w aqueous solution (0.27mL, 3.6mmol) to give intermediate Prepared according to the method used for the synthesis of 22 to give the title compound (244mg, 1.02mmol, 70% yield). LC-MS (ESI): m / z (M+1): 241.2 (method 1)

[0382] Intermediate 210: 2-Methyl-2,7-diazaspiro[3.5]nonane dihydrochloride Method Used to Synthesize Intermediate 173 Starting Intermediate 210 from tert-Butyl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (Intermediate 209, 244 mg, 1.01 mmol) to give the title compound (202 mg, 0.95 mmol, y=94%). 1 H NMR (400 MHz, methanol-d4) δ ppm 4.07 (s, 4H), 3.20 (t, J = 5.9 Hz, 4H), 2.96 (s, 3H), 2.17 - 2.10 (m, 4H)

[0383] Intermediate 211: tert-butyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate Intermediate 211 was prepared starting with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.05 g, 4.63 mmol) and formaldehyde 37% w / w aqueous solution (348 mL, 46.31 mmol) to give intermediate Prepared according to the method used for the synthesis of 22 to give the title compound (718 mg, 2.99 mmol, y=64%). LC-MS (ESI): m / z (M+1): 241.2 (method 2)

[0384] Intermediate 212: 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride Method Used to Synthesize Intermediate 173 Starting Intermediate 212 from tert-Butyl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate (Intermediate 211, 718 mg, 2.99 mmol) to give the title compound (620 mg, 2.9 mmol, y=97%). 1 H NMR (500 MHz, methanol-d4) δ ppm 3.82 - 4.10 (m, 4 H), 3.48 (br. s, 2 H), 3.05 (br. s, 2 H), 2.86 (s, 3 H), 2.32 (br.s, 2H), 2.04 (br.s, 2H)

[0385] Intermediate 213: N-(4-bromopyridin-2-yl)-2-(morpholin-4-yl)acetamide Synthesis of intermediate 176 starting with intermediate 213 from N-(4-bromopyridin-2-yl)-2-chloroacetamide (intermediate 159, 250 mg, 1 mmol) and morpholine (0.13 mL, 1.5 mmol) to give the title compound (200 mg, 0.67 mmol, y=66%). LC-MS (ESI): m / z (M+1): 302.1 (method 1)

[0386] Intermediate 214: N-(4-bromopyridin-2-yl)-3-(thiomorpholin-4-yl)propanamide Intermediate 214 was synthesized starting from N-(4-bromopyridin-2-yl)prop-2-enamide (intermediate 29, 150 mg, 0.66 mmol) and thiomorpholine (154 mg, 1.49 mmol) to intermediate 30. Prepared according to the method used for synthesis to give the title compound (174 mg, 0.53 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 332.0 (method 1)

[0387] Intermediate 215: 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (500 mg, 1.82 mmol) was charged to SCX and 1N NH 3of MeOH solution. Fractions were concentrated under reduced pressure and then treated with HCl (4N in dioxane) (1.82 mL, 7.3 mmol). The mixture was concentrated under reduced pressure to give 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (140 mg, 0.76 mmol, y=41%) as a white solid. LC-MS (ESI): m / z (M+1): 113.0 (method 1)

[0388] Intermediate 216: N-(4-bromopyridin-2-yl)-3-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}propanamide Intermediate 216 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 60 mg, 0.26 mmol), 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride. The title compound (78 mg, 0.23 mmol, 87% yield) was prepared following the method used for the synthesis of Intermediate 30 starting from the salt (Intermediate 215, 59 mg, 0.32 mmol) and TEA (0.11 mL, 0.79 mmol). rate). LC-MS (ESI): m / z (M+1): 340.9 (method 2)

[0389] Intermediate 217: (1R,4R)-2-(1H-imidazole-1-carbonyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (1R,4R)-2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (200 mg, 1.08 mmol) and 1,1′-carbonyldiimidazole (192.73 mg, 1.19 mmol) under stirring. To a DCM (5.4 mL) suspension was added TEA (0.31 mL, 2.22 mmol) and the reaction was stirred overnight at RT. Dilute the mixture with water and add saturated Na 2 CO 3 The pH was adjusted to about 9 using the solution. The phases were separated and the aqueous phase was extracted with DCM (2x). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give (1R,4R)-2-(1H-imidazole-1-carbonyl)-5-methyl-2,5-diazabicyclo[2.2.1] Heptane (225 mg, 1.08 mmol, quantitative yield) was obtained as a pale yellow oil. LC-MS (ESI): m / z (M+1): 207.0 (Method 2)

[0390] Intermediate 218: N-(4-bromopyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide Intermediate 218 was prepared starting from N-(4-bromopyridin-2-yl)-2-(piperazin-1-yl)acetamide (Intermediate 177, 200 mg, 0.67 mmol) and TEA (0.14 mL, 1 mmol). , at RT following the method used for the synthesis of intermediate 69 to give the title compound (204 mg, 0.53 mmol, 80% yield). LC-MS (ESI): m / z (M+1): 381.3 (method 2)

[0391] Intermediate 219: N-(4-bromopyridin-2-yl)-3-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)propanamide Intermediate 219 was prepared from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol) and thiomorpholine-1,1-dioxide (135 mg, 3.5 mmol) in MeCN. Prepared following the method used for the synthesis of intermediate 30 at reflux temperature, starting from , to give the title compound (225 mg, 0.62 mmol, 94% yield). LC-MS (ESI): m / z (M+1): 364.0 (method 1)

[0392] Intermediate 220: 1-(azetidin-3-yl)pyrrolidine 1-(Azetidin-3-yl)pyrrolidine dihydrochloride (150 mg, 0.75 mmol) was dissolved in MeOH and loaded onto SCX (2 g, washed with MeOH, 1N NH 3 of MeOH solution). Evaporation of the basic fractions gave 1-(azetidin-3-yl)pyrrolidine (:49 mg, 0.39 mmol, 51% yield) as a pale yellow oil. LC-MS (ESI): m / z (M+1): 127.0 (Method 2)

[0393] Intermediate 221: tert-Butyl 7-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4,7-diazaspiro[2.5]octane-4-carboxylate Intermediate 221 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate. (243 mg, 1.15 mmol) and TEA (0.24 mL, 1.76 mmol) in MeOH, prepared according to the method used for the synthesis of intermediate 30 to give the title compound (360 mg, 0.82 mmol, 93% yield). got LC-MS (ESI): m / z (M+1): 439.1 (method 2)

[0394] Intermediate 222: N-(4-bromopyridin-2-yl)-3-{4,7-diazaspiro[2.5]octan-7-yl}propanamide Intermediate 222 was converted to tert-butyl 7-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 221, 360 mg, 0.82 mmol) and prepared according to the method used for the synthesis of intermediate 21 to give the title compound (277 mg, quantitative yield). LC-MS (ESI): m / z (M+1): 339.1 (method 2)

[0395] Intermediate 223: N-(4-bromopyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}propanamide Intermediate 223 was treated with N-(4-bromopyridin-2-yl)-3-{4,7-diazaspiro[2.5]octan-7-yl}propanamide (Intermediate 222, 277 mg, 0.82 mmol) and formaldehyde 37 Prepared following the method used for the synthesis of Intermediate 22 starting from % w / w aqueous solution (0.09 mL, 1.22 mmol) to give the title compound (256 mg, 0.72 mmol, 89% yield). LC-MS (ESI): m / z (M+1): 353.0 (method 2)

[0396] Intermediate 224: N-(4-Bromopyridin-2-yl)-3-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}propanamide Intermediate 224 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol), 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride ( 146 mg, 1.2 mmol) and TEA (0.32 mL, 2.31 mmol) in MeOH, following the method used for the synthesis of intermediate 30 to give the title compound (100 mg, 0.29 mmol, 47% yield). Obtained. LC-MS (ESI): m / z (M+1): 339.1 (method 2)

[0397] Intermediate 225: N-(4-bromopyridin-2-yl)-3-(4,4-difluoropiperidin-1-yl)propanamide Intermediate 225 was prepared from N-(4-bromopyridin-2-yl)prop-2-enamide (intermediate 29, 200 mg, 0.88 mmol), 4,4-difluoropiperidine hydrochloride (166 mg, 1.06 mmol) and TEA ( 0.24 mL, 1.76 mmol) in MeOH and prepared according to the method used for the synthesis of intermediate 30 to give the title compound (288 mg, 0.83 mmol, 94% yield). LC-MS (ESI): m / z (M+1): 348.0 (Method 2)

[0398] Intermediate 226: N-(4-bromopyridin-2-yl)-3-(4-hydroxypiperidin-1-yl)propanamide Intermediate 226 was prepared using N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 100 mg, 0.44 mmol), 4-piperidinol (53 mg, 0.53 mmol) and TEA (0.12 mL, 0.88 mmol). ) in MeOH to give the title compound (110 mg, 0.33 mmol, 76% yield) following the method used for the synthesis of intermediate 30. LC-MS (ESI): m / z (M+1): 328.0 (Method 2)

[0399] Intermediate 227: N-(4-bromopyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide 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 under nitrogen. 2Added below. After 10 minutes, the reaction was cooled in an ice bath and treated with N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 350 mg, 1.39 mmol) followed by a catalytic amount of potassium iodide. added. The reaction mixture was brought to RT and stirred at this temperature for 2 hours. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc. Na 2 SO 4 and filtered. The solvent was evaporated and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex~45% EtOAc) to give N-(4-bromopyridin-2-yl)-2-{6-methyl-2 ,6-diazaspiro[3.3]heptan-2-yl}acetamide (330 mg, 1.01 mmol, y=73%) was obtained. LC-MS (ESI): m / z (M+1): 327.0 (Method 2)

[0400] Intermediate 228: tert-Butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate N-(4-bromopyridin-2-yl)-2-chloroacetamide (intermediate 159, 250 mg, 1 mmol), 4-boc-4,7-diazaspiro[2.5] octane (255 mg, 1.2 mmol) and DIPEA (0.35 mL, 2 mmol) in dry DCM (10 mL) was stirred at RT for 48 h. Conversion was almost complete so the mixture was stirred at 40° C. for 16 hours. The mixture was then washed with water and brine. Separate the organic solvent and Na 2 SO 4 and filtered. Evaporation of the solvent gave tert-butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (450 mg, recovery was quantitative). ) was obtained as a yellow crude which was not further purified. LC-MS (ESI): m / z (M+1): 425.1 (method 1)

[0401] Intermediate 229: N-(4-bromopyridin-2-yl)-2-{4,7-diazaspiro[2.5]octan-7-yl}acetamide Intermediate 229 was converted to tert-butyl 7-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-4,7-diazaspiro[2.5]octane-4-carboxylate (Intermediate 228, 450 mg, 1 mmol). Prepared according to the method used for the synthesis of intermediate 21 starting from to give the title compound (322 mg, 0.99 mmol, y=94%). LC-MS (ESI): m / z (M+1): 325.0 (method 2)

[0402] Intermediate 230: N-(4-bromopyridin-2-yl)-2-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}acetamide Intermediate 230 was treated with N-(4-bromopyridin-2-yl)-2-{4,7-diazaspiro[2.5]octan-7-yl}acetamide (Intermediate 229, 322 mg, 0.99 mmol) and formaldehyde 37%. Prepared according to the method used for the synthesis of intermediate 22 starting from w / w aqueous solution (0.11 mL, 1.48 mmol) to give the title compound (218 mg, 0.64 mmol, 65% yield). LC-MS (ESI): m / z (M+1): 330.0 (method 1)

[0403] Intermediate 231: N-(4-bromopyridin-2-yl)-3-(3,4-dimethylpiperazin-1-yl)propanamide Intermediate 231 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), 1,2-dimethyl-piperazine (160 mg, 1.41 mmol) and TEA (0.18 mL, 1.32 mmol) and prepared according to the method used for the synthesis of intermediate 30 to give the title compound (297 mg, 0.87 mmol, 99% yield). LC-MS (ESI): m / z (M+1): 341.0 (Method 2)

[0404] Intermediate 232: tert-Butyl 3-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate Intermediate 232 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- Prepared according to the method used for the synthesis of intermediate 30 starting from carboxylate (262 mg, 1.32 mmol) and TEA (0.24 mL, 1.76 mmol) to give the title compound (395 mg, recovery assumed quantitative). rice field. LC-MS (ESI): m / z (M+1): 425.1 (method 1)

[0405] Intermediate 233: N-(4-bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptan-3-yl}propanamide HCl, 4M in dioxane (1.18 mL, 4.7 mmol) and MeOH (0.392 mL) were added to tert-butyl 3-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3,6-diazabicyclo[ 3.1.1] added to heptane-6-carboxylate (Intermediate 232, 200 mg, 0.47 mmol). The mixture was stirred at RT for 3 hours. Volatiles were removed under reduced pressure. NaHCO 3 s.s. and extracted with DCM three times. The aqueous phase was further extracted with EtOAc (3x). The combined organic layers were filtered through a phase separator and evaporated under reduced pressure to give N-(4-bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptan-3-yl} Propanamide (140 mg, 0.43 mmol, 92% yield) was obtained as a white solid. LC-MS (ESI): m / z (M+1): 325.0 (method 1)

[0406] Intermediate 234: N-(4-bromopyridin-2-yl)-3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}propanamide Intermediate 234 was converted to N-(4-bromopyridin-2-yl)-3-{3,6-diazabicyclo[3.1.1]heptan-3-yl}propanamide (Intermediate 233, 140 mg, 0.43 mmol) and Prepared following the method used for the synthesis of Intermediate 22 starting from formaldehyde 37% w / w aqueous solution (0.05 mL, 0.65 mmol) to give the title compound (121 mg, 0.36 mmol, 83% yield). LC-MS (ESI): m / z (M+1): 339.0 (Method 2)

[0407] Intermediate 235: tert-Butyl 8-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate Intermediate 235 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 150 mg, 0.66 mmol), tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane- Prepared according to the method used for the synthesis of intermediate 30, starting from 2-carboxylate (196 mg, 0.86 mmol) and TEA (0.14 mL, 0.99 mmol), the title compound (364 mg, recovery assumed quantitative) got LC-MS (ESI): m / z (M+1): 455.1 (method 2)

[0408] Intermediate 236: N-(4-bromopyridin-2-yl)-3-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide Intermediate 236 was converted to tert-butyl 8-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (intermediate 235, 364 mg, 0.66 mmol, previous step recovery assumed quantitative), prepared according to the method used for the synthesis of intermediate 233 to give the title compound (215 mg, 0.60 mmol, 92% yield). got LC-MS (ESI): m / z (M+1): 355.0 (method 2)

[0409] Intermediate 237: N-(4-bromopyridin-2-yl)-3-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide Intermediate 237 was converted to N-(4-bromopyridin-2-yl)-3-{5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide (Intermediate 236, 215 mg, 0.60 mmol ) and formaldehyde 37% w / w aqueous solution (0.07 mL, 0.91 mmol), prepared according to the method used for the synthesis of intermediate 22 to give the title compound (106 mg, 0.29 mmol, 48% yield). rice field. LC-MS (ESI): m / z (M+1): 368.6 (Method 2)

[0410] Intermediate 238: tert-butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate Intermediate 238 was prepared starting from tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (3.16 g, 13.15 mmol) and formaldehyde 37% w / w aqueous solution (4.95 mL, 65.77 mmol) to intermediate Prepared according to the method used to synthesize isomer 22 to give the title compound (1.37 g, 5.41 mmol, 41% yield). LC-MS (ESI): m / z (M+1): 255.4 (Method 2)

[0411] Intermediate 239: 2-Methyl-2,8-diazaspiro[4.5]decane dihydrochloride Intermediate 239 was used in the synthesis of Intermediate 173 starting from tert-butyl 2-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (Intermediate 238, 1.37g, 5.4mmol) Prepared according to the method to give the title compound (912mg, 4mmol, 74% yield). 1 H NMR (500 MHz, methanol-d 4 ) δ ppm3.76 (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 = 12.1Hz, 1H), 2.97 (s, 3H), 2.15 - 2.26 (m, 1H), 1.87 - 2.10 (m, 5H)

[0412] Intermediate 240: N-(4-bromopyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide Intermediate 240 was converted to N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 153, 200 mg, 0.63 mmol) and 2-methyl-2,8-diazaspiro[4.5]decane. Prepared following the method used to synthesize Intermediate 154 starting from the dihydrochloride salt (Intermediate 239, 157 mg, 0.69 mmol) to give the title compound (103 mg, 0.29 mmol, 46% yield). LC-MS (ESI): m / z (M+1): 353.1 (method 1)

[0413] Intermediate 241: N-{4-[(6-Chloro-3-methylpyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 32, 752mg, 2.3mmol), Cs 2 CO 3 (1.37 g, 4.18 mmol), Xantphos (145 mg, 0.25 mmol), 6-chloro-3-methylpyridazin-4-amine (300 mg, 2.09 mmol) in dioxane (4 mL) and N 2 for 5 min, then Pd(OAc) 2 (23.67 mg, 0.100 mmol) was added. The resulting reaction mixture was heated at 100° C. for 2 hours. The solids were collected by filtration, washed with EtOAc, the volatiles were removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica NH cartridge (20% cHex to 10% MeOH in EtOAc) and purified by N- {4-[(6-Chloro-3-methylpyridazin-4-yl)amino]pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide (610 mg, 1.56 mmol, 75% yield) rate) was obtained as a foam. LC-MS (ESI): m / z (M+1): 390.9 (method 2)

[0414] Intermediate 242: tert-Butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate Intermediate 242 was converted to N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 600 mg, 2.4 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (722 mg, 3.6 mmol) and prepared according to the method used for the synthesis of intermediate 176 to give the title compound (740 mg, 1.79 mmol, y=40%). LC-MS (ESI): m / z (M+1): 414.3 (method 2)

[0415] Intermediate 243: tert-butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}-1,4 -Diazepane-1-carboxylate Intermediate 243 was converted to tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}-1,4-diazepane-1-carboxylate (Intermediate 242, 140 mg, 0.34 mmol) and 6- Prepared according to the method used for the synthesis of Intermediate 31 starting from (5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 70 mg, 0.29 mmol) to give the title compound (80 mg, 0.14 mmol, 48% yield) was obtained as a yellow solid. LC-MS (ESI): m / z (M+1): 570.2 (method 1)

[0416] Intermediate 244: Ethyl 1-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)-1H-pyrazole-4-carboxylate Diisopropyl azodicarboxylate (1.73 mL, 8.8 mmol) was mixed with tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.5 g, 8.56 mmol), ethyl 1H-, in stirring THF (20 mL). Pyrazole-4-carboxylate (800mg, 5.61mmol) and PPh 3 (2.32 g, 8.65 mmol) at 0° C., then the reaction mixture was warmed to 55° C. and stirred at this temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (cHex~45% EtOAc) on a Biotage silica cartridge to give ethyl 1-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)-1H-pyrazole- 4-carboxylate (1.42 g, 4.77 mmol, 84% yield) was obtained as a pale yellow solid. LC-MS (ESI): m / z (M+1): 298.2 (method 1)

[0417] Intermediate 245: tert-butyl N-(2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate To a stirring solution of 4-bromopyridin-2-amine (585 mg, 3.38 mmol) in THF (13 mL) was added -78 °C and N 2 Below, 1.6N n-butyllithium in hexanes (1.85 mL, 2.96 mmol) was added portionwise over 10 minutes, then the reaction mixture was stirred at −78° C. for 1 hour. Ethyl 1-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)-1H-pyrazole-4-carboxylate (Intermediate 244, 400 mg, 1.35 mmol) in THF (6 mL) for 10 min. It was added in portions at -78°C. After 5 minutes 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 cartridge (cHex~95% EtOAc) and then further purified by flash chromatography on a Biotage silica cartridge (cHex~90% EtOAc) to give tert-butyl N-( 2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate (94 mg, 0.22 mmol, 16% yield) was obtained as a pale yellow oil. obtained as LC-MS (ESI): m / z (M+1): 425.5 (Method 2)

[0418] Intermediate 246: tert-Butyl N-(2-{4-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]- 1H-pyrazol-1-yl}ethyl)-N-methylcarbamate Intermediate 246 was converted to tert-butyl N-(2-{4-[(4-bromopyridin-2-yl)carbamoyl]-1H-pyrazol-1-yl}ethyl)-N-methylcarbamate (Intermediate 245, 94 mg, 0.22 mmol) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 64 mg, 0.27 mmol) was used in the synthesis of intermediate 31. Prepared according to the method to give the title compound (71 mg, 0.12 mmol, 55% yield). LC-MS (ESI): m / z (M+1): 581.3 (method 1)

[0419] Intermediate 247: N-(4-bromopyridin-2-yl)-2-(1-methylpiperidin-4-yl)acetamide Synthesis of Intermediate 245 starting with Intermediate 247 from ethyl 2-(1-methylpiperidin-4-yl)acetate (150mg, 0.81mmol) and 4-bromopyridin-2-amine (350mg, 2.02mmol) to give the title compound (100 mg, 0.32 mmol, 40% yield). LC-MS (ESI): m / z (M+1): 312.0 (Method 2)

[0420] Intermediate 248:tert-Butyl 4-{3-[(4-bromopyridin-2-yl)carbamoyl]propyl}-1,4-diazepane-1-carboxylate Intermediate 248 was converted to N-(4-bromopyridin-2-yl)-4-chlorobutanamide (Intermediate 41, 350 mg, 1.26 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (758 mg, 3.78mmol) and prepared according to the method used for the synthesis of intermediate 140 to give the title compound (260mg, 0.59mmol, y=47%). LC-MS (ESI): m / z (M+1): 441.2 (method 1)

[0421] Intermediate 249: tert-butyl 4-{3-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]propyl}-1 ,4-diazepane-1-carboxylate Intermediate 249 was converted to tert-butyl 4-{3-[(4-bromopyridin-2-yl)carbamoyl]propyl}-1,4-diazepane-1-carboxylate (Intermediate 248, 167 mg, 0.38 mmol) and Starting from 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 75 mg, 0.32 mmol), at 120° C., following the method used for the synthesis of Intermediate 112. Worked up to give the title compound (140mg, 0.23mmol, y=74%). LC-MS (ESI): m / z (M+1): 598.2 (method 1)

[0422] Intermediate 250: tert-Butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate Intermediate 250 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 250 mg, 1.10 mmol) and commercially available tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate. Prepared as described for intermediate 30 starting from (310mg, 1.4mmol) to give the title compound (410mg, 0.92mmol, 84% yield). LC-MS (ESI): m / z (M+1): 444.6 (Method 2)

[0423] Intermediate 251: tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-3 -(Hydroxymethyl)piperazine-1-carboxylate Intermediate 251 was converted to tert-butyl 4-{2-[(4-bromopyridin-2-yl)carbamoyl]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate (Intermediate 250, 182 mg, 0.41 mmol ) and 6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 85 mg, 0.36 mmol) following the procedure used for the synthesis of Intermediate 31. to give the title compound (70 mg, 0.12 mmol, 33% yield). LC-MS (ESI): m / z (M+1): 600.3 (Method 2)

[0424] Intermediate 252: N-(4-{[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(hydroxymethyl)piperazine-1 -yl]propanamide Intermediate 252 was converted to tert-butyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl ]ethyl}-3-(hydroxymethyl)piperazine-1-carboxylate (Intermediate 251, 70 mg, 0.12 mmol) was prepared according to the method used for the synthesis of Intermediate 21 to give the title compound (40 mg, 0.08 mmol, y=67%). LC-MS (ESI): m / z (M+1): 500.2 (method 2)

[0425] Intermediate 253: tert-butyl 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazine-1- carboxylate Intermediate 253 was converted to tert-butyl 4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazine-1-carboxylate (Intermediate 176, 120 mg, 0.29 mmol) and 6-(5-chloro- Starting from a solution of 2-fluorophenyl)-3-methylpyridazin-4-amine (Intermediate 90, 60 mg, 0.25 mmol) in 1,2-dimethoxyethane / toluene (3 / 1 ratio) at 120° C. for 1 h. Prepared according to the method used for the synthesis of intermediate 9 in 45 minutes to give the title compound (55 mg, 0.10 mmol, 39% yield). LC-MS (ESI): m / z (M+1): 556.2 (method 2)

[0426] Intermediate 254: 1-methyl-4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]piperazine 2-(4-methylpiperazin-1-yl)ethan-1-ol (765 mg, 5.31 mmol), PPh 3 (2.5 g, 9.55 mmol) and 3-nitro-1H-pyrazole (600 mg, 5.31 mmol) in THF (21 mL) was treated with di-tert-butyl azodicarboxylate (2.07 g, 9.02 mmol) at RT. The mixture was stirred for 16 hours and then concentrated under reduced pressure; the residue was loaded onto SCX, washed with MeOH and 1N NH. 3 of MeOH solution. Evaporation of the basic fractions gave crude material, which was purified by flash chromatography on a Biotage silica cartridge (DCM to 30% MeOH) to give 1-methyl-4-[2-(3-nitro-1H- Pyrazol-1-yl)ethyl]piperazine (355 mg, 1.48 mmol, 28% yield) was obtained as a pale yellow oil. LC-MS (ESI): m / z (M+1): 239.7 (method 2)

[0427] Intermediate 255: 1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine A solution of 1-methyl-4-[2-(3-nitro-1H-pyrazol-1-yl)ethyl]piperazine (Intermediate 254, 58 mg, 0.24 mmol) in ethanol (0.40 mL) was treated with 10% w / w Pd / Treated with C (5.03 mg), H 2 Stirred at RT for 5 h under atmosphere. The mixture was filtered through a pad of Celite® and then concentrated under reduced pressure to give 1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine (48 mg, 0.23 mmol, 97% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M+1): 210.3 (method 2)

[0428] Intermediate 256: 4-Chloro-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl}pyridin-2-amine In a sealed container, Cs 2 CO 3 (83 mg, 0.26 mmol), Xantphos (6 mg, 0.01 mmol), 1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-amine (Intermediate 255, 28 mg, 0.13 mmol) , Pd 2 (dba) 3 (6 mg, 0.01 mmol) and 2,4-dichloropyridine (18 mg, 0.12 mmol) in 1,2-dimethoxyethane (1.22 mL) in N 2 Suspended. The suspension was degassed by several vacuum / nitrogen gas cycles followed by N 2 was bubbled through the mixture at RT (10 min). The mixture was then immediately warmed to 100° C. and stirred for 4 hours. The mixture was filtered through a pad of Celite® and washed with EtOAc. The crude material was purified by flash chromatography (cHex~100% EtOAc) on a Biotage silica NH cartridge to give 4-chloro-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H -pyrazol-3-yl}pyridin-2-amine (17 mg, 0.05 mmol, 44% yield) was obtained as a pale yellow oil. LC-MS (ESI): m / z (M+1): 321.4 (method 2)

[0429] Intermediate 257: 1-tert-butyl 3-methyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate Step 1: To a stirring solution of DMSO (1.19 mL, 16.76 mmol) in DCM (20 mL), -78 °C and N 2Below, oxalyl dichloride (0.72 mL, 8.38 mmol) was added portionwise and the mixture was stirred for 10 min at −78° C., followed by 2-(1-methylpiperidin-4-yl)ethan-1-ol (1 g, 6.98 mmol) in DCM (5 mL) was added over 10 minutes and the resulting reaction mixture was stirred at -78°C for 15 minutes. TEA (4.9 mL, 35.18 mmol) was then added in portions over 10 minutes and the reaction mixture was stirred at -78°C for 10 minutes. The cooling bath was removed and the reaction mixture was brought to RT and stirred for 30 min at RT. The reaction mixture was filtered, DCM was added to a total of 45 mL, and this solution containing the aldehyde derivative (6.98 mmol, recovery assumed quantitative) was used as is.

[0430] Step 2: In a stirring solution of 2-(1-methylpiperidin-4-yl)acetaldehyde (6.98 mmol theoretical from step 1) in DCM (45 mL) at RT, 1-tert-butyl 3-methylpiperazine- 1,3-dicarboxylate (1.23 g, 5.05 mmol) was added in portions. After 10 min sodium triacetoxyborohydride (2.25 g, 10.61 mmol) was added portionwise and the resulting reaction mixture was stirred at RT for 3 h. NaHCO 3 Washed with saturated solution. Na 2 SO 4 dried at rt, filtered, the solvent removed under reduced pressure and the crude material purified by flash chromatography on a Biotage silica NH cartridge (cHex-25% EtOAc) to give 1-tert-butyl 3-methyl 4-[2 -(1-Methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate (1.61 g, 4.36 mmol, 86% yield) was obtained as a pale yellow oil. LC-MS (ESI): m / z (M+1): 371.6 (method 2)

[0431] Intermediate 258: Lithium 4-[(tert-butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate 1-tert-butyl 3-methyl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate (Intermediate 257, 1.61g, 4.36mmol) in THF (14mL) and Lithium hydroxide hydrate (205 mg, 4.89 mmol) in MeOH (4 mL). 2 A solution of O (5 mL) was added and the mixture was heated at 48° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give lithium 4-[(tert-butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate (1.56 g, 4.36 mmol). , recovery assumed quantitative) was obtained as a white solid, which was used as is. LC-MS (ESI): m / z (M-1): 354.3 (method 1)

[0432] Intermediate 259: 1-tert-butyl 3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate Lithium 4-[(tert-butoxy)carbonyl]-1-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-2-carboxylate (Intermediate 258, 550 mg) in stirring MeCN (13 mL) , 1.52 mmol) at RT, HATU (814 mg, 2.14 mmol) and DIPEA (0.81 mL, 4.67 mmol) were then added. After 10 minutes, 3-oxesetanol (0.33 mL, 5.04 mmol) was added portionwise to the solution, then the resulting reaction mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure and the residue was treated with DCM and NaHCO. 3 Dissolved in a saturated solution, extracted the aqueous phase with DCM, collected the organic phases and removed the solvent under reduced pressure. The crude material was purified by flash chromatography (cHex~25% EtOAc) on a Biotage silica NH cartridge to give 1-tert-butyl 3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl ) Ethyl]piperazine-1,3-dicarboxylate (371 mg, 0.90 mmol, 64% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M-1): 413.3 (Method 2)

[0433] Intermediate 260: methyl 4-chloro-7-hydroxyquinoline-6-carboxylate Boron tribromide (5.96 mL, 5.96 mmol) was added to a stirring solution of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (500 mg, 1.99 mmol) in DCM (20 mL) at 0 °C with N 2 dripped down. The reaction was stirred at 0° C. for 1 hour and then at RT for another hour. The reaction was cooled in an ice bath and MeOH was added dropwise. The solvent was removed under reduced pressure and the residue was treated with NaHCO 3 Treated with aqueous solution and extracted with DCM. Separate the organic layer and Na 2 SO 4 dried at rt, filtered and evaporated to give methyl 4-chloro-7-hydroxyquinoline-6-carboxylate (320 mg, 1.35 mmol, 68% yield). LC-MS (ESI): m / z (M-1): 238.1 (method 1)

[0434] Intermediate 261: Methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate Di-tert-butyl azodicarboxylate (581 mg, 2.52 mmol) was added at RT in N 2 Below, methyl 4-chloro-7-hydroxyquinoline-6-carboxylate (Intermediate 260, 300 mg, 1.26 mmol), 1-(2-hydroxyethyl)-4-methylpiperazine in dry DCM (50 mL) with stirring (225mg, 1.56mmol) and PPh 3 (662 mg, 2.52 mmol) was added in portions. After 3 hours, the mixture was replaced with H 2 Wash with O, separate the organic layer, Na 2 SO 4 , filtered and evaporated. The residue was treated with 0,1N HCl, the aqueous phase was washed with EtOAc and NaHCO 3 to pH 9 and extracted with DCM. Separate the organic layer and Na 2 SO 4 and evaporated to give methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate (350mg, 0.96mmol, 76% yield) . LC-MS (ESI): m / z (M-1): 365.5 (method 2)

[0435] Intermediate 262: tert-butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate Intermediate 262 was prepared starting from tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (300 mg, 1.39 mmol) and formaldehyde 37% w / w aqueous solution (0.1 mL, 1.39 mmol). Prepared according to the method used for synthesis to give the title compound (270 mg, 1.17 mmol, 85% yield). LC-MS (ESI): m / z (M-1): 231.3 (method 2)

[0436] Intermediate 263: (1-methylpiperazin-2-yl)methanol dihydrochloride A solution of 3M HCl in cyclopentyl methyl ether (1.56 mL, 4.69 mmol) was added to a stirring solution of tert-butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (Intermediate 262, 270 mg, 1.17 mmol) in MeOH. (4 mL) was added to the solution. The reaction mixture was stirred overnight, then the volatiles were removed under reduced pressure to give (1-methylpiperazin-2-yl)methanol dihydrochloride (250 mg, recovery assumed quantitative) as a white solid. LC-MS (ESI): m / z (M-1): 131.3 (method 2)

[0437] Intermediate 264: N-(4-Bromopyridin-2-yl)-3-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide Intermediate 264 was converted to N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and (1-methylpiperazin-2-yl)methanol dihydrochloride (232 mg, 1.15 mmol) and prepared as described for intermediate 30 to give the title compound (170 mg, 0.48 mmol, 54% yield). LC-MS (ESI): m / z (M+1): 358.6 (Method 2)

[0438] Intermediate 265: N-(4-bromopyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide Intermediate 265 was prepared starting from N-(4-bromopyridin-2-yl)-2-chloroacetamide (intermediate 159, 150 mg, 0.6 mmol) and 1-methylpiperazine (120 mg, 1.2 mmol) to obtain intermediate Prepared according to the method used for the synthesis of 176 to give the title compound (168mg, 0.54mmol, y=89%). LC-MS (ESI): m / z (M+1): 313.3 (method 2)

[0439] Intermediate 266: 6-chloro-3-cyclopropylpyridazin-4-amine K.3 P.O. 4 (328 mg, 1.52 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 mL, 0.610 mmol) and 3,6-dichloropyridazin-4-amine (100 mg) , 0.61 mmol) in 1,4-dioxane (3 mL) / H 2 Mixed in O (1 mL). N the reaction mixture 2 for 2 min, then Pd(dppf)Cl 2 DCM (25 mg, 0.03 mmol) was added and then heated at 100° C. overnight. The mixture was cooled to RT and then another 2 equivalents of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, K 3 P.O. 4 (328 mg, 1.52 mmol) and Pd(dppf)Cl 2 DCM (25 mg, 0.03 mmol) was added and then stirred at 100° C. for 6 hours. After cooling, the reactants were treated with H 2 Diluted with O and EtOAC, the organic phase was separated, dried and evaporated under reduced pressure. The residue was subjected to reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH-20% MeCN) to give 6-chloro-3-cyclopropylpyridazin-4-amine (57 mg, 0.34 mmol, 55% yield) as an off-white solid. LC-MS (ESI): m / z (M+1): 170.0 (method 2)

[0440] Intermediate 267: 6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-amine Toluene (0.80ml), EtOH (0.80ml) and H 2 5-Chloro-2-fluorobenzeneboronic acid (76 mg, 0.44 mmol), 6-chloro-3-cyclopropylpyridazin-4-amine (intermediate 266, 57 mg, 0.34 mmol) and Na in O (0.80 ml) 2 CO 3 A mixture of (53 mg, 0.50 mmol) was 2 Degas for 2 min at PdCl 2 (PPh 3 ) 2 (24 mg, 0.03 mmol) was added and the mixture was irradiated in the microwave at 90° C. for 1 hour. Additionally 5-chloro-2-fluorobenzeneboronic acid (76 mg, 0.44 mmol), Na 2 CO 3 (53 mg, 0.50 mmol) and PdCl 2 (PPh 3 ) 2 (23.66 mg, 0.030 mmol) was added and irradiated at 90° C. for 40 minutes. After cooling to RT, the mixture was 2 Treated with O and extracted with EtOAc. The organic layer was separated, dried and evaporated. The residue was subjected to reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH-80% MeCN) to give 6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-amine (58 mg, 0.22 mmol, 65% yield) as a white solid. . LC-MS (ESI): m / z (M+1): 264.1 (method 1)

[0441] Intermediate 268: Methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate 1-(2,4-Dimethoxyphenyl)methanamine (1.8 mL, 7.97 mmol) was mixed with stirring methyl 4,6-dichloropyridazine-3-carboxylate (1.5 g, 7.25 mmol) and DIPEA (3.27 mL, 14.49 mmol). ) in dry MeCN (20 mL) at RT with N 2 was added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was treated with EtOAc and NH 4 Washed with Cl aqueous solution. Separate the organic phase and Na 2 SO 4 , filtered and evaporated. The residue was treated with hot EtOAc and after cooling, Et 2 O was added and the solid filtered through methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate (1.2 g, 3.55 mmol, 49% yield) to Methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate (1.2 g, 3.55 mmol, 49% yield) was obtained. LC-MS (ESI): m / z (M+1): 340.1 (method 2)

[0442] Intermediate 269: Methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxylate DIPEA (1.55 mL, 8.88 mmol) was added to methyl 6-chloro-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine-3-carboxyl in dry 1,4-dioxane (15 mL) with stirring. Lato (intermediate 268, 1.0 g, 2.96 mmol), 5-chloro-2-fluorobenzeneboronic acid (1.55 g, 8.88 mmol) and Pd (PPh 3 ) 4 (239 mg, 0.21 mmol) was added to the mixture. reactant to N 2 and the vial was sealed and irradiated at MW at 110° C. for 6 hours. After cooling, the solvent was removed under reduced pressure. The residue is H 2 Treated with O, extracted with EtOAc, separated organic layer, NH 4 Na 2 SO 4 , filtered and evaporated. The residue was purified by flash chromatography on a Biotage silica cartridge (cHex~30% EtOAc as eluent) to give methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxy Phenyl)methyl]amino}pyridazine-3-carboxylate (710 mg, 1.64 mmol, 56% yield) was obtained. LC-MS (ESI): m / z (M+1): 432.2 (method 1)

[0443] Intermediate 270: [6-(5-Chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol A 2 M solution of lithium aluminum hydride in THF (0.7 mL, 1.4 mmol) was added to stirring methyl 6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazine. -3-carboxylate (Intermediate 269, 600 mg, 1.15 mmol) in dry THF (10 mL) at 0 °C with N 2 dripped down. After 1 hour the reaction was warmed to RT and stirred for 1 hour. The mixture was then cooled to 0 °C and successively added 0.1 mL of H 2 THF solution of O, 0.1 mL 15% NaOH and 0.3 mL H 2 Added O. The reaction was warmed to RT for 1 hour. The mixture was filtered through a Celite® pad and washed with THF. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~60% EtOAc) to give [6-(5-chloro-2-fluorophenyl)-4-{[(2 ,4-Dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol (420 mg, 1.04 mmol, 90% yield) was obtained. LC-MS (ESI): m / z (M+1): 404.2 (method 1)

[0444] Intermediate 271: [4-Amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol TFA (1.0 mL, 17.4 mmol) was added to stirring [6-(5-chloro-2-fluorophenyl)-4-{[(2,4-dimethoxyphenyl)methyl]amino}pyridazin-3-yl]methanol (Intermediate 270, 220 mg, 0.54 mmol) in DCM (4 mL) at RT with N 2 Added below. The reaction was stirred for 40 hours. The solvent was removed by vacuum and the residue was treated with water and dissolved in NaHCO. 3 solution and EtOAc. Separate the organic layer and Na 2 SO 4 Dried at rt, filtered and evaporated to give [4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol (150 mg, recovery assumed quantitative). LC-MS (ESI): m / z (M+1): 254.1 (method 1)

[0445] Intermediate 272: 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine Tert-Butyl(chloro)dimethylsilane (113.64 mg, 0.75 mmol) was added to stirring [4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl]methanol (Intermediate 271, 150 mg). , 0.50 mmol), TEA (0.14 mL, 1.01 mmol) and a catalytic amount of DMAP in dry DCM (12.26 mL) at RT with N 2Added below. After 24 h, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on a Biotage silica cartridge (cHex~20% EtOAc) to give 3-{[(tert-butyldimethylsilyl)oxy]methyl}- 6-(5-Chloro-2-fluorophenyl)pyridazin-4-amine (100 mg, 0.27 mmol, 54% yield) was obtained. LC-MS (ESI): m / z (M+1): 369.1 (Method 2)

[0446] Intermediate 273: N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}- 3-(4-methylpiperazin-1-yl)propanamide Cs 2 CO 3 (157 mg, 0.48 mmol) of N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide ( Intermediate 32, 94 mg, 0.29 mmol), 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 100 mg, 0.24 mmol), Pd(OAc) 2 (3 mg, 0.01 mmol) and Xantphos (14 mg, 0.02 mmol) at RT. N the mixture 2 The vial was sealed and irradiated at MW (120° C. for 2 hours). After cooling to RT, the mixture was filtered through a pad of Celite®, washed with EtOAc, the solvent was removed by vacuum and the residue was flash chromatographed on a Biotage silica NH cartridge (DCM~2%MeOH / 0.2%). H. 2 O) to give N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino] Pyridin-2-yl}-3-(4-methylpiperazin-1-yl)propanamide (105 mg, 0.17 mmol, 71% yield) was obtained. LC-MS (ESI): m / z (M+1): 614.5 (Method 2)

[0447] Intermediate 274: N-(4-Bromopyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide Intermediate 274 was converted to tert-butyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 197, 150 mg, 0.33 mmol) and prepared according to the method used for the synthesis of intermediate 21 to give the title compound (90 mg, 0.25 mmol, 77% yield). LC-MS (ESI): m / z (M+1): 358.0 (method 2)

[0448] Intermediate 275: Methyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate Intermediate 275 was converted to N-(4-bromopyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide (Intermediate 274, 90 mg, 0.25 mmol) and Prepared following the method used to synthesize intermediate 102 starting from methyl chloroformate (0.021 mL, 0.28 mmol) to give the title compound (90 mg, 0.22 mmol, 86% yield). LC-MS (ESI): m / z (M+1): 416.1 (method 1)

[0449] Intermediate 276: Methyl N-[2-[4-[2-[[4-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(5-chloro-2-fluorophenyl)pyridazine-4- yl]amino]pyridin-2-yl]amino]-2-oxoethyl]piperazin-1-yl]ethyl]-N-methylcarbamate Intermediate 276 was converted to methyl N-[2-(4-{[(4-bromopyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate (Intermediate 275, 90 mg, 0.22 mmol) and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 70 mg, 0.19 mmol). was prepared according to the method used for the synthesis of intermediate 31 to give the title compound (20mg, 0.03mmol, 15% yield). LC-MS (ESI): m / z (M+1): 701.4 (method 1)

[0450] Intermediate 277: N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}- 2-(4-methylpiperazin-1-yl)acetamide Intermediate 277 was treated with N-(4-bromopyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (Intermediate 265, 71 mg, 0.23 mmol) and 3-{[(tert-butyl Following the procedure used for the synthesis of Intermediate 273, starting from dimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 70 mg, 0.19 mmol). Worked up to give the title compound (56 mg, 0.09 mmol, 49% yield). LC-MS (ESI): m / z (M+1): 600.2 (method 1)

[0451] Intermediate 278: 4-bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline 33% HBr in AcOH (0.63 mL, 2.53 mmol) was mixed with 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (Intermediate 23, 90 mg, 0.25 mmol) and sodium; bromide (263 mg, 2.53 mmol) at RT. The vial was sealed and the reaction was heated at 80° C. for 12 hours. After cooling, the mixture was treated with cold NaHCO 3 Poured into aqueous solution and extracted with EtOAc. Separate the organic layer and Na 2 SO 4 Dried and evaporated to give 4-bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (80mg, 0.23mmol, 90% yield). LC-MS (ESI): m / z (M+1): 352.0 (Method 2)

[0452] Intermediate 279: N-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)-7-[2-(4-methylpiperazine-1 -yl)ethoxy]quinolin-4-amine Intermediate 279 was converted to 4-bromo-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline (Intermediate 278, 71 mg, 0.20 mmol) and 3-{[(tert-butyldimethylsilyl)oxy ]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 50 mg, 0.14 mmol), prepared according to the method used for the synthesis of Intermediate 273, The title compound (70 mg, 0.11 mmol, 81% yield) was obtained. LC-MS (ESI): m / z (M+1): 637.5 (Method 2)

[0453] Intermediate 280: N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}- 2-(4-methyl-1,4-diazepan-1-yl)acetamide Intermediate 280 was converted to N-(4-bromopyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide (Intermediate 175, 124 mg, 0.38 mmol) and 3-{Synthesis of Intermediate 273 starting from [(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 100 mg, 0.25 mmol) to give the title compound (90 mg, 0.15 mmol, 56% yield). LC-MS (ESI): m / z (M+1): 614.1 (method 2)

[0454] Intermediate 281: N-(4-bromopyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide Intermediate 281 was converted to N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, 100 mg, 0.4 mmol) and 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride ( Prepared following the method used for the synthesis of intermediate 176 starting from intermediate 210 (101 mg, 0.48 mmol) to give the title compound (80 mg, 0.23 mmol, y=57%). LC-MS (ESI): m / z (M+1): 355.1 (Method 2)

[0455] Intermediate 282:N-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]pyridin-2-yl}- 2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide Intermediate 282 was converted to N-(4-bromopyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide (Intermediate 281, 48 mg, 0.14 mmol). and 3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 272, 50 mg, 0.14 mmol), intermediate Prepared according to the method used to synthesize isomer 273 to give the title compound (45 mg, 0.07 mmol, 52% yield). LC-MS (ESI): m / z (M+1): 640.5 (method 2)

[0456] Intermediate 283: 2-[5-(difluoromethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In a vial, 1-bromo-5-difluoromethyl-2-fluorobenzene (0.5 g, 2.22 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.67 g, 2.64 mmol), Pd(dppf)Cl 2 To a mixture of DCM (91 mg, 0.11 mmol) and potassium acetate (661 mg, 6.67 mmol) was added 1,2-dimethoxyethane (9 mL) and the vial was sealed and stirred at 90° C. for 7 hours. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic solvent was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica cartridge (cHex~55% EtOAc) to yield 2-[5-(difluoromethyl)-2-fluorophenyl]-4,4. ,5,5-tetramethyl-1,3,2-dioxaborolane (376 mg, 1.38 mmol, 62% yield) was obtained as a whitish waxy solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.87 - 7.95 (m, 1 H), 7.60-766 (m, 1 H), 7.14 (t, J = 8.69 Hz, 1 H), 6.49 - 6.82 (m , 1 H), 1.39 (s, 12 H)

[0457] Intermediate 284: N-(4-bromopyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide Intermediate 284 was prepared from N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 2-(1-piperazinyl)ethanol (229 mg, 1.76 mmol) in MeOH. Prepared according to the method used for the synthesis of intermediate 30, starting from , to give the title compound (283 mg, 0.79 mmol, 90% yield). LC-MS (ESI): m / z (M+1): 357.1 (Method 2)

[0458] Intermediate 285: N-(4-Bromopyridin-2-yl)-3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)propenamide N-(4-bromopyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide (Intermediate 284, 283mg, 0.79mmol) and TEA (0.28mL, 1.98mmol) ) in DCM (5 mL) was added tert-butyl(chloro)dimethylsilane (239 mg, 1.58 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with DCM and saturated NaHCO 3 Washed with aqueous solution. 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 2% MeOH) to give N-(4-bromopyridin-2-yl)-3-(4-{2-[(tert-butyl Dimethylsilyl)oxy]ethyl}piperazin-1-yl)propenamide (365 mg, 0.77 mmol, 98% yield) was obtained. LC-MS (ESI): m / z (M+1): 471.3 (method 2)

[0459] Intermediate 286: 3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-( Trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)propenamide Intermediate 286 was converted to N-(4-bromopyridin-2-yl)-3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperazin-1-yl)propenamide (Intermediate 285 , 107 mg, 0.23 mmol) and 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine (intermediate 293, 60 mg, 0.21 mmol) to prepare intermediate 31 to give the title compound (116 mg, 0.17 mmol, 83% yield). LC-MS (ESI): m / z (M+1): 682.5 (Method 2)

[0460] Intermediate 287: N-(4-bromopyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propanamide Intermediate 287 was treated with N-(4-bromopyridin-2-yl)prop-2-enamide (Intermediate 29, 200 mg, 0.88 mmol) and 3-(1-piperazinyl)propanenitrile (245 mg, 1.76 mmol) in MeOH. Starting from solution, it was prepared following the method used for the synthesis of intermediate 30 to give the title compound (277mg, 0.76mmol, 86% yield). LC-MS (ESI): m / z (M+1): 366.1 (Method 2)

[0461] Intermediate 288: 2,5-dioxopyrrolidin-1-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate Intermediate 288 was prepared according to this procedure: 2-(4-methylpiperazine- 1-yl)ethan-1-amine (300 mg, 2.094 mmol) was added and the reaction was stirred at 80° C. for 1 hour. The resulting suspension was then directly subjected to the next step.

[0462] Intermediate 289: 1-(4-bromopyridin-2-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea To a solution of 4-bromopyridin-2-amine (434 mg, 2.51 mmol) in dry THF (10 ml) precooled to −78° C. was added dropwise a solution of 2M LDA in THF (3.14 mL, 6.28 mmol). The reaction was stirred for 10 minutes and 2,5-dioxopyrrolidin-1-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate (Intermediate 288, 595 mg, 2.093 mmol) in THF (10 mL) The solution was added slowly over 30 minutes. The reaction was stirred for 30 min at −78° C. and RT for 12 h. The reaction was then poured into brine (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were filtered through a phase separator cartridge and the solvent removed under reduced pressure. The crude was purified by NH flash chromatography (SNAP 50 g eluent DCM:EtOH 100:0 to 95:5) with gradient elution to give the title compound (120 mg, 0.351 mmol, 17% yield) as an orange solid. rice field. LC-MS (ESI): m / z (M+1): 342.2, rt = 0.30 min (Method 1)

[0463] Intermediate 290: 2,5-dioxopyrrolidin-1-yl ((1-methylpiperidin-4-yl)methyl)carbamate To a solution of bis-(2,5-dioxopyrrolidin-1-yl)carbonate (0.999 g, 3.90 mmol) in dry THF (10 mL) was added (1-methylpiperidin-4-yl)methanamine (0.5 g, 3.90 mmol). was added and the reaction was stirred at 80° C. for 1 hour. The resulting suspension was then directly subjected to the next step.

[0464] Intermediate 291: 1-(4-bromopyridin-2-yl)-3-((1-methylpiperidin-4-yl)methyl)urea Intermediate 291 was prepared starting from 4-bromopyridin-2-amine (0.809g, 4.68mmol) to give 2,5-dioxopyrrolidin-1-yl ((1-methylpiperidin-4-yl)methyl)carbamate Prepared following the method used in the synthesis of intermediate 289 using (intermediate 290, 1.05g, 3.90mmol). The crude was purified by NH flash chromatography (SNAP 50g eluent DCM:EtOH 100:0 to 95:5) with gradient elution to give the title compound (160mg, 0.489mmol, 12% yield) as an orange solid. rice field. LC-MS (ESI): m / z (M+1): 326.9, rt = 0.45 min (Method 1)

[0465] Intermediate 292: 6-Chloro-3-(trifluoromethyl)pyridazin-4-amine To a solution of 6-chloropyridazin-4-amine (2 g, 15.44 mmol) in DCM (6 mL) was added water (2 mL) and zinc bistrifluoromethylsulfinate (7.68 g, 23.16 mmol) and the biphasic system was brought to 60 °C. warmed up. After 20 minutes TFA (5.28 g, 46.3 mmol) and t-BuOOH (8.35 g, 93 mmol) were added and the reaction was stirred for 6 hours. Additional zinc bistrifluoromethylsulfinate (7.68 g, 23.16 mmol), TFA (5.28 g, 46.3 mmol) and t-BuOOH (8.35 g, 93 mmol) were added. After completion, the reaction was diluted with DCM and saturated NaHCO 3 An aqueous solution (20 mL) was added. The two phases were separated and the aqueous layer was extracted with DCM (50 mL x 3). Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude product was subjected to C18 flash chromatography ((H 2 O / MeCN))95:5+0.1%HCOOH}:{(MeCN / H 2 O) 95:5 + 0.1% HCOOH} 100:0 to 70:30 to give two regioisomers 6-chloro-5-(trifluoromethyl)pyridazin-4-amine and the title compound 6-chloro. A nearly 1:1 mixture of -3-(trifluoromethyl)pyridazin-4-amine (1.08 g) was obtained. LC-MS (ESI): m / z (M+1): 198.22, rt = 0.60 min (Method 1)

[0466] Intermediate 293: 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine The 1,4- Dioxane (16 mL) / H 2 O (4 mL) solution, PdCl2(dppf) (0.400 g, 0.547 mmol), K 2 CO 3 (1.133 g, 8.20 mmol) and (2-chloro-5-fluorophenyl)boronic acid (0.715 g, 4.10 mmol) were added and the reaction was stirred at 110° C. for 3 hours. 1,4-dioxane was then removed under reduced pressure; the residue was diluted with DCM and saturated NaHCO 3 An aqueous solution (20 mL) was added. The two phases were separated and the aqueous layer was extracted with DCM (50 mL x 3). Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The crude product was subjected to C18 flash chromatography ((H 2 O / MeCN)) 95:5+0.1%HCOOH}:{(MeCN / H 2 O) 95:5 + 0.1% HCOOH} 100:0 to 60:40 to give 6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-amine (150 mg, 0.514 mmol, 19% yield) and 6-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridazin-4-amine (150 mg, 0.514 mmol, 19% yield). yield) was obtained as the second eluting regioisomer. LC-MS (ESI): m / z (M+1): 292.23, rt = 0.85 min (Method 1)

[0467] Intermediate 294: Methyl 3-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)propanoate 4-Methoxy-4-oxobutyric acid (44.3 mg, 0.33 mmol), N-hydroxyphthalimide (54.7 mg, 0.33 mmol) and DMAP (1.4 mg, 0.01 mmol) in DMSO (1 mL) was diluted with DIC (0.05 ml, 0.33 mmol) was added and the mixture was stirred at rt for 12 h. followed by 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (intermediate 3, 50 mg, 0.22 mmol), (1S)-(+)-10-camphorsulfonic acid (104 mg, 0.45 mmol) and A solution of 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (17.4 mg, 0.02 mmol) in DMSO (1 mL) was added. The resulting solution was vigorously bubbled with nitrogen, sealed and treated with two blue Kessil LED Photoredox light PR160L lamps (390–456 nm, 352 mW / cm). 2 ) was placed between The reaction was stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure and 7N NH 3 A 2 g SCX cartridge was eluted with a methanol solution of . The resulting solution was concentrated under reduced pressure and purified by flash chromatography on a Biotage NH-silica column (eluent: DCM:DCM / MeOH 9 / 1 100:0 to 0:100) to give the title compound (30 mg, 0.097 mmol, 43.3% yield). LC-MS (ESI): m / z (M+1): 309.8, rt = 0.43 min (Method 1)

[0468] Intermediate 295: Methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)cyclohexane-1-carboxylate Intermediate 295 was prepared with methyl 4-methoxycarbonylcyclohexane-1-carboxylic acid (125 mg, 0.61 mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 100 mg, 0.447 mmol). Methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)cyclohexane-1-carboxy was prepared according to the method used for the synthesis of intermediate 294 starting from Rat (30 mg, 0.08 mmol, 18% yield) was obtained as a mixture of cis-trans stereoisomers. LC-MS (ESI): m / z (M+1): 364.2, rt = 0.57-0.60 min (Method 1)

[0469] Intermediate 296: Methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)butanoate Intermediate 296 was prepared from 5-methoxy-5-oxopentanoic acid (0.245g, 1.676mmol) and 6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 3, 250mg, 1.118mmol). Starting with the method used for the synthesis of intermediate 294, methyl 4-(4-amino-6-(5-chloro-2-fluorophenyl)pyridazin-3-yl)butanoate (37 mg, 0.114 mmol , 10% yield) was obtained as a yellowish solid. LC-MS (ESI): m / z (M+1): 323.9, rt = 0.47 min (Method 1)

[0470] Intermediate 297: cis Ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate 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 in portions and the resulting reaction mixture was stirred overnight at RT. MeOH (30 mL) was added cautiously and the mixture was stirred for 30 minutes then concentrated under reduced pressure. The crude material was dissolved in MeOH and the solution was loaded onto SCX, washed with MeOH and 1N NH 3 of MeOH solution. Evaporation of the basic fractions gave crude material, which was purified by flash chromatography on a Biotage silica NH cartridge (c-Hex to 30% EtOAc) to give cis ethyl 3-(4-methylpiperazin-1-yl ) Cyclobutane-1-carboxylate (927 mg, 4.1 mmol, 82% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M+1): 227.3 (method 2)

[0471] Intermediate 298: cis N-(4-bromopyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide Intermediate 298 was converted to cis ethyl 3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxylate (Intermediate 297, 300 mg, 1.33 mmol) and 4-bromopyridin-2-amine (577 mg, 3.34 mmol). Prepared according to the method used for the synthesis of intermediate 245, starting from , to give the title compound (221 mg, 0.63 mmol, 47% yield). LC-MS (ESI): m / z (M+1): 354.1 (method 2)

[0472] Intermediate 299: methyl 4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-yl)amino]-7-[2-(4- Methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate Intermediate 299 was converted to methyl 4-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate (Intermediate 261, 93 mg, 0.26 mmol) and 3-{[(tert -Butyldimethylsilyl)oxy]methyl}-6-(5-chloro-2-fluorophenyl)pyridazin-4-amine (Intermediate 272, 80 mg, 0.21 mmol) Used in the synthesis of Intermediate 273 Prepared according to the method to give the title compound (50mg, 0.07mmol, 44% yield). LC-MS (ESI): m / z (M+1): 695.5 (Method 2)

[0473] Production of Example Compounds Example 1: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide [formation] Intermediate 37 (57mg, 0.18mmol), Cs 2 CO 3 (117 mg, 0.36 mmol), Xantphos (12 mg, 0.02 mmol) and intermediate 3 (40 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and N 2 for 5 min, then Pd(OAc) 2 (2 mg, 0.01 mmol) was added. The resulting reaction mixture was heated at 100° C. for 12 hours. The solids were filtered, the volatiles were removed under reduced pressure and the residue was flash chromatographed on a Biotage silica NH cartridge (DCM-5% MeOH) followed by a further flash chromatography on a Biotage silica cartridge (cHex-100% EtOAC). to give the title compound as a white solid. LC-MS (ESI): m / z (M+1): 458.1 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 11.22 (s, 1 H), 9.03 (d, J = 2.7 Hz, 1 H), 8.23 ​​(d, J = 5.7 Hz, 1 H), 8.19 (dd, J = 6.7, 2.7 Hz, 1 H), 8.05 (d, J = 2.1 Hz, 1 H), 7.70 (dd, J = 2.5, 1.5 Hz, 1 H), 7.42 (ddd, J = 8.8, 4.2, 2.8 Hz, 1 H), 7.15 (dd, J = 10.5, 8.8 Hz, 1 H), 6.97 (s, 1 H), 6.95 (dd, J = 5.7, 2.2 Hz, 1 H), 3.88 (t, J = 4.5Hz, 4H), 2.73 - 2.81 (m, 2H), 2.64 (brs, 4H), 2.56 - 2.60 (m, 2H)

[0474] Example 2: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide [formation] Intermediate 31 (70 mg, 0.13 mmol) was dissolved in DCM (4 mL) and TFA (0.05 mL, 0.63 mmol) was added. The reaction solution was stirred at RT for 1 hour. Volatiles were removed under reduced pressure and the residue was loaded onto SCX, washed with MeOH and 1N NH. 3 of MeOH solution. The basic fractions were collected and evaporated to give the title compound (56mg, 0.12mmol, 98% yield) as a white solid. LC-MS (ESI): m / z (M+1): 456.2 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.75 (s, 1 H), 9.88 (s, 1 H), 9.06 (d, J = 2.7 Hz, 1 H), 8.18 (d, J = 5.5 Hz, 1 H), 8.06 (d, J = 1.6 Hz, 1 H), 8.00 (dd, J = 6.4, 2.9 Hz, 1 H), 7.67 (dd, J = 2.5, 1.4 Hz, 1 H), 7.62 - 7.66 (m, 1 H), 7.47 ( dd, J = 10.6, 8.9 Hz, 1 H), 7.01 (dd, J = 5.8, 2.2 Hz, 1 H), 4.04 - 5.96 (m, 1 H), 2.80 (t, J = 4.8 Hz, 4 H) , 2.59 - 2.66 (m, 2H), 2.52 - 2.57 (m, 2H), 2.42 (br s, 4H)

[0475] Example 3: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(morpholin-4-yl)ethoxy]quinolin-4-amine [formation] Intermediate 3 (0.2 g, 0.89 mmol), Intermediate 17 (376 mg, 1.03 mmol) and Cs in dry 1,4-dioxane (9 mL) 2 CO 3 A mixture of (586 mg, 1.79 mmol) was 2 for 2 min, then Pd(OAc) 2 (10 mg, 0.04 mmol) and Xantphos (52 mg, 0.09 mmol) were added. The mixture was irradiated at MW (110° C., 2 hours). Observed conversion was minor and hence more Pd(OAc) 2 (10 mg, 0.04 mmol) and Xantphos (52 mg, 0.09 mmol) were added and the mixture was again irradiated at 120° C. for 1 hour 30 minutes. The suspension was partitioned between EtOAc and water and the entire mixture was filtered to remove some debris. The organic phase was separated and the aqueous phase was further extracted with EtOAc. The combined organic layers were washed with brine and Na 2 SO 4 and filtered. Evaporation of the solvent gave the composition, which was loaded onto an SCX cartridge, washed with MeOH, and treated with 1N NH 3 of MeOH solution. The basic fractions were pooled and evaporated, and the residue was subjected to reverse-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH-55% MeCN) followed by flash chromatography on a Biotage silica NH cartridge (DCM-2% MeOH) to give the title compound (92 mg, 0.19 mmol, 21% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 480.3 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.78 (br s, 1 H), 9.19 (br s, 1 H), 8.66 (br s, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 8.00 (dd, J = 6.6 , 2.7 Hz, 1 H), 7.70 (br s, 1 H), 7.58 - 7.66 (m, 1 H), 7.46 (dd, J = 10.6, 8.9 Hz, 1 H), 7.40 (br s, 2 H) , 7.30 (dd, J = 9.1, 1.9 Hz, 1 H), 4.27 (t, J = 5.8 Hz, 2 H), 3.51 - 3.71 (m, 4 H), 2.77 (t, J = 5.6 Hz, 2 H ), 2.46 - 2.55 (m, 4H)

[0476] Example 4: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(morpholin-4-yl)ethyl]quinoline-7-carboxamide [formation] Intermediate 14 (80 mg, 0.20 mmol) was dissolved in DMF (3 mL), then HATU (99 mg, 0.26 mmol) and DIPEA (0.14 mL, 0.80 mmol) were added followed by 2-(4-morpholinyl)ethanamine (0.03). mL, 0.26 mmol) was added after stirring for 5 minutes. The mixture was stirred overnight at RT, then the volatiles were removed under reduced pressure and the residue was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH and treated with 1N NH. 3 in MeOH; the basic fractions were collected and evaporated to give a yellow oil which was subjected to reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%NH 4 OH-50% MeCN) to give the title compound (30 mg, 0.06 mmol, 30% yield). LC-MS (ESI): m / z (M+1): 507.4 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.87 (br s, 1 H), 9.25 (br s, 1 H), 8.68 - 8.91 (m, 2 H), 8.50 (br s, 1 H), 8.37 (d, J = 8.8 Hz, 1 H), 7.97 - 8.09 (m, 2H), 7.78 (br s, 1H), 7.64 (ddd, J = 8.9, 4.2, 2.9Hz, 2H), 7.46 (dd, J = 10.6, 8.9Hz, 1 H), 3.58 (t, J = 4.5 Hz, 4 H), 3.46 (q, J = 6.6 Hz, 2 H), 2.51 - 2.55 (m, 2 H), 2.45 (br s, 4 H)

[0477] Example 5: 2-(morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate [formation] Intermediate 57 (50 mg, 0.125 mmol) was dissolved in DMF (3 mL), then HATU (62 mg, 0.16 mmol) and DIPEA (64 mg, 0.50 mmol) were added followed by 4-(2-hydroxyethyl)morpholine (21 mg). , 0.16 mmol) was added after stirring for 5 minutes. The mixture was stirred at RT for 90 min, then the volatiles were removed under reduced pressure and the residue purified by reverse-phase flash chromatography on a Biotage C18 cartridge under basic conditions, followed by further flash chromatography on a Biotage silica NH cartridge. Purification by (DCM to 35% EtOAc) gave the title compound (20 mg, 0.04 mmol, 31% yield). LC-MS (ESI): m / z (M+1): 508.3 (method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.71 - 10.60 (m, 1 H), 9.24 (br s, 1 H), 9.01 (d, J = 1.5 Hz, 1 H), 8.58 - 8.92 (m, 1 H), 8.18 - 8.30 (m , 1 H), 7.96 - 8.15 (m, 2 H), 7.78 (br s, 1 H), 7.37 - 7.70 (m, 3 H), 4.48 (t, J = 5.8 Hz, 2 H), 3.50 - 3.62 (m, 4H), 2.73 (t, J = 5.9Hz, 2H), 2.42 - 2.53 (m, 4H)

[0478] Example 6: 2-(morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate [formation] The title compound (11 mg, 0.02 mmol, 17% yield) was obtained as intermediate 14 (50 mg, 0.12 mmol) and 4-(2-hydroxyethyl)morpholine (21 mg, 0.16 mmol). LC-MS (ESI): m / z (M+1): 508.4 (method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.74 - 10.13 (m, 1 H), 9.24 (d, J = 1.1 Hz, 1 H), 8.73 - 8.83 (m, 1 H), 8.55 (br s, 1 H), 8.44 (d, J = 8.8 Hz, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.01 (dd, J = 6.6, 2.9 Hz, 1 H), 7.77 (br s, 1 H), 7.64 (ddd, J = 8.9, 4.3, 2.9 Hz, 2 H), 7.46 (dd, J = 10.6, 8.9 Hz, 1 H), 4.49 (t, J = 5.7 Hz, 2 H), 3.54 - 3.62 (m, 4 H), 2.76 (t, J=5.7Hz, 2H), 2.48 - 2.53 (m, 4H)

[0479] Example 7: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide [formation] The compound of Example 7 was prepared (35 mg, 0.09 mmol, 20% yield). LC-MS (ESI): m / z (M+1): 384.2 (method 1) 1 H NMR (400 MHz, DMSO-d 6) δ ppm 10.76 (s, 1 H), 9.85 (s, 1 H), 9.05 (d, J = 2.6 Hz, 1 H), 8.18 (d, J = 5.7 Hz, 1 H), 8.05 (d, J = 2.0Hz, 1H), 7.99 (dd, J = 6.6, 2.9Hz, 1H), 7.60 - 7.68 (m, 2H), 7.46 (dd, J = 10.4, 8.9Hz, 1H), 6.98 (dd , J = 5.6, 2.1 Hz, 1 H), 1.95 - 2.06 (m, 1 H), 0.72 - 0.92 (m, 4 H)

[0480] Example 8: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-4-(morpholin-4-yl)butanamide [formation] The compound of Example 8 was prepared according to the method used for the synthesis of Example 3 starting from Intermediate 42 (56 mg, 0.17 mmol) and Intermediate 3 (35 mg, 0.16 mmol) to give the title compound (28 mg, 0.06 mmol, 38% yield). LC-MS (ESI): m / z (M+1): 471.3 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.43 (s, 1 H), 9.88 (s, 1 H), 9.05 (d, J = 2.7 Hz, 1 H), 8.17 (d, J = 5.5 Hz, 1 H), 8.07 (d, J = 1.6 Hz, 1 H), 8.00 (dd, J = 6.6, 2.7 Hz, 1 H), 7.68 (dd, J = 2.7, 1.4 Hz, 1 H), 7.61 - 7.66 (m, 1 H), 7.46 ( dd, J = 10.4, 8.8 Hz, 1 H), 7.00 (dd, J = 5.8, 2.2 Hz, 1 H), 3.52 (t, J = 4.5 Hz, 4 H), 2.40 (t, J = 7.1 Hz, 2H), 2.25 - 2.37 (m, 6H), 1.74 (quin, J = 7.2Hz, 2H)

[0481] Example 9: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine [formation] The compound of Example 9 was prepared following the method used for the synthesis of Example 2 starting from Intermediate 19 (30 mg, 0.05 mmol) to give the title compound (17 mg, 0.03 mmol, 69% yield). rice field. LC-MS (ESI): m / z (M+1): 479.4 (method 2) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.65 - 9.90 (m, 1 H), 9.19 (br s, 1 H), 8.54 - 8.83 (m, 1 H), 8.18 (d, J = 9.2 Hz, 1 H), 8.00 (dd, J = 6.6, 2.8 Hz, 1 H), 7.70 (br s, 1 H), 7.60 - 7.67 (m, 1 H), 7.45 (dd, J = 10.6, 8.9 Hz, 1 H), 7.39 (br s, 2 H), 7.25 - 7.33 (m, 1H), 4.25 (t, J = 5.7Hz, 2H), 2.58 - 2.88 (m, 7H), 2.43 (br s, 4H)

[0482] Example 10: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(piperazin-1-yl)ethyl]quinoline-7-carboxamide [formation] The compound of Example 10 was prepared following the method used for the synthesis of Example 2 starting from Intermediate 16 (48mg, 0.08mmol) to give the title compound (15mg, 0.03mmol, 37% yield) as a yellow Obtained as a solid. LC-MS (ESI): m / z (M+1): 506.4 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 9.22 (d, J = 1.9 Hz, 1 H), 8.91 (d, J = 4.9 Hz, 1 H), 8.41 (s, 1 H), 8.17 (dd, J = 6.6, 2.6 Hz, 1 H), 8.11 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.74 (br s, 2 H), 7.51 (d, J = 4.8 Hz, 1 H), 7.36 - 7.45 (m, 1 H), 7.20 (t, J = 4.3 Hz, 1 H), 7.13 (dd, J = 10.4, 9.0 Hz, 1 H), 3.64 (q , J = 5.3 Hz, 2 H), 2.93 (t, J = 4.7 Hz, 4 H), 2.61 - 2.73 (m, 2 H), 2.51 (br s, 4 H)

[0483] Example 11:N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide [formation] The compound of Example 11 was prepared according to the method used for the synthesis of Example 1 starting from Intermediate 32 (154 mg, 0.47 mmol) and Intermediate 3 (100 mg, 0.45 mmol) to give the title compound (114 mg, 0.24 mmol, 54% yield) as a white solid. LC-MS (ESI): m / z (M+1): 470.4 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 11.32 (s, 1 H), 9.04 (d, J = 2.6 Hz, 1 H), 8.24 (d, J = 5.5 Hz, 1 H), 8.18 (dd, J = 6.7, 2.7 Hz, 1 H), 8.05 (d, J = 2.0 Hz, 1 H), 7.70 (dd, J = 2.4, 1.5 Hz, 1 H), 7.41 (ddd, J = 8.8, 4.2, 2.9 Hz, 1 H), 7.10 - 7.20 (m, 2 H), 6.95 (dd, J = 5.6, 2.1 Hz, 1 H), 2.49 - 2.90 (m, 12 H), 2.37 (s, 3 H).2.50 - 2.84 (m, 8H), 2.45 (q, J = 7.26Hz, 2H), 1.12 (t, J = 7.26Hz, 3H)

[0484] Example 12: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine [formation] The compound of Example 12 was prepared according to the method used for the synthesis of Example 3 starting from Intermediate 23 (159 mg, 0.52 mmol) and Intermediate 3 (100 mg, 0.43 mmol) to give the title compound (80 mg, 0.16 mmol, 37% yield). LC-MS (ESI): m / z (M+1): 493.1 (method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.76 (s, 1H), 9.19 (s, 2H), 8.67 (s, 1H), 8.18 (d, J = 9.25 Hz, 2H), 8.00 (dd, J = 6.58, 2.78 Hz, 2H), 7.69 (s, 2H), 7.63 (ddd, J = 8.80, 4.25, 2.77 Hz, 2H), 7.45 (dd, J = 10.63, 8.87 Hz, 3H), 7.39 (s, 3H), 7.29 (d, J = 9.24 Hz, 2H), 4.25 (t, J = 5.74 Hz, 4H), 2.76 (t, J = 5.68 Hz, 4H), 2.52 (s, 13H), 2.33 (s, 4H), 2.15 (s, 6H) , 1.23 (s, 1H)

[0485] Example 13: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]quinoline-7-carboxamide [formation] The compound of Example 13 was prepared by the method used in the synthesis of Example 4 starting from Intermediate 15 (74 mg, 0.19 mmol) and 1-(2-aminoethyl)-4-methylpiperazine (36 mg, 0.26 mmol). to give the title compound (23 mg, 0.04 mmol, 24% yield). LC-MS (ESI): m / z (M+1): 520.3 (method 2) 1 H NMR (400 MHz, chloroform-d) δ ppm 9.26 (d, J = 2.64 Hz, 1 H), 8.87 - 8.97 (m, 1 H), 8.39 (br.s, 1 H), 8.09 - 8.21 (m , 2H), 7.92-7.99 (m, 2H), 7.77 (br.s, 1H), 7.49 - 7.58 (m, 1H), 7.39 - 7.46 (m, 1H), 7.08 - 7.21 (m , 2 H), 3.65 (q, J = 5.28 Hz, 2 H), 2.68 (t, J = 5.83 Hz, 2 H), 2.45 - 2.66 (m, 7 H), 2.33 (s, 3 H)

[0486] Example 14: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]quinoline-7-carboxamide [formation] The compound of Example 14 was prepared by the method used in the synthesis of Example 4 starting from Intermediate 15 (49 mg, 0.12 mmol) and 2-(1-methylpiperidin-4-yl)ethanamine (25 mg, 0.18 mmol). to give the title compound (8.5 mg, 0.02 mmol, 13% yield). LC-MS (ESI): m / z (M+1): 519.4 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 9.23 (d, J = 2.53 Hz, 1 H), 8.89 (d, J = 4.51 Hz, 1 H), 8.36 (br.s, 1 H), 8.10 - 8.19 (m, 2H), 7.91 - 7.98 (m, 2H), 7.75 (br.s, 1H), 7.50 (d, J = 4.40Hz, 1H), 7.42 (ddd, J = 8.80, 4.29 , 2.75 Hz, 1 H), 7.13 (dd, J = 10.67, 8.80 Hz, 1 H), 6.52 (t, J = 5.50 Hz, 1 H) 3.54 - 3.63 (m, 2 H), 2.84-2.91 (m , 2 H), 2.29 (s, 3 H) 1.96 (t, J = 11.17 Hz, 2 H) 1.57 - 1.84 (m, 5 H) 1.35 - 1.43 (m, 2 H)

[0487] Example 15: N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide [formation] Intermediate 33 (65 mg, 0.25 mmol), Intermediate 47 (50 mg, 0.28 mmol), Xantphos (22 mg, 0.04 mmol) and K in suitable vials. 3 P.O. 4 (109 mg, 0.51 mmol) was mixed in 1,4-dioxane (4 mL). N. 2 for 2 min, then Pd 2 (dba) 3 (24 mg, 0.03 mmol) was added, then the vial was sealed and subjected to a MW cycle at 100° C. for 5 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography on a Biotage silica NH cartridge (cHex-60% EtOAc) to give the title compound (32 mg, 0.08 mmol, 32% yield). LC-MS (ESI): m / z (M+1): 413.3 (method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.72 (s, 1 H), 8.83 (s, 1 H,) 8.15 (d, J = 5.50 Hz, 1 H), 8.07 (d, J = 1.76 Hz, 1 H), 7.97 (dd, J = 6.49, 2.75 Hz, 1 H), 7.71 (s, 1 H), 7.61 (ddd, J = 8.86, 4.24, 2.75 Hz, 1 H), 7.43 (dd, J = 10.56, 8.80 Hz, 1 H), 6.96 (dd, J = 5.50, 2.20Hz, 1H), 2.67 (s, 3H), 1.93 - 2.10 (m, 1H), 0.76 - 0.87 (m, 4H)

[0488] Example 16: N-(4-{[6-(5-Chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl) propanamide [formation] The compound of Example 16 was prepared according to the method used for the synthesis of Example 15 starting from Intermediate 36 (113 mg, 0.43 mmol) and Intermediate 33 (100 mg, 0.39 mmol) to give the title compound (734 mg, 0.15 mmol, 39% yield). LC-MS (ESI): m / z (M+1): 484.3 (method 1) 1 H NMR (500 MHz, DMSO-d 6) δ ppm 10.63 (s, 1 H), 8.85 (s, 1 H), 8.14 (d, J = 5.8 Hz, 1 H), 8.08 (d, J = 1.6 Hz, 1 H), 7.98 (dd, J = 6.5, 2.8 Hz, 1 H), 7.71 (d, J = 1.0 Hz, 1 H), 7.60 (ddd, J = 8.9, 4.2, 2.7 Hz, 1 H), 7.42 (dd, J = 10.5, 8.9 Hz , 1 H), 6.97 (dd, J = 5.7, 2.1 Hz, 1 H), 2.68 (s, 3 H), 2.58 - 2.62 (m, 2 H), 2.51 - 2.54 (m, 2 H), 2.17 - 2.54 (m, 8H), 2.14 (s, 3H)

[0489] Example 17: N-[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinolin-4-amine [formation] Sodium triacetoxyborohydride (70.5 mg, 0.33 mmol) was added to a mixture of intermediate 26 (106 mg, 0.22 mmol) and paraformaldehyde (13 mg, 0.44 mmol) in DCM (10 mL) / MeOH (2 mL) followed by 1 drop. of AcOH was added. The resulting mixture was stirred overnight at RT. The reaction was not complete so more paraformaldehyde (13 mg, 0.44 mmol) and sodium triacetoxyborohydride (70.5 mg, 0.330 mmol) were added. After another 2 h at RT, the mixture was quenched with NaHCO 3 s.s. and then diluted with DCM. The aqueous phase was further extracted with DCM, then the combined organic layers were washed with brine and Na 2 SO 4 and filtered. Evaporation of the solvent gave a yellow composition, which was subjected to reversed-phase flash chromatography on a Biotage C18 cartridge (H 2 O+0.1%HCOOH~30%MeCN+0.1%HCOOH). Evaporate the appropriate fractions and redissolve the resulting product in 1N NH 3 Purification by SCX cartridge eluting with a solution of 3 in MeOH gave the title compound (55 mg, 0.11 mmol, 50% yield) as a yellow solid. LC-MS (ESI): m / z (M+1): 492.4 (method 1) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.78 (br s, 1 H), 9.18 (br d, J = 1.5 Hz, 1 H), 8.65 (br s, 1 H), 8.17 (d, J = 9.2 Hz, 1 H), 8.00 ( dd, J = 6.6, 2.7 Hz, 1 H), 7.69 (br s, 1 H), 7.63 (ddd, J = 8.9, 4.2, 2.8 Hz, 1 H), 7.45 (dd, J = 10.6, 8.9 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.28 (dd, J = 9.1, 2.1 Hz, 1 H), 4.19 (t, J = 6.5 Hz, 2 H), 2.74 (br d, J = 11.4 Hz, 2H), 2.13 (s, 3H), 1.82 (td, J = 11.6, 2.0Hz, 2H), 1.66 - 1.77 (m, 4H), 1.38 - 1.54 (m, 1H), 1.24 (qd, J = 12.3, 3.5Hz, 2H)

[0490] Example 18: N-(4-{[6-(5-Chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[methyl(oxetan-3-yl)amino]propanamide [formation] The compound of Example 18 was prepared according to the method used for the synthesis of Example 3, starting from Intermediate 40 (174 mg, 0.55 mmol) and Intermediate 3 (95 mg, 0.42 mmol) to give the title compound (19 mg , 0.04 mmol, 10% yield). LC-MS (ESI): m / z (M+1): 457.1 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.56 (s, 1 H), 9.90 (s, 1 H), 9.05 (d, J = 2.7 Hz, 1 H), 8.18 (d, J = 5.6 Hz, 1 H), 8.07 (d, J = 1.1 Hz, 1 H), 8.00 (dd, J = 6.6, 2.7 Hz, 1 H), 7.68 (dd, J = 2.5, 1.3 Hz, 1 H), 7.64 (ddd, J = 8.9, 4.2, 2.9 Hz , 1 H), 7.46 (dd, J = 10.5, 8.9 Hz, 1 H), 7.02 (dd, J = 5.6, 2.2 Hz, 1 H), 4.31 - 4.54 (m, 4 H), 3.51 (quin, J = 6.5Hz, 1H), 2.46 - 2.53 (m, 4H), 2.08 (s, 3H)

[0491] Example 19: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-1-methylpiperidine-4-carboxamide [formation] The compound of Example 19 was prepared according to the method used for the synthesis of Example 1 starting from Intermediate 45 (117 mg, 0.39 mmol) and Intermediate 3 (80 mg, 0.36 mmol) to give the title compound (47 mg, 0.11 mmol, 30% yield) as a white solid. LC-MS (ESI): m / z (M+1): 441.1 (method 1) 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.41 (s, 1 H), 9.85 (s, 1 H), 9.06 (d, J = 2.7 Hz, 1 H), 8.17 (d, J = 5.8 Hz, 1 H), 8.07 (d, J = 1.9 Hz, 1 H), 8.00 (dd, J = 6.5, 2.8 Hz, 1 H), 7.67 (dd, J = 2.6, 1.4 Hz, 1 H), 7.64 (ddd, J = 8.8, 4.2, 2.7 Hz , 1 H), 7.47 (dd, J = 10.6, 8.8 Hz, 1 H), 6.99 (dd, J = 5.6, 2.2 Hz, 1 H), 2.74 - 2.84 (m, 2 H), 2.44 (tt, J = 11.5, 4.0 Hz, 1 H), 2.14 (s, 3 H), 1.83 (td, J = 11.6, 2.4 Hz, 2 H), 1.57 - 1.77 (m, 4 H)

[0492] Example 20: 1-Methylpiperidin-4-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate [formation] SOCl 2 (0.65 mL, 9.01 mmol) to intermediate 15 (100 mg, 0.25 mmol), N 2 Added at RT below. The mixture was stirred and warmed to 80° C. for 30 minutes. excess SOCl 2 was evaporated under reduced pressure. The residue was cooled to 5-10° C. and a solution of 1-methyl-4-piperidinol (286 mg, 2.48 mmol) and TEA (0.13 mL, 0.74 mmol) in DCM (6.5 mL) was added under stirring. The reaction was brought to RT and stirred for 2 hours. The mixture was treated with water. Separate the organic layer and Na 2 SO 4 dried and evaporated. The residue was purified by flash chromatography on a Biotage silica cartridge (DCM to 3% MeOH) to give the title compound (15 mg, 0.03 mmol, 12% yield). LC-MS (ESI): m / z (M+1): 492 (Method 2) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.93 (s, 1H), 9.25 (s, 2H), 8.83 (s, 1H), 8.56 (s, 2H), 8.43 (d, J = 8.79 Hz, 2H), 8.10 (d, J = 8.60 Hz, 2H), 8.01 (dd, J = 6.56, 2.80 Hz, 2H), 7.78 (s, 2H), 7.63 (ddd, J = 8.87, 4.27, 2.75 Hz, 4H), 7.46 (dd, J = 10.61, 8.84 Hz, 2H), 5.03 (dd, J = 8.28, 4.17 Hz, 2H), 2.62 (s, 3H), 2.28 (t, J = 9.68 Hz, 4H), 2.21 (s, 6H), 1.98 (s, 3H), 1.75 - 1.87 (m, 4H)

[0493] Example 21:4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3 -b] pyridine-3-carboxamide [formation] TFA (0.04 mL, 0.56 mmol) was added to a solution of intermediate 8 (36 mg, 0.06 mmol) in DCM (2 mL). The reaction mixture was stirred overnight, then volatiles were removed, the residue was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH, and 1N NH. 3 of MeOH solution. The basic fractions were collected, evaporated and purified by flash chromatography on a Biotage silica NH cartridge (EtOAc to 10% MeOH) to give the title compound (8.2 mg, 0.02 mmol, 29% yield) as a pale orange solid. rice field. LC-MS (ESI): m / z (M+1): 509.1 (method 1) 1 H NMR (400 MHz, chloroform-d) δ ppm 12.07 (s, 1 H), 10.64 (br s, 1 H), 9.22 (d, J = 2.6 Hz, 1 H), 8.29 (d, J = 5.5 Hz , 1 H), 8.19 (dd, J = 6.5, 2.7 Hz, 1 H), 7.86 (br s, 1 H), 7.69 (s, 1 H), 7.37 - 7.49 (m, 2 H), 7.22 (d , J = 5.5 Hz, 1 H), 7.16 (dd, J = 10.3, 8.9 Hz, 1 H), 6.98 (br s, 1 H), 3.59 (q, J = 5.3 Hz, 2 H), 2.67 (t , J = 5.8 Hz, 2 H), 2.36 - 2.71 (m, 8 H), 2.32 (s, 3 H)

[0494] Example 22: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-2-oxopiperazin-1-yl) propanamide [formation] The compound of Example 22 was prepared according to the method used for the synthesis of Example 1 starting from Intermediate...

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, R １ is optionally a halogen atom, -(C １ -C ６ ) alkyl and -(C １ -C ６ ) aryl substituted with one or more groups selected from haloalkyl; A is A1, A2 and A3 【Chemistry 2】 selected from the group consisting of: R ２ Ha-NR ５ C(O)R ６ and -NR ５ R ６ selected from the group consisting of: X １ is C, CH or N; R ３ HA -C(O)NR ５ R ７ , -C(O)OR ７ , -OC(O)R ７ , -OR ７ , -NR ５ C(O)R ７ and -OC(O)NR ５ R ７ selected from the group consisting of: R ３’ is H or -(C １ -C ６ )alkoxy, —OH, —C(O)O—(C １ -C ６ )alkyl and —C(O)NH-heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of one —(C １ -C ６ ) alkyl substituted; R ４ HA -C(O)NR ５ R ７ and —C(O)heterocycloalkyl, wherein said heterocycloalkyl optionally has one or more —(C １ -C ６ ) alkyl substituted; R ５ is H or -(C １ -C ６ ) alkyl; R ６ Ha-(C １ -C ６ ) alkylene-NR Ａ R Ｂ -NH-(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally comprises one or more —(C １ -C ６ ) alkyl); optionally substituted with -(C １ -C ６ ) alkylene-NR Ａ R Ｃ and -(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally comprises one or more —(C １ -C ６ heteroaryl substituted with one or more groups selected from -(C ) alkyl; １ -C ６ ) alkylene-NR Ｃ -(C １ -C ６ ) alkylene-NR Ａ R Ｃ ;-(C １ -C ６ ) alkylene-NR Ａ -C(O)O-(C １ -C ６ ) alkyl; optionally heterocycloalkyl (wherein the heterocycloalkyl is optionally one or more —(C １ -C ６ cycloalkyl optionally substituted with one or more -(C )alkyl; １ -C ６ ) alkyl-substituted heterocycloalkyl; １ -C ６ ) alkylene-N-oxide-heterocycloalkyl; and -(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally —OH, halogen, —(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-CN, -(C １ -C ６ ) haloalkyl, —C(O)—(C １ -C ６ ) alkyl, —C(O)OH, —C(O)O(C １ -C ６ ) alkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —(C １ -C ６ ) alkylene-C(O)O-R Ｃ , -(C １ -C ６ ) alkylene-NR Ｃ -C(O)O-(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NH ２ , -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NHSO ２ -(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; R ７ teeth - (C １ -C ６ ) alkylene-NR Ａ R Ｂ ; - Depending on the circumstances - (C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , heterocycloalkyl, —C(O)O-heterocycloalkyl, —(C １ -C ６ ) alkylene-heterocycloalkyl, each of which is optionally substituted with one or more groups selected from -(C １ -C ６ ) alkyl substituted); - - (C １ -C ６ ) alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl optionally comprises one or more —(C １ -C ６ ) alkyl-substituted); and - - (C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally —(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-CN, -(C １ -C ６ ) haloalkyl, —C(O)—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, —C(O)O—(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NH ２ , -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , -(C １ -C ６ ) alkylene-CONR Ａ R Ｃ , -(C １ -C ６ ) alkylene-NR Ｃ -Co(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-NR Ｃ -C(O)O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NHSO ２ -(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) alkyl and -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) substituted with one or more groups selected from alkyl selected from the group consisting of: R Ａ Ha-(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-OH; R Ｂ is heterocycloalkyl; R ｃ is H or -(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-OH; R ８ is H or -(C １ -C ６ ) alkyl, cycloalkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, -cycloalkyl-C(O)O—(C １ -C ６ ) alkyl and -(C １ -C ６ ) haloalkyl. and pharmaceutically acceptable salts thereof.

2. Formula (Ia) 【Transformation 3】 A is represented by 【Chemistry 4】 A compound of formula (I) wherein R １ is optionally a halogen atom, -(C １ -C ６ ) alkyl and -(C １ -C ６ ) aryl substituted with one or more groups selected from haloalkyl; R ２ Ga-NR ５ C(O)R ６ and -NR ５ R ６ selected from the group consisting of: R ５ is H or -(C １ -C ６ ) alkyl; R ６ But-(C １ -C ６ ) alkylene-NR Ａ R Ｂ -NH-(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally contains one or more —(C １ -C ６ ) alkyl); optionally substituted with -(C １ -C ６ ) alkylene-NR Ａ R Ｃ and -(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally contains one or more —(C １ -C ６ heteroaryl substituted with one or more groups selected from -(C ) alkyl; １ -C ６ ) alkylene-NR Ｃ -(C １ -C ６ ) alkylene-NR Ａ R Ｃ ;-(C １ -C ６ ) alkylene-NR Ａ -C(O)O-(C １ -C ６ ) alkyl; optionally heterocycloalkyl (wherein the heterocycloalkyl optionally comprises one or more —(C １ -C ６ cycloalkyl optionally substituted with one or more -(C )alkyl; １ -C ６ ) alkyl-substituted heterocycloalkyl; １ -C ６ ) alkylene-N-oxide-heterocycloalkyl; and -(C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally —OH, halogen, —(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-CN, -(C １ -C ６ ) haloalkyl, —C(O)—(C １ -C ６ ) alkyl, —C(O)OH, —C(O)O(C １ -C ６ ) alkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —(C １ -C ６ ) alkylene-C(O)O-R Ｃ , -(C １ -C ６ ) alkylene-NR Ｃ -C(O)O-(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NH ２ , -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NHSO ２ -(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) substituted with one or more groups selected from alkyl and oxo; R Ａ But-(C １－ C ６ ) alkyl; R Ｂ is heterocycloalkyl; R ｃ is H or -(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-OH; R ８ is H or -(C １ -C ６ ) alkyl, cycloalkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, -cycloalkyl-C(O)O—(C １ -C ６ ) alkyl and -(C １ -C ６ ) haloalkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

3. 3. A compound of formula (Ia) according to claim 2, selected from at least one of the following: N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-4-(morpholin-4-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)cyclopropanecarboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[methyl(oxetan-3-yl)amino]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-1-methylpiperidine-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-2-oxopiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methyl-3-oxopiperazin-1-yl)propanamide; 3-(4-acetylpiperazin-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(3-methyl-1,3-diazinan-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methanesulfonylpiperazin-1-yl)propanamide; 3-(3-acetyl-1,3-diazinan-1-yl)-N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(3-methanesulfonyl-1,3-diazinan-1-yl)propanamide; N-4-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-N2-[3-(4-methylpiperazin-1-yl)propyl]pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methylpiperazin-1-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(piperazin-1-yl)propanamide; 3-[4-(2-aminoethyl)piperazin-1-yl]-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(morpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[3-ethoxy-3-(hydroxymethyl)azetidin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]carbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methanesulfonylethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-methylpiperazine-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-methylpiperidine-4-carboxamide; Methyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazine-2-carboxylate; 4-(3-((4-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyridin-2-yl)amino)-3-oxopropyl)piperazine-2-carboxylic acid; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{[2-(methylamino)ethyl]amino}propanamide; Methyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylic acid; Methyl 2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)acetate; Methyl 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate; Methyl 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazin-2-yl)acetate; Methyl 1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazine-2-carboxylate; Methyl 2-(1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-4-methylpiperazin-2-yl)acetate; Methyl 2-(1-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{4-[2-(methylamino)ethyl]piperazin-1-yl}propanamide; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-1-yl)ethyl]-N-methylcarbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{4-[2-(methylamino)ethyl]piperazin-1-yl}acetamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate; 2-[4-(2-aminoethyl)piperazin-1-yl]-N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)acetamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]carbamate; 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1,1-dimethylpiperazin-1-ium hydrochloride chloride; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]propanamide; Methyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-(propan-2-yl)piperazine-2-carboxylate; 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}piperazin-2-yl)acetic acid; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(morpholin-4-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(thiomorpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl}propanamide hydrochloride; Ethyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; 4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}morpholin-4-ium-4-olate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propanamide; propan-2-yl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; Cyclopropyl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; Oxetan-3-yl 4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]ethyl}-1-methylpiperazine-2-carboxylate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(1-oxo-1λ4-thiomorpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methanesulfonamidoethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4,4-difluoropiperidin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-hydroxypiperidin-1-yl)propanamide; 1-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea; 1-(4-((6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl)amino)pyridin-2-yl)-3-((1-methylpiperidin-4-yl)methyl)urea; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{6-methyl-2,6-diazaspiro[3.3]heptan-2-yl}acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-{4-methyl-4,7-diazaspiro[2.5]octan-7-yl}acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(3,4-dimethylpiperazin-1-yl)propenamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-{2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl}propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-carboxamide; N-(4-{[6-(5-chloro-2,4-difluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-[2-(methylamino)ethyl]-1H-pyrazole-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(1-methylpiperidin-4-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(1,4-diazepan-1-yl)butanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-4-(4-methyl-1,4-diazepan-1-yl)butanamide; cis N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[2-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(piperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-4-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-N-2-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-3-yl}pyridine-2,4-diamine; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-3-[3-(hydroxymethyl)-4-methylpiperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-cyclopropylpyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; Methyl N-[2-(4-{[(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)carbamoyl]methyl}piperazin-1-yl)ethyl]-N-methylcarbamate; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}pyridin-2-yl)-2-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}acetamide; N-(4-((6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl)amino)pyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-methanesulfonylethyl)piperazin-1-yl]propanamide; N-(4-{[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]amino}pyridin-2-yl)-3-[4-(2-cyanoethyl)piperazin-1-yl]propanamide; Methyl 3-[6-(5-chloro-2-fluorophenyl)-4-({2-[3-(4-methylpiperazin-1-yl)propanamido]pyridin-4-yl}amino)pyridazin-3-yl]propanoate; Methyl (1s,4s)-4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)cyclohexane-1-carboxylate; Methyl (1r,4r)-4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)cyclohexane-1-carboxylate; N-[4-({6-[5-(difluoromethyl)-2-fluorophenyl]-3-methylpyridazin-4-yl}amino)pyridin-2-yl]-3-(4-methylpiperazin-1-yl)propanamide; Methyl 4-(6-(5-chloro-2-fluorophenyl)-4-((2-(3-(4-methylpiperazin-1-yl)propanamido)pyridin-4-yl)amino)pyridazin-3-yl)butanoate.

4. Formula (Ib) 【Transformation 5】 A is represented by A2 【Transformation 6】 A compound of formula (I) wherein R １ optionally a halogen atom and -(C １ -C ６ ) aryl substituted with one or more groups selected from alkyl; X １ is C, CH or N; R ３ -C(O)NR ５ R ７ , -C(O)OR ７ , -OC(O)R ７ , -OR ７ , -NR ５ C(O)R ７ and -OC(O)NR ５ R ７ selected from the group consisting of: R ３’ is H or -(C １ -C ６ )alkoxy, —OH, —C(O)O—(C １ -C ６ )alkyl and —C(O)NH-heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of one —(C １ -C ６ ) alkyl substituted; R ５ is H or -(C １ -C ６ ) alkyl; R ７ but - (C １－ C ６ ) alkylene-NR Ａ R Ｂ ; - Depending on the circumstances - (C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , heterocycloalkyl, —C(O)O-heterocycloalkyl, —(C １ -C ６ ) alkylene-heterocycloalkyl, each of which is optionally substituted with one or more groups selected from -(C １ -C ６ ) alkyl substituted); - - (C １ -C ６ ) alkylene-C(O)-heterocycloalkyl, wherein the heterocycloalkyl optionally contains one or more —(C １ -C ６ ) alkyl-substituted); and - - (C １ -C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally —(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkoxy, -(C １ -C ６ ) alkylene-OH, -(C １ -C ６ ) alkylene-CN, -(C １ -C ６ ) haloalkyl, —C(O)—(C １ -C ６ ) alkyl, —C(O)O—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-C(O)O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NH ２ , -(C １ -C ６ ) alkylene-NR Ａ R Ｃ , -(C １ -C ６ ) alkylene-CONR Ａ R Ｃ , -(C １ -C ６ ) alkylene-NR Ｃ Common (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-NR Ｃ -C(O)O-(C １ -C ６ ) alkyl, -(C １ -C ６ ) Alkylene-NHSO ２ -(C １ -C ６ ) alkyl, -SO ２ -(C １ -C ６ ) alkyl and -(C １ -C ６ ) Alkylene-SO ２ -(C １ -C ６ ) substituted with one or more groups selected from alkyl selected from the group consisting of: R Ａ But-(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-OH; R Ｂ is heterocycloalkyl; R ｃ is H or -(C １ -C ６ ) alkyl and -(C １ -C ６ ) alkylene-OH; R ８ is H or -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkylene-OH and -(C １ -C ６ ) haloalkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

5. A compound of formula (Ib) of claim 4 selected from at least one of the following: N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(morpholin-4-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(morpholin-4-yl)ethyl]quinoline-7-carboxamide; 2-(morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-6-carboxylate; 2-(morpholin-4-yl)ethyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(piperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(piperazin-1-yl)ethyl]quinoline-7-carboxamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]quinoline-7-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]quinoline-7-carboxamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinolin-4-amine; 1-methylpiperidin-4-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-(1-methylazetidin-3-yl)-1,7-naphthyridine-6-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-(1-methylpiperidin-4-yl)-1,7-naphthyridine-6-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-methylpiperazine-1-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-ethylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide; 1-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethan-1-one; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(4-methanesulfonylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-{6-[2-fluoro-5-(propan-2-yl)phenyl]pyridazin-4-yl}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]-1-(4-methylpiperazin-1-yl)ethan-1-one; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy}quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-{2-[methyl(oxetan-3-yl)amino]ethoxy}quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]carbamate; N-[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl N-methyl-N-[2-(1-methylpiperidin-4-yl)ethyl]carbamate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[3-(3-methyl-1,3-diazinan-1-yl)propoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(2-methanesulfonylethyl)piperazine-1-carboxylate; (3R)-1-methylpyrrolidin-3-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}ethoxy)quinolin-4-amine; 1-(3-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}-1,3-diazinan-1-yl)ethan-1-one; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(2-hydroxyethyl)piperazine-1-carboxylate; (3S)-1-methylpyrrolidin-3-yl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinoline-7-carboxylate; Methyl 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)propanoate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(dimethylamino)ethyl]piperazine-1-carboxylate; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(3-methyl-1,3-diazinan-1-yl)ethoxy]quinolin-4-amine; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)-N-methylpropanamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate; 7-{2-[4-(2-aminoethyl)piperazin-1-yl]ethoxy}-N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]quinolin-4-amine; N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]methanesulfonamide; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-(2-{4-[2-(dimethylamino)ethyl]piperazin-1-yl}ethoxy)quinolin-4-amine; N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]acetamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[2-(4-methylpiperazin-1-yl)ethyl]piperidine-1-carboxylate; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)propanenitrile; 2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethan-1-ol; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(1-methylpiperidin-4-yl)oxy]quinolin-4-amine; 2-{[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl](2-hydroxyethyl)amino}ethan-1-ol; Methyl N-[2-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)ethyl]carbamate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1-carboxylate; 3-(4-{2-[(4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl)oxy]ethyl}piperazin-1-yl)pentane-1,5-diol; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[(1-methylpiperidin-4-yl)methoxy]quinolin-4-amine; N-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]-7-[2-(3-methylimidazolidin-1-yl)ethoxy]quinolin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-[(1-methylpiperidin-4-yl)methyl]piperazine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2,8-diazaspiro[4.5]decane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 8-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,6-diazaspiro[3.4]octane-6-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 3-(pyrrolidin-1-yl)azetidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 4-(azetidin-1-yl)piperidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-6-ol; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 3-(pyrrolidin-1-yl)azetidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl 4-(azetidin-1-yl)piperidine-1-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; Methyl 4-{[6-(5-chloro-2-fluorophenyl)-3-(hydroxymethyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate; 1-(4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}quinolin-7-yl)3-oxetan-3-yl 4-[2-(1-methylpiperidin-4-yl)ethyl]piperazine-1,3-dicarboxylate; Methyl 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate; Methyl 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinoline-6-carboxylate; [6-(5-chloro-2-fluorophenyl)-4-({7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yl}amino)pyridazin-3-yl]methanol; N-[6-(5-chloro-2-fluorophenyl)-3-(trifluoromethyl)pyridazin-4-yl]-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-amine.

6. R ３ Ga-OR ７ and R ７ -2-(morpholin-4-yl)ethyl, -2-(piperazin-1-yl)ethyl, -2-(4-methylpiperazin-1-yl)ethyl, 2-(1-methylpiperidin-4-yl)ethyl, -3-(4-methylpiperazin-1-yl)propyl, -2-(4-ethylpiperazin-1-yl)ethyl, -4-ethyl-1-(piperazin-1-yl)ethan-1-one, -2-(4-methanesulfonylpiperazin-1-yl)ethyl, -1-(4-methylpiperazin-1-yl)ethan-1-one, 2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl, -2-[methyl(oxetan-3-yl)amino]ethyl, -3-(3-methyl-1,3-diazinan-1-yl)propyl, -2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}ethyl, -1-(3-ethyltetrahydropyrimidin-1(2H)-yl)ethan-1-one, methyl-[4-ethyl-(piperazin-1-yl)]propanoate, -2-(3-methyl-1,3-diazinan -1-yl)ethyl, -3-(4-ethylpiperazin-1-yl)-N-methylpropanamide, -2-[4-(2-aminoethyl)piperazin-1-yl]ethyl, -4-ethyl-[(piperazin-1-yl)ethyl]methanesulfonamide, -4-[2-(dimethylamino)ethyl]piperazin-1-yl-ethyl, N-(2-(4-ethylpiperazin-1-yl)ethyl)acetamide, -3-(4-ethylpiperazin-1-yl)propanenitrile, -2-(4-ethylpiperazin-1-yl) 5. The compound of formula (Ib) of claim 4, wherein the compound is selected from the group consisting of methyl (2-(4-ethylpiperazin-1-yl)ethyl)carbamate, -3-(4-ethylpiperazin-1-yl)pentane-1,5-diol, -(1-methylpiperidin-4-yl)methyl, and -2-(3-methylimidazolidin-1-yl)ethyl.

7. Formula (Ic) 【Transformation 7】 A is represented by A3 【Transformation 8】 A compound of formula (I) wherein R １ is aryl optionally substituted with one or more halogen atoms; R ４ -C(O)NR ５ R ７ and —C(O)heterocycloalkyl, wherein said heterocycloalkyl optionally has one or more —(C １ -C ６ ) alkyl substituted; R ５ is H or -(C １ -C ６ ) alkyl; R ７ is 1 or more -(C １－ C ６ ) alkyl-substituted heterocycloalkyl and -(C １－ C ６ ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl optionally contains one or more —(C １ -C ６ ) substituted with alkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

8. The compound of formula (Ic) of claim 7, selected from at least one of the following: 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-[2-(1-methylpiperidin-4-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 6-(5-chloro-2-fluorophenyl)-N-[2-(4-methylpiperazine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyridazin-4-amine; 4-{[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide. 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-{[6-(5-chloro-2-fluorophenyl)-3-methylpyridazin-4-yl]amino}-N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide.

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 8 in admixture with one or more pharmaceutically acceptable carriers or excipients.

10. 10. The pharmaceutical composition of claim 9, which is administered by inhalation.

11. A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutical composition according to claims 9 and 10 for use as a medicament.

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

13. 13. A compound of formula (I) or a pharmaceutical composition for use according to claims 11 and 12 in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

14. 14. A compound of formula (I) or a pharmaceutical composition for use according to claim 13 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.

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