Novel FYN and VEGFR2 kinase inhibitors

Abstract

The present invention relates to N-phenylcarbamoyl compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of diseases and disorders involving at least one tyrosine kinase selected from Fyn and VEGFR2, for the inhibition of one or both kinases. [Formula 1] JPEG2023505684000127.jpg1840

Description

[Technical field]

[0001] The N-phenylcarbamoyl compounds of the present invention of formula (I) as FYN and VEGFR2 kinase inhibitors. [Background technology]

[0002] Protein kinases are promising drug targets for treating several disorders ranging from cancer, autoimmune pathology, inflammation, or neurodegenerative diseases. Fyn is an intracellular tyrosine kinase that belongs to the Src family kinases (SFKs) and is involved in several biological processes (e.g., growth factor and cytokine receptor signaling, T-cell and B-cell receptor signaling, ion channel function, platelet activation, and natural killer cell differentiation). Many literature data have demonstrated that Fyn plays a major role in mediating pain. Phosphorylation of NMDA receptors, which is essential for the maintenance of neuropathic pain, mainly depends on Fyn activation. This role of Fyn goes even deeper, suggesting that Fyn-dependent phosphorylation of NMDA and AMPA is also significantly involved in inflammatory pain experimental models and is important for the development of tactile allodynia in prediabetic neuropathy conditions in mice.

[0003] Recent studies have demonstrated that, among the SFK family, Fyn is the only protein that is most strongly upregulated in degenerated and damaged articular cartilage in aged mice. Furthermore, Fyn levels were elevated in both experimental OA mouse cartilage and human OA cartilage in subjects undergoing total knee arthroplasty (Li, K. et al. Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway. Ann. Rheum. Dis. annrheumdis-2017-212658, 2018).

[0004] In the later stages of OA in affected patients, expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been found to be increased in articular cartilage, synovium, synovial fluid, subchondral bone and serum. Evaluation of VEGF as a biomarker in OA patients has demonstrated that increased synovial fluid VEGF not only correlates with the grade of OA severity, but also with the degree of OA pain. VEGF signaling is mediated by three kinase insert domain receptors (receptor tyrosine kinases, or RTKs), VEGFR-1, -2 and 3, with VEGFA / VEGFR2 being the most prominent ligand-receptor complex of the VEGF system, which has a key role in angiogenesis. In endothelial cells, VEGF / VEGFR2 binding leads to Fyn activation, which triggers a series of downstream signaling pathways, the outcome of which is actin polymerization, stress fiber formation and endothelial cell migration, which are essential to promote new blood vessel growth. (Lamalice et al, Phosphorylation of Tyr1214 within VEGFR-2 Triggers the Recruitment of Nck and Activation of Fyn Leading to SAPK2 / p38 Activation and Endothelial Cell Migration in Response to VEGF,281,34009-34020,2006).

[0005] Furthermore, numerous studies have found that VEGF signaling in chondrocytes affects pro-catabolic mediators (i.e., matrix metalloproteinases, aggrecanases) and that the dual effects of VEGF and inflammatory cytokines on chondrocytes can enhance cartilage degeneration. Inflammatory pathways are associated with OA progression, with angiogenesis stimulating inflammation and inflammation promoting angiogenesis (Hamilton, JLet al, Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain. J. Bone Miner. Res. 31, 911-924 (2016)). Furthermore, inflammation is a classical mediator of sensitization of delicate unmyelinated sensory nerves that mediate OA pain.

[0006] Angiogenesis is a key component of both inflammation and pathogenesis in inflammatory bowel disease (IBD), of which there are two major types: ulcerative colitis (UC) and Crohn's disease (CD). Chronic inflammation and angiogenesis are closely related processes, and in fact immune / inflammatory cells secrete multiple angiogenic factors (i.e., growth factors, cytokines). VEGF levels have been found to be elevated in the serum of IBD patients, with the source being inflamed intestinal tissue and peripheral blood mononuclear cells. In IBD, physiological angiogenesis turns into pathological angiogenesis in the early stages of the disease, and the factor or factors that cause the conversion from physiological to pathological angiogenesis remain unknown (Angiogenesis in Inflammatory Bowel Disease-C.Alkim et al.-International Journal of Inflammation,Volume 2015,Article ID970890). Summary of the Invention

[0007] The present inventors have unexpectedly discovered a novel class of compounds that exhibit a previously undescribed dual profile in selectively and potently inhibiting both the VEGF receptor VEGFR-2 (often referred to as the KDR receptor) and the Src family member Fyn.

[0008] Thus, the present invention relates to an N-phenylcarbamoyl compound of formula (I) or a salt thereof, [ka] In the formula, A is [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle; Y is an optionally substituted 5- or 6-membered heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10 ) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently selected from (C1-C3) alkyl and halogen.

[0009] This unprecedented profile makes this series a highly promising compound candidate in the treatment of diseases such as osteoarthritis, where two kinases acting in synergy have a detrimental role. This series is endowed with an unexpected and unique pharmacokinetic profile that favors local treatment at high doses without a parallel increase in concentrations in blood or in non-affected tissues, thus guaranteeing an unprecedented safety profile.

[0010] The present invention therefore provides an N-phenylcarbamoyl compound of formula (I) for use as a medicament [ka] or a pharma- ceutically acceptable salt thereof, In the formula, A is [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle; Y is an optionally substituted (C5-C6)heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10 ) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently (C1-C3) alkyl or halogen.

[0011] In another aspect, the present invention also provides N-phenylcarbamoyl compounds of formula (I) for use in the treatment of diseases and disorders involving at least one tyrosine kinase selected from Fyn and VEGFR2, for the inhibition of one or both kinases. [ka] or a pharma- ceutically acceptable salt thereof, A is, [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle; Y is an optionally substituted (C5-C6)heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10 ) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently (C1-C3) alkyl or halogen.

[0012] Thus, the compounds of formula (I) act as tyrosine kinase inhibitors of two kinases, Fyn and VEGFR, and are therefore dual kinase inhibitors. This multi-target therapy has therapeutic potential for treating osteoarthritis as well as other conditions and diseases involving both kinases.

[0013] In particular, the compounds of the present invention are disclosed for use in the treatment of disorders / diseases / conditions selected from the group consisting of osteoarthritis, ocular diseases, e.g., intraocular neovascular disorders, e.g., age-related macular degeneration, diabetic macular edema and other ischemia-related retinopathies, or immune-mediated corneal graft rejection; skin disorders, such as psoriasis or rosacea; acute or chronic pain; pulmonary diseases, such as acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and systemic sclerosis (SSc); cancers, such as metastatic colorectal cancer, non-squamous non-small cell lung cancer, metastatic renal cell carcinoma, recurrent glioblastoma multiforme, gynecological malignancies, metastatic breast cancer, etc.

[0014] In a preferred embodiment, the compounds of the present invention are disclosed for use in the treatment of acute and chronic pain selected from neuropathic pain, inflammatory pain, osteoarthritic pain, ocular pathological pain. [Brief description of the drawings]

[0015] [Figure 1] Local analgesic efficacy of compound 3 in rat CFA assay. Activity is reported as mechanical threshold (weight borne by CFA inflamed paw). Data from naive animals treated with vehicle with test substance are also shown, demonstrating the lack of effect on normal pain threshold. [Diagram 2] Dose-response curves for the local analgesic potency of different doses of Compound 3 in the rat CFA assay. Activity is reported as the mechanical threshold (weight borne by the CFA inflamed paw). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention relates to pharmaceutical compositions containing dual VEGF2 / Fyn inhibitors that can act locally in resolving diseases resistant to other drugs without causing general systemic toxicity.

[0017] Thus, the present invention provides an N-phenylcarbamoyl compound of formula (I) [ka] or a salt thereof, In the formula, A is [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle; Y is an optionally substituted (C5-C6)heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently (C1-C3) alkyl or halogen.

[0018] In the present invention, the following terms may be used: "Compound of the invention" or "compound of this invention" means a compound of formula (I) as defined above in any form, i.e. in any salt or non-salt form (e.g. as a free acid or free base form or as a salt, in particular a pharma- ceutically acceptable salt thereof) and in any physical form thereof (e.g. non-solid form (e.g. liquid or semi-solid form) and solid form (e.g. amorphous or crystalline form, particular polymorphic form, solvate form, including hydrate form (e.g. monohydrate, dihydrate and hemihydrate)), as well as mixtures of the various forms; "Optionally substituted" means a group or ring that is unsubstituted or that is substituted with one or more of the specified substituents; "5- or 6-membered saturated heterocycle" means a saturated carbocycle in which one or two carbon atoms are replaced by a heteroatom such as nitrogen, oxygen or sulfur, non-limiting examples being tetrahydropyran, pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine and morpholine; "(C1-C3) alkyl" means a linear or branched saturated hydrocarbon group containing 1 to 3 carbon atoms; "(C1-C4) alkyl" means a linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms; "Saturated (C3-C6)cycloalkyl" means a 3-6 membered saturated all-carbon monocyclic ring, non-limiting examples being cyclopropane, cyclobutane, cyclopentane, cyclohexane; - "Azaspiro (C7~C 10 ) "Alkyl" means an 8-10 membered saturated ring of carbon atoms and one N atom, forming a cyclic ring with a spiro atom; "Halogen" means chloro, fluoro, bromo and iodo atoms; - "5- or 6-membered heteroaryl ring" means an unsaturated carbocyclic ring in which 1 to 3 carbon atoms are replaced by a heteroatom such as nitrogen, oxygen or sulfur, non-limiting examples are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, pyrrolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl.

[0019] According to the invention, A is [ka] It is.

[0020] X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle.

[0021] X may be an optionally substituted 5- or 6-membered heteroaryl ring. The 5- or 6-membered heteroaryl ring is preferably pyrazine, pyridine or pyrimidine, optionally substituted with one or more substituents selected from the group consisting of (C1-C3) alkyl, (morpholino) methyl, (dimethylmorpholino) methyl, pyrrolidin-1-ylmethyl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 3-hydroxyazetidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, (2-hydroxyethyl)-1H-pyrazol-4-yl, morpholin-1-yl and cyano. More preferably, the substituent (C1-C3) alkyl is methyl.

[0022] X may be an optionally substituted 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, and when substituted, is preferably substituted with one or more substituents selected from the group consisting of (C1-C3)alkyl, hydroxy(C1-C3)alkyl, and ((C1-C3)alkyl)CO-, more preferably ethyl, 2-hydroxyethyl, and acetyl.

[0023] X may be an optionally substituted (5- or 6-membered heteroaryl)CO-. Preferably, the (5- or 6-membered heteroaryl)CO- is (pyridine)CO- or (pyrimidine)CO-. When substituted, it is preferably substituted with one or more (C1-C3) alkyls.

[0024] X may be optionally substituted (phenyl)CO-. When substituted, it is preferably substituted with one or more substituents selected from the group consisting of halogen, (1-isopropylazetidin-3-yl)oxy, 4-methylpiperazin-1-yl, and 1-methylpiperidin-4-yl. When it is halogen, it is more preferably fluoro.

[0025] Y is an optionally substituted (C5-C6)heteroaryl ring. The optionally substituted (C5-C6)heteroaryl ring is preferably an optionally substituted pyrazine, more preferably unsubstituted. When the pyrazine is substituted, it is preferably substituted with one or more (C1-C3)alkyl, even more preferably methyl.

[0026] R1 and R2, which may or may not be present at the same time, are independently (C1-C3) alkyl or halogen. Preferably, R1 is (C1-C3) alkyl, more preferably methyl. Preferably, R2 is H or halogen. When R1 is halogen, it is preferably fluoro or chloro, more preferably fluoro. When R2 is halogen, it is preferably fluoro.

[0027] B may be an optionally substituted phenyl. When B is a substituted phenyl, it is preferably substituted with one or more substituents selected from the group consisting of (C1-C3)alkyl, R'SO2-, R'R''N(C1-C3)alkyl, R'NH(C1-C3)alkyl-, R'R''N-, trifluoromethyl, difluoromethyl, halogen, R'R''NSO2-, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-NH-, NR'(C3-C6)cycloalkyl-, where R' and R'' are each independently (C1-C3)alkyl, more preferably methyl. Among the preferred substituents of phenyl, the following may be mentioned: CH3SO2-, -CH2N(CH3)2, CH3, CF3, CHF2, fluoro, -SON(CH3)2, (N-ethyl)aminocyclopropyl.

[0028] B may be an optionally substituted 5- or 6-membered heteroaryl ring. The optionally substituted 5- or 6-membered heteroaryl ring is preferably pyridine or oxazole. If the (C5-C6)heteroaryl ring is substituted, it is preferably substituted with one or more hydroxy(C1-C3)alkyl, CF3, (C1-C4)alkyl, cyano(C1-C3)alkyl and (C3-C6)cycloalkyl-SO2-. Among the preferred substituents of the (C5-C6)heteroaryl ring, preferably pyridine and oxazole, there may be mentioned the following 2-cyanopropan-2-yl, 2-cyanopropan-2-yl, CH3, CF3, fluoro, isobutyl or cyclopropylsulfonyl.

[0029] B is azaspiro (C7~C 10 ) alkyl. Preferably, it is azaspiro[3,4]octane or azaspiro[4,5]decane.

[0030] B may be an optionally substituted 5- or 6-membered saturated heterocycle, preferably pyrrolidine, more preferably pyrrolidine substituted with one or more (C1-C3) alkyl, even more preferably ethyl.

[0031] B may be an optionally substituted saturated (C3-C6) cycloalkyl-NH-, preferably 4,4-(dimethylcyclohexyl)-NH-, cyclopentyl-NH-.

[0032] In a preferred embodiment, A is [ka] It is.

[0033] In this preferred embodiment, X is preferably an optionally substituted 5- or 6-membered heteroaryl ring, more preferably an optionally substituted pyrazine.

[0034] B is preferably optionally substituted phenyl, preferably substituted with CF3.

[0035] In a preferred embodiment, the compound of formula (I) is 1) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 2) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 4) 4-(1-(ethylamino)cyclopropyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 5) 2-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 6) 2-methyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)oxazole-4-carboxamide, 7) 2-fluoro-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)benzamide, 8) 4-(cyclopropylsulfonyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 9) N-(3-(2-fluoro-5-(6-isobutylnicotinamido)phenethyl)-1H-pyrazol-5-yl)pyrimidine-2-carboxamide 10) N-(4-fluoro-3-(2-(5-((2-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide 11) 2-(2-cyanopropan-2-yl)-N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 12) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 13) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 14) N-(3-(2-(5-((3,5-dimethylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 15) N-(4-fluoro-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 16) N-(4-chloro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 17) N-(3-(2-(5-((2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 18) N-(5-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenethyl)-1H-pyrazol-3-yl)picolinamide, 19) N-(3-(2-(3-(4-fluorobenzamido)-1H-pyrazol-5-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 20) N-(4-methyl-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-6-azaspiro[3.4]octane-6-carboxamide, 21) 3,3-diethyl-N-(4-methyl-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)pyrrolidine-1-carboxamide, 22) 3,3-diethyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)pyrrolidine-1-carboxamide, 23) N-(3-(5-(3-(4,4-dimethylcyclohexyl)ureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-((1-isopropylazetidin-3-yl)oxy)benzamide, 24) N-(3-(5-(3-cyclopentylureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, 25) N-(3-(5-(3-(4,4-dimethylcyclohexyl)ureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, 26) N-(4-fluoro-3-(2-(3-((2-methyl-6-(morpholinomethyl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 27) N-(3-(2-(3-((6-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 28) N-(4-fluoro-3-(2-(3-((2-methyl-6-(pyrrolidin-1-ylmethyl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 29) N-(3-(2-(3-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 30) N-(4-fluoro-3-(2-(3-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 31) N-(4-fluoro-3-(2-(3-((6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 32) (S)—N-(3-(2-(3-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 33) 3-(difluoromethyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 34) N-(3-(2-(5-((2-acetyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 35) 3-(isopropylsulfonyl)-N-(4-methyl-3-(2-(5-((3-methylpyridin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 36) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-((3-methylpyridin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 37) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(N,N-dimethylsulfamoyl)benzamide, 38) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-8-azaspiro[4.5]decane-8-carboxamide, 39) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-fluorophenyl)-4-((dimethylamino)methyl)-3-(trifluoromethyl)benzamide, 40) N-(4-fluoro-3-(2-(5-((2-methylpyrimidin-5-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 41) 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 42) N-(4-fluoro-3-(2-(3-((6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 43) N-(2-fluoro-5-(2-(5-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 44) N-(2-fluoro-5-(2-(3-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 45) N-(5-(2-(3-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzamide, 46) N-(2-fluoro-5-(2-(3-((6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 47) 4-((dimethylamino)methyl)-N-(3-(2-(5-(4-morpholinobenzamido)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 48) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 49) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, and 50) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)isonicotinamide.

[0036] More preferably, the compound of formula (I) is 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 6) 2-methyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)oxazole-4-carboxamide, 8) 4-(cyclopropylsulfonyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 13) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 15) N-(4-fluoro-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 34) N-(3-(2-(5-((2-acetyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 49) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, and Even more preferably, the compound of the present invention is 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide.

[0037] The compounds of the present invention may be in the form of a salt, preferably a pharma-ceutically acceptable salt. Therefore, any acid addition salt or salt with a base is included in the present invention, so long as it is a pharma-ceutically acceptable salt.

[0038] Examples include salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, etc. Ammonium, calcium, magnesium, lithium, potassium and sodium salts are preferred. Salts derived from pharma- ceutically acceptable organic non-toxic bases may also be included, such as salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0039] Pharmaceutically acceptable salts can be prepared from pharma- ceutically acceptable non-toxic acids, including inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are particularly preferred.

[0040] General schemes for preparing compounds of the invention are outlined below. [ka]

[0041] The method outlined in Scheme 1 comprises the following steps: a) conversion of compound II (Z=Br) to compound III (Y=H) by addition of ammonia in the presence of copper iodide; or conversion of compound II (Z=Br) to compound III (Y=COR3) by addition of benzamide NH2COR3 in the presence of an organometallic catalyst, such as, for example, tris(dibenzylideneacetone)dipalladium(0); or conversion of compound II (Z=NH2) to compound III (Y=COOtBu) by addition of di-tert-butyl dicarbonate in dichloromethane as solvent; b) conversion of compound III to compound IV by addition of halo-heterocycle X-R2 in the presence of an organometallic catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0) or amide coupling using standard coupling agents such as N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and dimethylaminopyridine in dichloromethane as solvent; c) removal of the tert-butyloxycarbonyl protecting group when Y=COOtBu using HCl or trifluoroacetic acid in dichloromethane as solvent; d) amide coupling using standard coupling agents or urea formation using reagents such as carbonyldiimidazole in tetrahydrofuran to obtain compound VI; e) removal of the protecting group with formic acid to obtain compound I; and f) removal of the protecting group using formic acid when Y=COR3 gives compounds of formula (I).

[0042] Specifically, the general synthesis used to prepare compounds of formula (I) is described in Schemes 1-4.

[0043] The steps of Scheme 1 are reported below. Scheme 1 [ka] The method outlined in Scheme 1 comprises the following steps: a1) conversion of compound V to compound VI by addition of a halo-heterocycle in the presence of an organometallic catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0) or amide coupling using standard coupling agents such as N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and dimethylaminopyridine in dichloromethane as solvent; b1) removal of the tert-butyloxycarbonyl protecting group using HCl or trifluoroacetic acid in dichloromethane as solvent; c1) obtaining compound VIII by amide coupling using standard coupling agents or urea formation using reagents such as carbonyldiimidazole in tetrahydrofuran; and d1) Removal of the protecting groups using formic acid to give compound I.

[0044] The steps of Scheme 2 are reported below. Scheme 2 [ka] a2) conversion of compound IX to compound X by addition of a benzamide in the presence of an organometallic catalyst, such as, for example, tris(dibenzylideneacetone)dipalladium(0); b2) Removal of the protecting group using formic acid to give compound XI. c2) Conversion of compounds XI to compounds I by addition of a halo-heterocycle in the presence of an organometallic catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0).

[0045] Another embodiment of the present invention for obtaining compounds of formula (I) is described in Scheme 3 below. Scheme 3 [ka] The method outlined in Scheme 3 comprises the following steps: a3) Conversion of compound XII to amine XIII using ammonia in the presence of copper iodide as catalyst at 100° C. in a sealed tube; b3) amide coupling using standard coupling agents to give compound XIV; c3) conversion of compound XV to compound XV by addition of a halo-heterocycle in the presence of an organometallic catalyst such as, for example, tris(dibenzylideneacetone)dipalladium(0) or amide coupling using standard coupling agents such as N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and dimethylaminopyridine in dichloromethane as solvent; and d3) Removal of the protecting groups using formic acid to give compound I.

[0046] The steps of Scheme 4 are reported below. Scheme 4 [ka] The method outlined in Scheme 4 comprises the following steps: a4) conversion of compound XVI to compound XVII by addition of a halo-heterocycle in the presence of an organometallic catalyst, such as, for example, tris(dibenzylideneacetone)dipalladium(0), or amide coupling using standard coupling agents such as N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride and dimethylaminopyridine in dichloromethane as solvent; b4) removal of the BOC protecting group using HCl or trifluoroacetic acid in dichloromethane as solvent; c4) Amide coupling using standard coupling agents to give compound I.

[0047] The compounds of formula (I) above can be used as medicines.

[0048] In another aspect, the present invention provides an N-phenylcarbamoyl compound of formula (I) for use as a medicament. [ka] or a pharma- ceutically acceptable salt thereof, In the formula, A is [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO-, (phenyl)CO-, and saturated (C5-C6) heterocycle; Y is an optionally substituted (C5-C6)heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10 ) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently selected from (C1-C3) alkyl and halogen.

[0049] The current trend in the development of tyrosine kinase inhibitors is the assumption that multi-target therapy, which simultaneously targets several signaling pathways, is more effective than single-target therapy. In cancer, the considerations for determining whether multiple single kinase inhibitors or a single multi-kinase inhibitor are preferred are based on the aspects related to efficacy, resistance, pharmacokinetics, selectivity and tumor environment. The clinical characteristics of OA are symptoms, which are mainly pain, and lesions of joint structures, both of which determine functional impairment, and then tyrosine kinase inhibitors, and multi-target therapy has therapeutic potential for OA treatment.

[0050] Thus, in another aspect, the present invention also provides an N-phenylcarbamoyl compound of formula (I) for use in the treatment of diseases and disorders involving at least one tyrosine kinase selected from Fyn and VEGFR2, for the inhibition of one or both kinases. [ka] or a pharma- ceutically acceptable salt thereof, In the formula, A is [ka] and X is an optionally substituted group selected from the group consisting of a 5- or 6-membered heteroaryl ring, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO—, (phenyl)CO—, and a 5- or 6-membered saturated heterocycle; Y is an optionally substituted (C5-C6)heteroaryl ring; B is phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C 10 ) alkyl and saturated (C3-C6) cycloalkyl-NH-, R1 and R2 may or may not be present at the same time and are independently (C1-C3) alkyl or halogen.

[0051] Specifically, unexpectedly, compounds of formula (I) are used to treat osteoarthritis. Without being bound by any theory, the inventors believe that compounds targeting two kinases, Fyn and VEGFR2, which appear to be crucial for determining both the symptoms and progression of OA, are ideal candidates, allowing them to overcome the classical dichotomy between structure and symptom modifiers. Furthermore, the intra-articular mode of action of the compounds, which provides maximum concentration at peripheral sites, combined with low systemic availability, allows for predicting good efficacy without possible systemic safety issues. The reduction in systemic drug exposure may be particularly relevant for patients with complex or severe comorbidities.

[0052] In accordance with the present invention, the compounds are used to treat other conditions in which local and concomitant inhibition of VEGF and Fyn is beneficial.

[0053] In particular, they include ocular diseases, such as intraocular neovascular disorders, such as age-related macular degeneration, diabetic macular edema and other ischemia-related retinopathies, or immune-mediated corneal graft rejection; skin disorders such as psoriasis, a common autoimmune disease characterized by a hyperplastic epidermis and a hypervascularized dermis; or rosacea, a common chronic condition that mainly affects the facial skin and is characterized by visible blood vessels, a central facial erythema, and often papules and pustules; acute or chronic pain, pulmonary diseases such as acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and systemic sclerosis (SSc); certain cancers, such as metastatic colorectal cancer, nonsquamous non-small cell lung cancer, metastatic renal cell carcinoma, recurrent glioblastoma multiforme, gynecological malignancies, metastatic breast cancer.

[0054] In a preferred embodiment, the compounds of the present invention are disclosed for use in the treatment of acute and chronic pain selected from neuropathic pain, inflammatory pain, osteoarthritic pain, ocular pathological pain.

[0055] Preferably, the compositions of the present invention are used in pharmaceutical compositions together with pharma- ceutically acceptable carriers and excipients.

[0056] Thus, the compositions may also contain pharma- ceutically acceptable excipients and may be administered in a pharmaceutical form appropriate for the desired route of administration.

[0057] The pharma- ceutically acceptable additives may be excipients, ligands, dispersants, colorants, humectants, etc., commonly used in the preparation of tablets, capsules, pills, solutions, suspensions, and emulsions for oral administration. Injectable solutions are also contemplated for parenteral administration, including subcutaneous, spinal, and transdermal administration.

[0058] The pharmaceutical composition according to the invention is preferably for intra-articular, intravenous, oral, transdermal, intrathecal, intranasal, intraperitoneal or intramuscular administration, more preferably for intra-articular administration.

[0059] The compound of formula (I) of the present invention is preferably administered at a dose of 0.25 to 500 mg / knee, more preferably at a dose of 1 to 200 mg / knee. These doses can be dissolved in a volume ranging from 0.5 mL / knee to 6 mL / knee.

[0060] The pharmaceutical compositions according to the invention can be used alone or in combination with or contain one or more additional drugs, which may include, but are not limited to, hyaluronic acid, chondroitin sulfate and glucosamine, glucosamine sulfate, and steroidal or non-steroidal anti-inflammatory drugs.

[0061] The invention will now be described in detail, for illustrative purposes and not for limiting purposes, with reference to examples for the preparation and testing of the inhibitory activity of the compounds of the invention.

[0062] Experimental Department The reagents used in the following examples were commercially available from various suppliers and were used without further purification. Solvents were used in anhydrous form. Reactions in anhydrous environment were carried out under a positive pressure of dry N2.

[0063] Proton nuclear magnetic resonance ( 1H NMR spectra were recorded on a Bruker Avance 400 MHz instrument. Chemical shifts are reported in ppm (δ) using residual solvent as internal standard. Splitting patterns are designated as follows: s singlet, d doublet, t triplet, q quartet, m multiplet, b broadening signal.

[0064] Mass spectra (MS) were performed on an Ion Trap Thermo LCQ classic spectrometer operating in positive ES (+) and negative ES (-) ionization mode.

[0065] UPLC spectra were performed on a Waters Acquity UPLC-SQD instrument using an Acquity UPLC-BEH C18 column (1.7 μM, 50 × 2.1 mm).

[0066] Chiral-HPLC spectra were performed using an Agilent 1200 instrument equipped with a UV-Vis detector.

[0067] Preparative HPLC was performed on a Waters GX-281 HPLC system equipped with a UV detector.

[0068] Flash silica gel chromatography was performed on a Biotage automated flash chromatography system (Sp1 and Isolera systems) using Biotage SNAP HP silica cartridges or Biotage SNAP KP-NH cartridges.

[0069] Reversed-phase chromatography was performed on a Biotage automated flash chromatography system (Isolera systems) using RediSep Gold C-18Aq cartridges.

[0070] Purification of several basic compounds was carried out using a Phenomenex Strata SCX cartridge (55 μm, 70A).

[0071] Thin layer chromatography was performed using Merck TLC plates Kieselgel 60F-254 and visualized with UV light, aqueous permanganic acid, and iodine vapor.

[0072] Microwave reactions were carried out in a Biotage Initiator instrument.

[0073] The following abbreviations are used herein: CAN: acetonitrile, AcOH: acetic acid, CDI: carbonyldiimidazole, cHex: cyclohexane, DIAD: diisopropyl(E)-diazene-1,2-dicarboxylate, Boc: tert-butyloxycarbonyl, Boc2O: di-tert-butyl dicarbonate, DCM: dichloromethane, DCE: 1,2-dichloroethane, TFA: trifluoroacetic acid, DMF: dimethylformamide, THF: tetrahydrofuran, RT: room temperature, DMAP: dimethylaminopyridine, AcOEt: ethyl acetate, NaOH: sodium hydrochloride. oxide, KOH: potassium hydroxide, DIPEA: N,N-diisopropylethylamine, TEA: triethylamine, NaHCO3: sodium bicarbonate, Na2SO4: sodium sulfate, PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) chloride, Cs2CO3: cesium carbonate, DIBAL-H: diisobutylaluminum hydride, LAH: lithium aluminium hydride, tBuOK: potassium tert-butoxide, iPr2O: diisopropyl ether, DIBAL-H: diisobutylaluminum hydride.

[0074] The following schemes (5, 6, 7, and 8) describe general synthetic routes to the intermediates (V, IX, XII, XVI) of schemes 1, 2, 3, and 4.

[0075] Scheme 5 for obtaining intermediate (V) is reported below. Scheme 5 [ka] Scheme 5 provides the following steps: a) Conversion of the starting material in a compound of formula XVI using a reducing agent such as DIBAL-H in DCM as solvent; R1 can be =F, Cl, Me; b) Wittig reaction using ethyl 2-(triphenylphosphoranylidene)acetate in water to give intermediate XVII; c) reduction of the double bond and the nitro group under hydrogen atmosphere and amine protection to give intermediates of formula XVIII; d) Formation of the aminopyrazole derivative (V) using tertbutylhydrazine in a polar solvent such as ethanol.

[0076] Scheme 6 [ka] Scheme 6 provides the following steps: a) reduction of the double bond under hydrogen atmosphere to give intermediate XIX; b) Formation of the aminopyrazole derivative IX using tertbutylhydrazine in a polar solvent such as ethanol.

[0077] Scheme 7 [ka] Scheme 7 provides the following steps: a) Ester formation using thionyl chloride in MeOH; b) Formation of the aminopyrazole derivative (XII) using tertbutylhydrazine in a polar solvent such as ethanol.

[0078] Scheme 8 [ka] Scheme 8 provides the following steps: a) protection of the starting amine to give intermediate XXI; b) conversion of intermediates of formula XXI to compounds XXII using ethyl acrylate in the presence of a palladium catalyst and triphenylphosphine; c) Reduction of the double bond with EtOH / ethyl acetate under a hydrogen atmosphere; d) Reduction of the ester group using a reducing agent such as LAH in THF; e) oxidation of intermediate XXIV with an oxidizing agent such as MnO2 to give aldehyde XXV; f) reaction of intermediate XXV with 1-((chloromethyl)sulfonyl)-4-methylbenzene in THF containing a base such as tBuOK to obtain intermediate XXVI; g) Formation of bromoaldehyde XXVII using MgBr2; h) Reaction of intermediate XXVII with thiourea in THF / water to form intermediate XVI.

[0079] Example 1: Preparation of intermediate (XVI) (intermediates 1-3) of scheme 5 General Procedure 1 To a stirred solution of nitrobenzoate (56.4 mmol) in DCM (300 ml) was added DIBAL-H 1M in DCM (67.6 ml, 67.6 mmol) dropwise at -78°C. After stirring for 20 min at -78°C, a mixture of DCM (150 mL) and saturated Rochelle's salt solution (250 mL) was added. After vigorously stirring at room temperature for 1 h, the resulting mixture was separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a clear oil. [Table 1]

[0080] Example 2: Preparation of intermediate (XVII) (intermediates 4-6) of scheme 5 General Procedure 2 A mixture of ethyl 2-(triphenylphosphoranylidene)acetate (21.09 g, 60.6 mmol) and nitrobenzaldehyde (60.6 mmol) in water was heated at 90° C. for 1 h.

[0081] The suspension was cooled to room temperature, extracted with DCM, dried over Na2SO4 and concentrated. The crude product was suspended in a mixture of cyclohexane and DCM, the precipitate was removed by filtration, and the filtrate was concentrated and purified on a silica gel column (340 g) eluted with cyclohexane to cyclohexane / AcOEt 8 / 2 to give the title compound as a yellow solid. [Table 2]

[0082] Example 3: Preparation of intermediate (XVIII) (intermediates 7-9) of scheme 5 General Step 3 To a solution of intermediates 4-6 (17.00 mmol) in THF (75 ml) was added BOC2O (4.45 g, 20.41 mmol) and Pd / C (0.452 g, 0.425 mmol). The resulting solution was stirred under a hydrogen atmosphere for 16 h.

[0083] The mixture was filtered to remove the catalyst, then the filtrate was concentrated and purified by silica gel column (100 g) eluting with cHex only to cHex / AcOEt 9:1 over 7 CV to give the title compound as an off-white solid. [Table 3]

[0084] Example 4: Preparation of intermediate (V) of scheme 5 (intermediates 10-14) General Procedure 4 To nBuLi in hexane (11.06 ml, 27.7 mmol) in anhydrous THF (52.7 ml) was added dropwise at -78°C, maintaining the temperature below -65°C. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. After this, a solution of intermediate 7, 8 or 9 (11.06 mmol) in THF (10 ml) was added dropwise again, maintaining the temperature below -65°C at all times. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. After this, the reaction was quenched with 10% w / v aqueous citric acid (20 ml) and allowed to warm to room temperature. HCl 1M (20 ml) was then added until pH 3 and the product was extracted twice with iPr2O.

[0085] The organic phase was washed with brine, dried and evaporated under reduced pressure to give a yellow oil. The intermediate was dissolved in ethanol (105 ml) and then hydrazine hydrochloride or tert-butylhydrazine hydrochloride (33.2 mmol) was added and the resulting mixture was heated to reflux for 3 hours.

[0086] The reaction was cooled to room temperature and the ethanol was evaporated under vacuum. To the remaining residue was added DCM (40 ml) and water / NaHCO3. After brief mixing, the two layers were separated and the organic layer was then dried over anhydrous sodium sulfate and evaporated. The resulting residue was loaded onto a silica gel column (100 g; gradient: DCM to DCM / iPr2O 9 / 1) to give the title compound as an off-white solid. [Table 4-1] [Table 4-2]

[0087] Example 5: Preparation of intermediate (XIX) (intermediate 15) of scheme 6 Methyl 3-(3-bromo-4-fluorophenyl)propanoate [ka] To (E)-methyl 3-(3-bromo-4-fluorophenyl)acrylate (5.3 g, 20.46 mmol) in THF (30 ml) was added 5% rhodium on carbon (1.179 g, 0.573 mmol). The resulting solution was placed under a hydrogen atmosphere (1 bar; room temperature).

[0088] The reaction was filtered to remove the catalyst. The filtrate was then concentrated in vacuo to remove the solvent. Yield 5.34 g (yellow oil). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.55-7.64(1 H,m),7.22-7.34(2 H,m),3.53-3.65(3 H,m),2.79-2.91(2 H,m),2.59-2.72(2 H,m). ESI+ m / z 262 [M+H]

[0089] Example 6: Preparation of intermediate (IX) (intermediate 16) of scheme 6 3-(3-bromo-4-fluorophenethyl)-1-(tert-butyl)-1H-pyrazol-5-amine [ka] To n-butyllithium in hexane (17.72 ml, 44.3 mmol) in anhydrous THF (100 ml) was added acetonitrile (2.314 ml, 44.3 mmol) dropwise at -78°C, maintaining the temperature below -65°C. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. After this, methyl 3-(3-bromo-4-fluorophenyl)propanoate (5.34 g, 22.15 mmol) was added dropwise, maintaining the temperature below -65°C at all times. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. After this, the reaction was quenched with 1M aqueous HCl (5 ml). The reaction was allowed to warm to room temperature and then the organic solvent was removed under vacuum.

[0090] To the remaining solution was added 1M aqueous HCl (15 ml) followed by DCM (50 ml). After brief mixing the organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to give a yellow oil.

[0091] Ethanol (150 ml) was then added to this yellow oil, followed by tert-butylhydrazine hydrochloride (4.14 g, 33.2 mmol) and sodium hydroxide (1.240 g, 31.0 mmol). The resulting mixture was then heated to reflux overnight. The next day, the reaction was cooled to room temperature and the ethanol was then removed. To the remaining residue was added water (50 ml), saturated aqueous sodium bicarbonate (50 ml) and DCM (100 ml). After brief mixing, the organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to give a brown oil. Purification: KP-NH silica gel column (110 g) eluting with cyHex / DCM 70:30. Yield: 6.64 g (yellow solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.55(1 H,dd),7.21-7.28(2 H,m),5.20(1 H,s),4.72(2 H,s),2.74-2.86(2 H,m),2.54-2.65(2 H,m),1.49(9 H,s). ESI+ m / z 341 [M+H]

[0092] Example 7: Preparation of intermediate (XX) (intermediate 17) of scheme 7 Methyl 3-(3-bromophenyl)propanoate [ka] To 3-(3-bromophenyl)propanoic acid (5 g, 21.83 mmol) in anhydrous methanol (44 ml) was added thionyl chloride (4.75 ml, 65.5 mmol) dropwise. Once addition was complete the reaction was allowed to warm to room temperature and left overnight. After stirring overnight the reaction was evaporated and dried under high vacuum. Yield 5.35 g (colorless oil). 1H NMR(400 MHz,DMSO-d6)δ ppm 7.35-7.50(2 H,m),7.21-7.28(2 H,m),3.59(3 H,s),2.77-2.91(2 H,m),2.59-2.70(2 H,m). ESI+m / z 245 [M+H]

[0093] Example 8 Preparation of intermediate (XII) (intermediate 18) of scheme 7 3-(3-bromophenethyl)-1-(tert-butyl)-1H-pyrazol-5-amine [ka] To nBuLi in hexane (17.90 ml, 44.8 mmol) in anhydrous Et2O (100 ml) was added acetonitrile (2.338 ml, 44.8 mmol) dropwise at -78°C, maintaining the temperature below -65°C. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. After this, intermediate 17 (5.44 g, 22.38 mmol) was added dropwise, maintaining the temperature below -65°C at all times. Once the addition was complete, the reaction was left stirring at -78°C for 1 hour. Therefore, the reaction was quenched with 1M aqueous HCl (20 ml), warmed to room temperature and then the organic solvent was removed under vacuum.

[0094] To the remaining aqueous solution was added further 1M aqueous HCl (35 ml) followed by DCM (50 ml). The organic phase was then dried over anhydrous sodium sulphate and evaporated to give a tan oil.

[0095] This intermediate was dissolved in ethanol (200 ml) and then tert-butylhydrazine hydrochloride (4.18 g, 33.6 mmol) and NaOH (1.253 g, 31.3 mmol) were added. The resulting mixture was heated to reflux for 3 h, then cooled to room temperature and the ethanol was evaporated under vacuum. To the remaining residue was added DCM (100 ml) and dilute aqueous sodium bicarbonate. After brief mixing, the two layers were separated and then the organic layer was dried over anhydrous sodium sulfate. Purification: KP-NH silica gel column (110 g) eluted with a gradient of cyclohexane / DCM 9:1 to cyclohexane / DCM 1:1. Yield 5.60 g (off-white solid). 1 H NMR(400MHz,CDCl3)δ ppm 7.39(d,J=1.5 Hz,1 H),7.33(td,J=2.2,6.8 Hz,1 H),7.16(s,1 H),7.15(s,1 H),5.37(s,1 H),2.94-2.88(m,2 H),2.85-2.77(m,2 H),1.65(s,9 H). ESI+m / z 323 [M+H]

[0096] Example 9: Preparation of intermediate (XXI) (intermediate 19) of scheme 8 tert-Butyl (3-bromo-4-methylphenyl)carbamate [ka] To a solution of 3-bromo-4-methylaniline (50.0 g, 0.269 mol), NaHCO3 (45.2 g, 0.538 mol) in MeOH (300 mL) and H2O (150 mL) was added Boc2O (70.0 g, 0.322 mol) slowly at 20-30 °C and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated and the crude product was diluted with DCM (800 mL), filtered and washed with H2O (2 x 100 mL). The combined organics were dried over Na2SO4 and concentrated to give 74.5 g of the title intermediate as a white solid. ESI+ m / z 286 [M+H]

[0097] Example 10 Preparation of intermediate (XXII) (intermediate 20) of scheme 8 Ethyl (E)-3-(5-((tert-butoxycarbonyl)amino)-2-methylphenyl)acrylate [ka] To a solution of intermediate 19 (74.5 g, 0.26 mol), TEA (105.0 g, 1.04 mol) and ethyl acrylate (260.0 g, 2.6 mol) in toluene (600 ml) was added Pd(OAc)2 / PPh3 (5.0 g / 13.6 g) at room temperature, and then the mixture was stirred at 112° C. for 4 days. The mixture was concentrated and purified by flash chromatography on silica gel (petroleum ether:AcOEt 50:1 to 5:1) to give the title intermediate (75 g) as a white solid. ESI+ m / z 306 [M+H]

[0098] Example 11 Preparation of intermediate (XXIII) (intermediate 21) of scheme 8 Ethyl 3-(5-((tert-butoxycarbonyl)amino)-2-methylphenyl)propanoate [ka] To a solution of intermediate 20 (75.0 g, 0.245 mol) in ethyl acetate (600 mL) and ethanol (1200 mL) was added Pd / C (6.0 g, 10%) and the mixture was stirred under hydrogen atmosphere (50 psi) at 35° C. for 2 days. The mixture was filtered and concentrated to give intermediate 21 (65 g) as a light gray solid. ESI+ m / z 308 [M+H]

[0099] Example 12 Preparation of intermediate (XXIV) (intermediate 22) of scheme 8 tert-Butyl (3-(3-hydroxypropyl)-4-methylphenyl)carbamate [ka] To a solution of intermediate 21 (8.0 g, 26.0 mmol) in THF (30 mL) was added LiAlH4 (1.0 g, 26.0 mmol) in Et2O (30 mL) at 0-5 °C, and the mixture was then stirred at room temperature for 3 h. The mixture was quenched with 1 mL of H2O, followed by 1 mL of 15% NaOH and 3 mL of H2O, filtered, and the filtrate was concentrated to give intermediate 22 (6.9 g) as a white solid. ESI + m / z 266 [M+H]

[0100] Example 13 Preparation of intermediate (XXV) (intermediate 23) of scheme 8 tert-Butyl (4-methyl-3-(3-oxopropyl)phenyl)carbamate [ka] To a solution of crude intermediate 22 (6.9 g, 26.0 mmol) in anhydrous DCM (100 mL) was added PCC (1.2 g, 18.3 mmol), and then the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated and purified by flash chromatography on silica gel (petroleum ether:AcOEt 30:1 to 10:1) to give the title intermediate (3.5 g) as a yellow oil. ESI+ m / z 264 [M+H]

[0101] Example 14 Preparation of intermediate (XXVI) (intermediate 24) of scheme 8 tert-Butyl (4-methyl-3-(2-(3-tosyloxiran-2-yl)ethyl)phenyl)carbamate [ka] To a solution of intermediate 23 (20.0 g, 0.076 mol) in THF (200 mL) was added 1-((chloromethyl)sulfonyl)-4-methylbenzene (18.6 g, 0.09 mol). After cooling to -65°C, t-BuOK (10.0 g, 0.09 mol) was added portionwise to the solution. The reaction was stirred at this temperature for 0.5 h and then at 0°C for 0.5 h. The reaction was quenched with AcOH / water, EtOAc (100 mL) was added and washed with water followed by brine.

[0102] Purification: flash chromatography on silica gel (petroleum ether:AcOEt 40:1) afforded the title intermediate (13.0 g) as a yellow solid. ESI+ m / z 432 [M+H]

[0103] Example 15 Preparation of intermediate (XXVII) (intermediate 25) of scheme 8 tert-Butyl (3-(3-bromo-4-oxobutyl)-4-methylphenyl)carbamate [ka] To a solution of intermediate 24 (8.0 g, 18.5 mmol) in Et2O (300 mL) was added MgBr2.Et2O (6.0 g, 23.0 mmol). After 18 h at room temperature, water (50 mL) was added and the reaction was filtered. The filtrate was separated and the organic phase was washed with water, brine, dried over Na2SO4 and evaporated to give the title intermediate (6.0 g) as a yellow solid. ESI+ m / z 357 [M+H]

[0104] Example 16 Preparation of intermediate (XVI) (intermediate 26) of scheme 8 tert-Butyl (3-(2-(2-aminothiazol-5-yl)ethyl)-4-methylphenyl)carbamate [ka] To a solution of intermediate 25 (6.0 g, 16.8 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was added thiourea (2.56 g, 33.7 mmol) and Et3N (4.6 mL), then the mixture was stirred at 90° C. for 3 h. The reaction was evaporated to dryness, water (20 mL) was added, extracted with AcOEt (3×30 mL), and dried over Na2SO4. Purification: Flash chromatography on silica gel (DCM:MeOH=100:1) afforded the title intermediate (2.5 g) as a yellow solid. 1H-NMR(300 MHz, CDCl3)δ ppm 7.20(s,1H),7.06-7.05(m,2H),6.74(s,1H),6.55(s,1H),4.87(bs,1H),2.87-2.84(m,4H),2.23(s,3H),1.53(s,9H). ESI+m / z 334 [M+H]

[0105] Example 17 Preparation of intermediate 27 Methyl 4-(1-(ethylamino)cyclopropyl)benzoate [ka] A solution of methyl 4-(1-aminocyclopropyl)benzoate, hydrochloride (1 g, 4.39 mmol; prepared as described in WO2008104055) and acetic acid (1.257 ml, 21.96 mmol) in DCE (30 ml) was stirred for 30 min, then sodium triacetoxyborohydride (1.396 g, 6.59 mmol) was added and the resulting mixture was left stirring at room temperature overnight.

[0106] The reaction was treated with saturated NaHCO3 and extracted with DCM (300 ml). The organic layer was washed with water, dried and concentrated. The residue was purified by reverse phase chromatography (50 g) (water / 0.1% AcOH to CH3CN / 0.1% AcOH) to give the title compound as a pale yellow oil (yield 0.8 g). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.87(1 H,d),7.43(1 H,d),3.84(3 H,s),2.44(2 H,q),0.91-1.05(7 H,m). ESI+m / z 220 [M+H]

[0107] Example 18 Preparation of intermediate 28 4-(1-(ethylamino)cyclopropyl)benzoic acid [ka] To a solution of intermediate 27 (0.8 g, 3.65 mmol) in dioxane (10 ml) was added lithium hydroxide hydrate (0.184 g, 4.38 mmol) dissolved in water (10 ml). After 1 h at room temperature, the reaction was concentrated and the residue was acidified with acetic acid (0.47 ml, 8.21 mmol) and purified by reverse phase chromatography (50 g, water / AcOH 0.1% to ACN / AcOH 0.1%). Yield 235 mg (white solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.91(2 H,d),7.38(2 H,d),2.14(6 H,s),0.89(2 H,d),0.78(2 H,d). ESI+m / z 206 [M+H]

[0108] Example 19 Preparation of intermediate 29 4-(Cyclopropylsulfonyl)picolinic acid [ka] A mixture of methyl 4-chloropicolinate (536 mg, 3.12 mmol), sodium cyclopropanesulfinate (400 mg, 3.12 mmol), leucolin (40.3 mg, 0.312 mmol) and copper(I) chloride (30.9 mg, 0.312 mmol) in NMP (5.5 ml) was heated at 150° C. for 1.5 h. Sodium cyclopropanesulfinate (50 mg, 0.390 mmol) was added and the reaction mixture was left stirring at 150° C. for a further 12 h. The reaction was acidified and loaded onto a reverse phase cartridge (50 g) eluting with HO-AcOH (0.1%) / CHCN-AcOH (0.1%). The residue was dissolved in water / EtOH and lithium hydrate (131 mg, 3.12 mmol) was added. The reaction mixture was left stirring at room temperature for 2 h.

[0109] The ethanol was evaporated and the crude product was loaded onto a reverse phase cartridge (50 g) eluted with HO-AcOH (0.1%) / CHCN-AcOH (0.1%). Yield 300 mg of an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 14.01-13.45(m,1H),9.09-9.01(m,1H),8.41-8.34(m,1H),8.16-8.09(m,1H),3.17-3.07(m,1H),1.27-1.09(m,J=4.4 Hz,4H). ESI+m / z 228 [M+H]

[0110] Example 20 Preparation of intermediate 30 2-(4-Methylpyridin-2-yl)propan-2-ol [ka] 1-(4-Methylpyridin-2-yl)ethanone (1.9 g, 14.06 mmol) was dissolved in THF (40 ml) under dry N2 atmosphere in a two-neck flask. The flask was cooled in an ice bath and a solution of MeMgBr in tert-butyl ether (45 ml, 45.0 mmol) was added dropwise to the flask. The solution was warmed to 40°C and stirred for 3 h. The reaction mixture was then cooled in an ice bath and quenched by the addition of saturated aqueous NH4Cl (100 ml), then extracted with diethyl ether (5 x 40 ml), the organics were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50 g) eluting with cyclohexane / AcOEt 9 / 1 to cyclohexane / AcOEt 7 / 3. Yield 1.09 g (light yellow oil). 1 H NMR(400 MHz,CDCl3)δ ppm 8.37(1 H,d),7.19(1 H,d),6.97-7.07(1 H,m),5.12(1H,br.s.),2.39(3 H,s),1.54(6 H,s). ESI+m / z 152 [M+H]

[0111] Example 21 Preparation of intermediate 31 2-(2-hydroxypropan-2-yl)isonicotinic acid [ka] A solution of intermediate 30 (500 mg, 3.31 mmol) in water (15 ml) at 60° C. was treated with KMnO4 (12 mmol). The reaction was heated to reflux for 20 h. The suspension was cooled to room temperature and then filtered through celite. The pH was adjusted to 2 by addition of 1N HCl and the aqueous phase was washed with AcOEt. The aqueous layer was neutralized by addition of solid NaHCO3, concentrated to a minimum volume, acidified with AcOH and loaded onto a reverse phase column (50 g) eluted with water + 0.1% AcOH only to acetonitrile + 0.1% AcOH only. Yield 322 mg (white solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.51(1 H,d),8.07(1 H,s),7.57(1 H,d),4.95-5.57(1 H,m),1.44(6 H,s). ESI+m / z 182 [M+H]

[0112] Example 22 Preparation of intermediate 32 3-(N,N-Dimethylsulfamoyl)benzoic acid [ka] To 3-(chlorosulfonyl)benzoic acid (500 mg, 2.26 mmol) in THF (6 ml) was added dimethylamine (5.6 mL, 11.3 mmol) under nitrogen. The resulting mixture was left stirring at room temperature overnight. The reaction was then stripped of solvent and AcOH (0.5 mL) and water (5 mL) were added and the resulting white solid was filtered and dried under vacuum at 50° C. for 5 hours to give 3-(N,N-dimethylsulfamoyl)benzoic acid (420 mg). 1H NMR(400 MHz,DMSO-d6)δ ppm 13.51(1 H,s),8.25(1 H,d,J=7.83 Hz),8.21(1 H,s),7.97-8.03(1 H,m),7.78-7.84(1 H,m),2.65(6 H,s). ESI+m / z 230 [M+H]

[0113] Example 23 Preparation of intermediate 33 3-(Isopropylsulfonyl)benzoic acid [ka] To a solution of 3-sulfinbenzoic acid (500 mg, 2.69 mmol) and potassium carbonate (1113 mg, 8.06 mmol) in DMF (10 mL) was added 2-iodopropane (1.611 mL, 16.1 mmol) slowly. The reaction was stirred at room temperature under nitrogen for 3 days.

[0114] To hydrolyze the intermediate ester, NaOH (400 mg, 10 mmol) was added and the mixture was left stirring at room temperature overnight. The reaction was stripped of solvent. To the remaining residue was then added DMSO (0.5 ml) and AcOH (0.8 mL). The resulting solution was loaded onto a reverse phase column (50 g; water + 0.1% AcOH only - 12 CV of ACN + 0.1% AcOH). Yield 290 mg (light yellow solid). 1 H NMR(400 MHz,methanol-d4)δ ppm 8.49(1 H,t,J=1.71 Hz),8.34-8.41(1 H,m),8.12(1 H,d,J=7.83Hz),7.79(1 H,s),3.35-3.45(1 H,m),1.29(6 H,d,J=6.85 Hz). ESI+m / z 227 [MH]

[0115] Example 24 Preparation of intermediate 34 1-(6-chloro-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)ethan-1-one [ka] Acetyl chloride (0.345 ml, 4.85 mmol) was added to a cooled (0° C.) solution of 6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (500 mg, 3.23 mmol, prepared as in WO2006082001) and DIPEA (0.847 ml, 4.85 mmol) in DCM (50 ml). The resulting mixture was stirred at room temperature for 16 h, then water was added and the phases were separated. The organic layer was concentrated and loaded onto a silica gel column (25 g) eluting with a gradient of 10 / 0 to 9 / 1 DCM / MeOH. Evaporation of the solvent gave the title compound (538 mg, off-white solid). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.41(d,J=2.4 Hz,1H),7.56(d,J=1.0 Hz,1H),4.86(s,2H),4.63(s,2H),2.06(d,J=3.4 Hz,3H). ESI+m / z 197 [MH]

[0116] Example 25 Preparation of intermediate 35 2-(2-cyanopropan-2-yl)isonicotinic acid [ka] Prepared as described in WO2014151616.

[0117] Example 26 Preparation of intermediate 36 42-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol [ka] To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in anhydrous DMF (5 ml) was added solid K2CO3 (2.137 g, 15.46 mmol) followed by 2-bromoethanol (0.548 ml, 7.73 mmol). The resulting mixture was then heated to 80 °C for 48 h. DMF was evaporated and DCM (20 ml) was added to the remaining residue, then the resulting mixture was filtered to remove solids and evaporated to give a brown oil. Purification: Silica gel column (25 g) eluted with cHex / AcOEt 1:1 to AcOEt 100%. Yield 150 mg (light yellow oil). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.89(1 H,s),7.57(1 H,s),4.84(1 H,t),4.15(2 H,t),3.72(2 H,q),1.25(12 H,s). ESI+m / z 239 [M+H]

[0118] Example 27 Preparation of intermediate 37 Ethyl 4-((1-benzhydrylazetidin-3-yl)oxy)benzoate [ka] A solution of 1-benzhydrylazetidin-3-ol (2.5 g, 10.45 mmol), ethyl 4-hydroxybenzoate (1.736 g, 10.45 mmol) and triphenylphosphine (2.74 g, 10.45 mmol) in acetonitrile (50 ml) was treated with (E)-diethyldiazene-1,2-dicarboxylate (4.76 ml, 10.45 mmol) and refluxed for 2 h. The reaction mixture was then concentrated and the resulting residue was dissolved in DCM, washed with water and concentrated. The residue was purified by silica gel chromatography (100 g, cyHex to cyHex / AcOEt 1 / 1) to give the title compound (4 g; colorless oil). 1H NMR(400 MHz,DMSO-d6)δ ppm 7.82-7.90(2 H,m),7.41-7.48(4 H,m),7.25-7.33(4 H,m),7.16-7.23(2 H,m),6.89-6.97(2 H,m),4.93(1 H,t),4.53(1 H,s),4.26(2 H,q),3.61-3.70(2 H,m),2.96-3.06(2 H,m),1.29(3 H,t). ESI+m / z 388 [M+H]

[0119] Example 28 Preparation of intermediate 38 Ethyl 4-(azetidin-3-yloxy)benzoate [ka] To a solution of ethyl 4-((1-benzhydrylazetidin-3-yl)oxy)benzoate (2 g, 5.16 mmol) in 1,2-dichloroethane (25 ml) was added ACE-Cl (0.845 ml, 7.74 mmol) and the reaction mixture was stirred at 70° C. for 2 h. After cooling to room temperature, ethanol (25 ml) was added and the reaction mixture was stirred at 70° C. for 36 h.

[0120] The reaction mixture was concentrated, loaded onto an SCX cartridge (10 g) and eluted with MeOH (3 CV) and MeOH with NH3 2.0 (2 CV). The ammoniacal fraction was evaporated and purified by chromatography (NH-KP 55 g, CH~AcOEt) to give 640 mg of the title compound (colorless oil). ESI+ m / z 222 [M+H]

[0121] Example 29 Preparation of intermediate 39 Ethyl 4-((1-isopropylazetidin-3-yl)oxy)benzoate [ka] Acetone (0.637 ml, 8.68 mmol) was added to a solution of ethyl 4-(azetidin-3-yloxy)benzoate (640 mg, 2.89 mmol) in acetic acid (15 ml, 262 mmol). The reaction mixture was left stirring at room temperature for 10 min, then sodium cyanotrihydridoborate (582 mg, 9.26 mmol) was added. The reaction mixture was left stirring at room temperature for 5 h. The solvent was evaporated to give the crude product, which was loaded onto a SNAP-C18 gold (150 g) cartridge eluted with HO-AcOH (0.1%) / CH3CN-AcOH (0.1%). Yield 750 mg (light yellow oil). ESI+ m / z 264 [M+H]

[0122] Example 30 Preparation of intermediate 40 4-((1-isopropylazetidin-3-yl)oxy)benzoic acid [ka] Intermediate 39 (750 mg, 2.85 mmol) was dissolved in MeOH (15 ml) and sodium hydroxide 2N (7.120 ml, 14.24 mmol) was added. The reaction was stirred for 16 hours. The reaction was concentrated and the residue was acidified with acetic acid and then loaded onto a Phenomenex Strata SCX 20 g column primed with MeOH. The column was then eluted with MeOH followed by ammonia / MeOH. Fractions containing the desired product were pooled and evaporated to give the title compound (380 mg; white solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.79-7.95(2 H,m),6.87-6.96(2 H,m),4.81(1 H,t),3.66-3.76(2 H,m),2.90-3.02(2 H,m),2.34(1 H,quin),0.88(6 H,d). ESI+m / z 236 [M+H]

[0123] Example 31 Preparation of intermediate 41 2-(6-chloro-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)ethan-1-ol [ka] To 2-chloro-4,5-bis(chloromethyl)pyridine (500 mg, 2.375 mmol; prepared as in WO2006082001) in anhydrous DMF (50 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.655 ml, 9.50 mmol) followed by 2-aminoethanol (0.143 ml, 2.375 mmol) in one portion as a solid. The resulting mixture was then heated to 100° C. under nitrogen for 18 hours.

[0124] The DMF was then removed from the reaction and DMSO (1 ml) was added to the remaining residue and purified on a reverse phase column (50 g; water + 0.1% AcOH only - 12 CV of ACN + 0.1% AcOH) to give 330 mg of the title compound (light brown oil). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.28(1 H,s),7.44(1 H,s),4.54(1 H,s),3.91(4 H,s),3.56(2 H,d,J=5.38 Hz),2.70-2.81(2 H,m). ESI+m / z 199 [M+H]

[0125] Example 32 Preparation of intermediate 42 4-((Dimethylamino)methyl)benzoyl chloride [ka] To 4-((dimethylamino)methyl)benzoic acid (0.730 g, 4.07 mmol) in anhydrous DCM (30 ml) was added oxalyl dichloride (3.45 ml, 40.7 mmol) followed by N,N-dimethylformamide (0.016 ml, 0.204 mmol). The resulting mixture was stirred at 45° C. overnight and then evaporated. A small sample was treated with MeOH and analyzed by mass. ESI+ m / z 194 [M+H] (methyl ester).

[0126] Example 33 Preparation of intermediate (VI) of scheme 1 (intermediates 43-63) General Step 5 To a solution of intermediate V (intermediate 10-14) (1 mmol) in dioxane (10 ml) was added cesium carbonate (2 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.0175 mmol). The resulting mixture was then degassed by vacuum and then the corresponding haloheterocycle R2X (1.05 mmol) was added. The reaction was heated at 90° C. for 3 h, cooled and evaporated. To the residue was added AcOEt (25 mL) and DCM (25 mL) and then the resulting mixture was filtered through Celite. The filtrate was then evaporated to give a brown residue which was purified on a silica gel column (25 g) eluting with DCM to DCM / AcOEt 1:1 to give the title intermediate.

[0127] General Step 6 To anhydrous DMSO (4 ml) containing intermediate V (intermediates 10-14) (1 mmol), the corresponding haloheterocycle R2X (1.05 mmol) was added, followed by N-ethyl-N-isopropylpropan-2-amine (2 mmol). The resulting mixture was stirred at 70° C. for 2-4 h.

[0128] The mixture was then added dropwise to water (50 mL) and extracted with DCM. The organic phase was washed with water, dried and evaporated under reduced pressure to give a residue which was purified on a silica gel column (25 g) eluted with DCM to DCM / AcOEt 1:1 to give the title intermediate.

[0129] General Step 7 The carboxylic acid R2COOH (1 mmol) was dissolved in toluene (5 ml). Thionyl chloride (80 mmol) was added and the reaction was stirred at reflux for 2 h.

[0130] The solvent was evaporated and the residue was added to a solution of intermediate V (intermediate 10-14) (1 mmol) in pyridine (75 mmol). The reaction was stirred at room temperature for 13 h and then dissolved in a mixture of water / DCM (20 / 20 ml). The phases were separated and the aqueous layer was extracted with DCM (2 x 20 ml). The combined organic layers were evaporated and the crude product was purified on a silica gel column (25 g) eluting with cyclohexane / AcOEt 1:1 to AcOEt 100% to give the title intermediate. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0131] Example 34: Preparation of intermediate (VII) of scheme 1 (intermediates 64-84) General Step 8 To intermediates 43-63 (1 mmol) in DCM (10 ml) was added TFA (5 ml) slowly. After 3 hours at room temperature, the reaction was stripped of volatiles in vacuo, DCM (40 ml) and saturated sodium bicarbonate solution (75 ml) were added, the organic phase was separated, dried over anhydrous sodium sulfate and evaporated to give the title intermediates. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0132] Example 35: Preparation of intermediate (VIII) of scheme 1 (intermediates 85-111) General Procedure 9 The acid chloride (1.5 mmol) was added to a solution of intermediate (VII) (Intermediate 65, 66, 67, 71, 72, 75, 76, 77, 80, 81, 82, 83, 84) (1 mmol) in pyridine (24 mmol) and the resulting mixture was stirred at room temperature for 1-4 hours.

[0133] The solvent was evaporated and the residue was purified by reverse phase column (50 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%). The fractions containing the desired product were loaded onto a Strata-XL-C 100 μm SPE (2 g) cartridge eluting with HO / MeOH and NH3 1M in MeOH. The ammonia fraction was evaporated to give the title intermediate.

[0134] General Procedure 10 Carboxylic acid (1.5 mmol), HOBT (1.5 mmol), EDC (1.5 mmol) and DIPEA (3 mmol) were dissolved in DMF (10 ml) under nitrogen. After 15 min activation, this mixture was added to a solution of intermediate (VII) (intermediates 65, 66, 67, 71, 72, 75, 76, 77, 80, 81, 82, 83, 84) (1 mmol) in DMF (7.5 ml). The resulting mixture was stirred at room temperature for 5-7 h. The solvent was evaporated and the residue was purified by reversed phase chromatography (50 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0135] Fractions containing the desired product were loaded onto a Strata-XL-C 100 μm SPE (2 g) cartridge eluted with H2O / MeOH and MeOH with NH3 1M. Evaporation of the ammoniacal fractions gave the title intermediate.

[0136] General Procedure 11 To a solution of intermediate (VII) (intermediates 65, 66, 67, 71, 72, 75, 76, 77, 80, 81, 82, 83, 84) (1 mmol) in DMF (8 ml) was added CDI (2 mmol). After 3 h, amine (4 mmol) was added and the resulting mixture was stirred at 50° C. for 1 h and then loaded onto a reverse phase column (50 g) eluted with water+0.1% AcOH only to acetonitrile+0.1% AcOH only to give the title intermediates. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9]

[0137] Example 36: Preparation of intermediate 112 Methyl 6-((5-(2-fluoro-5-(3-(trifluoromethyl)benzamido)phenethyl)-1H-pyrazol-3-yl)amino)-2-methylpyrimidine-4-carboxylate [ka] 3-(Trifluoromethyl)benzoyl chloride (0.098 ml, 0.648 mmol) was added to a solution of intermediate 72 (160 mg, 0.432 mmol) in pyridine (1 ml, 12.36 mmol) and the resulting mixture was stirred for 1 h. The solvent was evaporated, the residue was dissolved in MeOH and NaOMe (100 mg) was added. The mixture was stirred at room temperature overnight.

[0138] The solvent was evaporated and the residue was partitioned between AcOEt and dilute HCl. The separated organic phase was concentrated and the residue was purified on a silica gel column (25 g) eluted with cyclohexane 100% to AcOEt 100% to give the title intermediate (155 mg; yellow solid). ESI+ m / z 543 [M+H]

[0139] Example 37 Preparation of intermediate 113 N-(4-fluoro-3-(2-(3-((6-(hydroxymethyl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide [ka] To a solution of intermediate 112 (155 mg, 0.286 mmol) in THF (3 ml) was added LiBH4 in THF (0.179 ml, 0.714 mmol) and the mixture was stirred at room temperature for 1 h.

[0140] AcOH was added and the solution was evaporated. The residue was dissolved in AcOH (2 ml) and evaporated again. The residue was purified by reverse phase chromatography (50 g; water / AcOH 0.1% to ACN / AcOH 0.1%). The relevant fractions were collected, concentrated, basified with NaOH 1N, extracted with AcOEt, washed with brine, dried and concentrated to give the title intermediate (70 mg; white solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.08(1 H,br.s.),10.47(1 H,s),9.57(1 H,br.s),8.20-8.36(2 H,m),7.98(1 H,d),7.71-7.84(2 H,m),7.59-7.71(1 H,m),7.19(2 H,m),6.17(1 H,br.s),5.23-5.40(1 H,m),4.33(2 H,d),2.83-3.03(4 H,m),2.37(3 H,s). ESI+m / z 515 [M+H]

[0141] Example 38 Preparation of intermediate 114 (6-((5-(2-fluoro-5-(3-(trifluoromethyl)benzamido)phenethyl)-1H-pyrazol-3-yl)amino)-2-methylpyrimidin-4-yl)methyl methanesulfonate [ka] To a solution of intermediate 113 (70 mg, 0.136 mmol) and N,N-diethylethanamine (0.038 ml, 0.272 mmol) in THF (6 ml) at 0° C., mesyl chloride (0.016 ml, 0.204 mmol) was added and the resulting mixture was left stirring at room temperature for 3 hours. The solution was used directly in the subsequent reaction (see Example 46, compounds 26, 27 and 28).

[0142] Example 39 Preparation of intermediate 115 N-(3-(2-(5-((6-chloro-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide [ka] 3-(Trifluoromethyl)benzoyl chloride (0.098 ml, 0.648 mmol) was added to a solution of intermediate 78 (150 mg, 0.433 mmol) in pyridine (1 ml, 12.36 mmol) and the resulting mixture was stirred for 1 h. The solvent was evaporated, the residue was dissolved in MeOH and NaOMe (100 mg) was added. The mixture was stirred at room temperature overnight.

[0143] The solvent was evaporated and the residue was partitioned between AcOEt and dilute HCl. The separated organic phase was concentrated and the residue was purified on a silica gel column (25 g) eluted with cyclohexane 100% to AcOEt 100% to give the title intermediate (165 mg; yellow solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.21(1 H,br.s.),10.46(1 H,s),10.07(1 H,s),8.19-8.34(2 H,m),7.98(1 H,d),7.59-7.86(3 H,m),7.19(1 H,t),6.07(1 H,br.s.),2.83-3.01(4 H,m),2.40(3 H,s). ESI+m / z 519 [M+H]

[0144] Example 40: Preparation of Intermediate (X) (Intermediate 116) of Scheme 2 N-(5-(2-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)ethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzamide [ka] To intermediate 16 (500 mg, 1.470 mmol), 3-(trifluoromethyl)benzamide (834 mg, 4.41 mmol), tripotassium phosphate (936 mg, 4.41 mmol), tetramethyldi-tBuXPhos (70.6 mg, 0.147 mmol), tris(dibenzylideneacetone)palladium(0) (60.6 mg, 0.066 mmol) was added anhydrous dioxane (10 ml) under nitrogen. The resulting mixture was heated to 105° C. and left at this temperature overnight. The reaction was cooled to room temperature and then the dioxane was removed under vacuum. To the remaining residue was added DCM (15 ml) and water (20 ml). After brief mixing, the organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to give a brown residue. Purification: Silica gel column (25 g) eluting with DCM to DCM / AcOEt 1:1 to give the title intermediate (597 mg; brown solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.34(1 H,s),8.24-8.35(2 H,m),7.99(1 H,d),7.73-7.85(1 H,m),7.48(1 H,dd),7.08-7.23(2 H,m),5.25(1 H,s),4.72(2H,s),2.77-2.87(2H,m),2.57-2.66(2H,m),1.49(9H,s). ESI+m / z 449 [M+H]

[0145] Example 41: Preparation of intermediate (XI) (intermediate 117) of scheme 2 N-(5-(2-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)ethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzamide [ka] To intermediate 116 (590 mg, 1.316 mmol) was added formic acid (24.8 ml, 658 mmol). The resulting solution was heated to 100° C. for 24 hours. The reaction was then stripped of volatiles and the remaining residue was dissolved in DMSO (2 ml) and purified by reverse phase chromatography (50 g; water / AcOH 0.1% to ACN / AcOH 0.1%). Yield: 495 mg; yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ ppm 11.11(1 H,br.s.),10.36(1 H,s),8.22-8.37(2 H,m),7.99(1 H,d),7.73-7.86(1 H,m),7.48(1 H,dd),7.08-7.27(2 H,m),5.21(1 H,br.s.),4.41(2 H,br.s.),2.64-2.92(4 H,m). ESI+m / z 393 [M+H]

[0146] Example 42: Preparation of intermediate 118 N-(5-(2-(5-((6-chloro-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzamide [ka] To a solution of intermediate 117 (150 mg, 0.382 mmol) in anhydrous DMSO (2 mL) was added solid 4,6-dichloro-2-methylpyrimidine (68.6 mg, 0.421 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.200 mL, 1.147 mmol). The resulting mixture was left stirring at 60 °C for 24 h. The reaction was then stripped of volatiles and the remaining residue was dissolved in acetic acid (0.3 ml) and purified by reverse phase chromatography (50 g; water / AcOH 0.1% to ACN / AcOH 0.1%). Yield: 158 mg; yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.17(1 H,br.s.),10.36(1 H,s),10.07(1 H,s),8.19-8.36(2 H,m),7.99(1 H,d),7.80(1 H,t),7.52(1 H,dd),7.10-7.31(2 H,m),5.74-6.32(1 H,m),2.82-3.00(4 H,m),2.41(3 H,s). ESI+m / z 519 [M+H]

[0147] Example 43: Preparation of intermediate (XIII) (intermediate 119) of scheme 3 3-(3-aminophenethyl)-1-(tert-butyl)-1H-pyrazol-5-amine [ka] To copper monoidide (0.259 g, 1.358 mmol), (S)-pyrrolidine-2-carboxylic acid (0.313 g, 2.72 mmol) and potassium carbonate (2.252 g, 16.29 mmol) in a high pressure vial was added degassed anhydrous DMSO (8 ml). The resulting purple mixture was left to stir for 10 minutes. After 10 minutes, intermediate 18 (1.75 g, 5.43 mmol) was added as a solid in one portion. The vial was then sealed, at which point 28% aqueous ammonia (4 ml, 59.0 mmol) was added. The resulting mixture was then heated to 100° C. in a microwave for 8 hours. The reaction was cooled to room temperature and then added dropwise to water / DCM (20 ml). After brief mixing, the organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to give a dark blue oil. Purification: silica gel column (55 g) eluted with cHex / DCM 75:25, then reverse phase column (150 g) eluted with water / AcOH 0.1% to ACN / AcOH 0.1% to obtain 1.178 g of the title intermediate as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ ppm 6.90(1 H,t),6.45(1 H,t),6.30-6.42(2 H,m),5.23(1 H,s),4.89(2 H,br.s.),4.70(2 H,s),2.59-2.67(2 H,m),2.53-2.58(2 H,m),1.50(9 H,s). ESI+m / z 259 [M+H]

[0148] Example 44: Preparation of intermediate (XIV) (intermediate 120) of scheme 3 N-(3-(2-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)ethyl)phenyl)-4-((dimethylamino)methyl)benzamide [ka] To anhydrous DCM (4 ml) containing intermediate 119 (150 mg, 0.581 mmol) was added anhydrous pyridine (0.235 ml, 2.90 mmol). To the resulting solution was added intermediate 42 (163 mg, 0.697 mmol) dropwise. Once the addition was complete, the reaction was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was then added to the reaction. After brief mixing, the organic layer was separated, dried over anhydrous sodium sulfate, and then evaporated to give a brown oil. Purification: Silica gel column (25 g) eluting with cHex / AcOEt 1:1 to AcOEt. Yield 185 mg (yellow solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.12(1 H,s),7.93(2 H,d),7.68(1 H,s),7.62(1 ​​H,d),7.45(2 H,d),7.24(1 H,t),6.98(1 H,d),5.25(1 H,s),4.72(2 H,s),3.51(2 H,br.s.),2.80(2 H,dd),2.59-2.66(2 H,m),2.20(6 H,s),1.50(9 H,s). ESI+m / z 420 [M+H]

[0149] Example 45: Preparation of intermediate (XV) (intermediate 121) of scheme 3 N-(1-(tert-butyl)-3-(3-(4-((dimethylamino)methyl)benzamido)phenethyl)-1H-pyrazol-5-yl)-4-morpholinobenzamide [ka] To anhydrous DCM (4 ml) containing intermediate 120 (80 mg, 0.191 mmol) was added pyridine (0.077 ml, 0.953 mmol) followed by 4-morpholinobenzoyl chloride (86 mg, 0.381 mmol). The resulting mixture was left stirring overnight. To the reaction was added saturated aqueous sodium bicarbonate (2 ml) and water (2 ml) and the organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to give a dark brown residue. Purification: Reverse phase column (150 g) eluting with water / AcOH 0.1% to ACN / AcOH 0.1%. Yield 140 mg (light brown oil). ESI+ m / z 609 [M+H]

[0150] Example 46: Preparation of intermediate (XVII) (intermediate 122) of scheme 4 tert-Butyl (4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)carbamate [ka] An oven-dried microwave test tube equipped with magnetic stirring was charged with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.038 g, 0.066 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.018 g, 0.020 mmol), intermediate 26 (0.22 g, 0.660 mmol) and 2-bromopyrazine (0.066 ml, 0.726 mmol). The vessel was evacuated and backfilled with nitrogen (3 times). Dioxane (5 ml) was added to the vessel, evacuated and backfilled with nitrogen. The reaction was heated at 95° C. overnight, then cooled to room temperature, the volatiles were evaporated and the crude product was dissolved in DMSO (3 ml) and AcOH (2 ml). Purification: Reverse phase column (50 g) eluted with water / AcOH 0.1% to ACN / AcOH 0.1%. Yield 262 mg of the title intermediate (yellow solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 11.41-11.63(1 H,m),9.13(1 H,s),8.45(1 H,s),8.28(1 H,dd),8.09(1 H,d),7.79(1 H,s),7.43-7.53(1 H,m),7.27-7.43(3 H,m),7.11-7.21(2 H,m),7.02(1 H,d),2.78-3.01(4 H,m),2.21(3 H,s),1.46(9 H,s). ESI+m / z 412 [M+H]

[0151] Example 47: Preparation of intermediate (XVIII) (intermediate 123) of scheme 4 5-(5-amino-2-methylphenethyl)-N-(pyrazin-2-yl)thiazol-2-amine [ka] To a solution of intermediate 122 (369 mg, 0.897 mmol) in DCM (5 ml) at room temperature was slowly added TFA (0.691 ml, 8.97 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were evaporated and the crude product was loaded onto SPE-SCX (5 g). The basic fractions were collected and evaporated to give the title intermediate (196 mg; yellow solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 11.38-11.59(1 H,m),8.42-8.51(1 H,m),8.22-8.33(1 H,m),8.03-8.16(1 H,m),7.16(1 H,s),6.71-6.85(1 H,m),6.44(1 H,d),6.34(1 H,dd),4.68-4.91(2 H,m),2.86-2.98(2 H,m),2.74(2 H,br.s.),2.12(3 H,s). ESI+m / z 312 [M+H]

[0152] Example 48 General procedure used to prepare compounds of the present invention (formula I) of Scheme 1: General Step 12: Intermediates 85-111 (1 mmol) were dissolved in formic acid (100 mmol). The resulting mixture was heated at 95° C. for 2 h. The solvent was evaporated and the residue was purified on a reverse phase column (25 g) eluting with water / AcOH 0.1% to ACN / AcOH 0.1%. The fractions containing the desired product were loaded onto a Strata-XL-C 100 μm SPE (2 g) cartridge eluting with H2O / MeOH and MeOH with NH3 1M. The ammonia fraction was evaporated to give the title compound.

[0153] General Step 13: Carboxylic acid (1.5 mmol), HOBT (1.5 mmol), EDC (1.5 mmol) and DIPEA (3 mmol) were dissolved in DMF (10 ml) under nitrogen. After activation for 15 min, this mixture was added to a solution of intermediate (VII) (intermediate 67, 68, 69, 77) in DMF (7.5 ml). The resulting mixture was stirred at room temperature for 5-7 h. The solvent was evaporated and the residue was purified by reverse phase chromatography (50 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0154] Fractions containing the desired product were loaded onto a Strata-XL-C 100 μm SPE (2 g) cartridge eluted with H2O / MeOH and MeOH with NH3 1M. The ammoniacal fractions were evaporated to give the title compound.

[0155] General Step 14: To a solution of intermediate 115 (0.1 mmol) in anhydrous DMSO (3 ml) was added the corresponding amine (1 mmol). The resulting solution was then heated to 80° C. for 5-8 h, cooled to room temperature, acetic acid was added (0.5 ml), and the resulting mixture was purified by reverse phase chromatography (25 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0156] General Step 15: A solution of intermediate 114 (see Example 38) in THF was divided into three portions (each containing 0.045 mmol) and then the corresponding amine (0.18 mmol) was added. The resulting solution was then heated to 60° C. overnight, evaporated, MeOH (5 ml) and MeONa (50 mg) were added, the mixture was stirred at room temperature for 2 h, then evaporated. Purification: reverse phase chromatography (15 g) eluting with a gradient from HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0157] General Step 16: To a solution of intermediate (VII) (intermediate 67) (1 mmol) in DMF (8 ml) was added CDI (2 mmol). After 3 hours, amine (4 mmol) was added and the resulting mixture was stirred at 50° C. for 1 hour, then loaded onto a reverse phase column (50 g) eluted with water+0.1% AcOH only to acetonitrile+0.1% AcOH only to give the title compound.

[0158] With reference to Table 8 below, compounds 1-41 were prepared according to the procedures described above (column 3 of the table) starting from the intermediates prepared above (and shown in column 2 of the table below). [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10]

Table 8-11

Table 8-12

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

Table 8-21

[0159] Example 49: Preparation of Compound (I) of Scheme 1 (Compound 42) N-(4-fluoro-3-(2-(3-((6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide

change

[0160] Example 50 General procedure used to prepare compounds of the present invention (formula I) of Scheme 2: General Step 17: To a solution of intermediate 118 (0.1 mmol) in anhydrous DMSO (3 ml) was added the corresponding amine (1 mmol). The resulting solution was then heated to 80° C. for 5-8 h, cooled to room temperature, acetic acid was added (0.5 ml), and the resulting mixture was purified by reverse phase chromatography (25 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0161] With reference to Table 9 below, compounds 43-46 were prepared according to the procedures described above (column 3 of the table) starting from the intermediates prepared above (and shown in column 2 of the table below). [Table 9-1] [Table 9-2]

[0162] Example 51: Preparation of Compound (I) of Scheme 3 (Compound 47) 4-((Dimethylamino)methyl)-N-(3-(2-(5-(4-morpholinobenzamido)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide [ka] To intermediate 121 (80 mg; 0.191 mmol) was added formic acid (1.798 ml, 47.7 mmol) and the resulting solution was heated to 100° C. for 1 h. The formic acid was removed under vacuum and to the remaining residue was added DMSO (1 ml) and acetic acid (0.25 ml). Purification: reverse phase chromatography (15 g) eluting with a gradient from HO-AcOH (0.1%) to CHCN-AcOH (0.1%). Yield 28 mg (off-white solid). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.14(1 H,br.s.),10.37(1 H,br.s.),10.16(1 H,s),7.92(4 H,dd),7.57-7.78(2 H,m),7.44(2 H,d),7.27(1 H,t),6.88-7.06(3 H,m),6.42(1 H,br.s.),3.65-3.82(4 H,m),3.47(2 H,s),3.18-3.28(4 H,m),2.81-3.01(4 H,m),2.17(6 H,s). ESI+m / z 553 [M+H]

[0163] Example 52 General procedure used to prepare compounds of the present invention (formula I) according to Scheme 4: General Step 18: Carboxylic acid (1.5 mmol), HOBT (1.5 mmol), EDC (1.5 mmol) and DIPEA (3 mmol) were dissolved in DMF (10 ml) under nitrogen. After activation for 15 min, this mixture was added to a solution of intermediate (XVIII) (intermediate 123) in DMF (7.5 ml). The resulting mixture was stirred at room temperature for 5-7 h. The solvent was evaporated and the residue was purified by reverse phase chromatography (50 g) eluting with a gradient of HO-AcOH (0.1%) to CHCN-AcOH (0.1%).

[0164] With reference to Table 10 below, compounds 48-50 were prepared according to the procedures described above (column 3 of the table) starting from the intermediates prepared above (and shown in column 2 of the table below). [Table 10-1] [Table 10-2]

[0165] Pharmacological evaluation of the compounds of the present invention A number of compounds of formula (I) according to the present invention have been studied in vitro to establish their potential Fyn kinase and VEGFR2 kinase inhibitory activity and their potency in several cellular models, as well as to establish the potency of the best compounds resulting from the in vitro screening in experiments of induced hyperalgesia and pain behavior in rats.

[0166] The results obtained are summarized in Tables 11 to 16 below.

[0167] Example 53: In vitro kinase activity assay The Fyn kinase inhibitory activity of representative compounds of formula (I) was evaluated by the Z'-LYTE™ Kinase Assay Platform (Invitrogen). Compounds were evaluated for active Fyn (full length activity, molecular weight 87.1 kDa; Invitrogen). The enzyme (1.2 ng / μl) was incubated with a synthetic peptide substrate, ATP (50 μM) and 10-9 M~maximum 10 -5 The kinase reactions were incubated in 384 low volume microplates with various inhibitor concentrations spanning a final concentration of 100 mM. Samples showing 0% inhibition (or total enzyme activity) were in the presence of compound diluent (reaction buffer 50 mM Hepes, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35, pH 7.5, containing 1% DMSO final concentration). Kinase reactions were carried out in a total volume of 10 μl for 60 min at 25°C. Assay controls of 0% phosphorylation (i.e., no ATP) and 100% phosphorylation included on each plate allowed calculation of the percentage phosphorylation obtained in a particular reaction well. Results were expressed as percent inhibition and IC was calculated by nonlinear curve fitting using GraphPad™ Prism software (version 6 for Windows). 50 The value was calculated.

[0168] The Fyn kinase inhibitory activity of representative compounds of formula (I) is reported in Table 11 below. [Table 11]

[0169] result As shown in Table 11, the compounds of formula (I) are potent Fyn kinase inhibitors, with IC 50 Values ​​range from the low to mid nanomolar range. Only compounds 6 and 49 turned out to be active in the high nanomolar range (≧100 nM).

[0170] Example 54: In vitro kinase activity assay The VEGFR2 kinase inhibitory activity of representative examples of compounds of formula (I) assay was evaluated in Eurofins Cerep (France). The concentration range of inhibitors under investigation was 10 -8 M~maximum 10 -5 The final concentration was 10 -9 Some compounds were retested at a range of concentrations starting from 100 M. Results were expressed as a percentage of control activity (in the absence of test compound) and IC was calculated by nonlinear regression analysis of inhibition / concentration curves generated using the average replicate values. 50 value was determined.

[0171] The VEGFR2 kinase inhibitory activity of representative compounds of formula (I) is reported in Table 12 below. [Table 12]

[0172] result As shown in Table 12, the compound of formula (I) is a good VEGFR2 kinase inhibitor (IC 50 ≦10 nM), and compounds 1–17, 20–30, 32–36, 38, and 40–48 are potent VEGFR2 kinase inhibitors.

[0173] Example 55: In vitro kinase activity assay in the presence of high ATP concentrations Inhibition of Fyn and VEGFR2 kinase activity was assessed in the presence of a fixed ATP concentration (0.5 mM) close to the millimolar range present in cells. Assays were performed by ADP-Glo™ Kinase Assay (Promega), which monitors ADP generated in the kinase reaction. Kinase reactions were performed in 10 μl in white 384-well plates according to the supplier's instructions. Inhibitor solutions of DMSO / kinase buffer and kinase (Fyn 2.5 ng / μl and VEGFR2 0.5 ng / μl final concentrations in the assay) were pre-incubated for 15 min at room temperature. The range of inhibitor concentrations was 10 -10 M~maximum 10 -5 M (final concentration in the assay). To start the reaction, a substrate / ATP mixture (final concentration 0.5 mM, 10 × ATP K M A concentration of 100 mM NaCl (equivalent to IC50 value) was added to each sample. After 60 min incubation at room temperature, ADP-Glo™ reagent and kinase detection reagent were added and incubated in sequence according to the supplier's instructions to stop and develop the kinase reaction. The inhibition percentages calculated for the enzyme activity in the absence of test compounds and the corresponding inhibition curves were analyzed by nonlinear curve fitting (GraphPad software, version 7 for Windows) to obtain IC50 values. 50 This makes it possible to calculate the value.

[0174] result Compound 3 inhibited Fyn and VEGFR2 in a concentration-dependent manner in the presence of high ATP concentrations, with IC 50 The values ​​were 6.8 nM and 58 nM, respectively.

[0175] Example 56: Kinase selectivity The kinase selectivity of several representative compounds of formula (I) was analyzed with a standard panel of 46 human kinases, identifying 10 kinases that are more frequently affected. Compound 3 was therefore investigated for kinase selectivity, focusing on these 10 kinases. Assays were performed at Eurofins Cerep (France). The concentration range of the compounds under investigation was 10 -9 M~maximum 10 -5 The final concentration was 100 mM. The results are summarized in Table 13. [Table 13]

[0176] result As already shown in Table 12, compound 3 shows nanomolar potency in inhibiting Fyn and VEGFR2 kinase activity. In addition to effects on other kinases of the Src family (Src, Yes and Lyn-A), but less potency than that shown for Fyn and VEGFR2, compound 3 is inactive (>1000 nM) for the remaining kinases investigated.

[0177] Example 57: Cellular model for testing kinase inhibitor gene reporter (GR) assays To determine whether the compounds of the invention are also active in cell models, a gene reporter assay was established in a cell line (JB6 Cl 41-5a (P+)) known to activate Fyn kinase via an inflammatory stimulus (TNFα). The GR assay measures activation of the nuclear transcription factor NF-kB, which is located downstream of the Fyn activation pathway. Products active in this assay must penetrate cells and inhibit the NF-kB activation pathway.

[0178] The mouse epithelial cell line JB6 Cl 41-5a (P+) (ATCC® catalog #CRL-2010) was stably transfected with the pGL4.32[luc2P / NFkB-RE / Hygro] vector (Promega). Clonal selection was achieved by limiting with 80 μg / ml hygromycin B. Clones were tested for response to TNFα stimulation.

[0179] JB6(P+)NFkB-RE-luc2P transfected cells were used to analyze the regulation of NF-kB activity by Fyn inhibitors after TNFα stimulation.

[0180] Cells were pretreated with different compounds for 1 h and then stimulated with 2 ng / ml TNFα for 4 h. Each test condition was analyzed in quadruplicate.

[0181] Luciferase analysis was performed using the ONE-Glo™+ToxLuciferase Reporter and Cell Viability Assay kit (Promega). Results obtained at non-toxic concentrations as assessed by the CellTiter-Fluor™ cell viability assay are summarized in Table 14 below. [Table 14]

[0182] result As shown in Table 14, it was demonstrated that some compounds of the present invention can penetrate cells and inhibit Fyn kinase activation induced by TNF-α stimulation at sub-micromolar / micromolar concentrations. In particular, compounds 3, 8 and 15 had IC values ​​of less than 250 nM. 50 The values ​​were shown.

[0183] Example 58: Intracellular target binding to FYN enzyme in HEK293 transfected cells Intracellular target binding (TE) of Fyn kinase was demonstrated by nanoBRET technology (Promega), allowing the measurement of compound binding at a selected target protein in intact cells and the determination of apparent affinity of test compounds by competitive displacement of a NanoBRET™ tracer reversibly bound to a cellular NanoLuc® luciferase fusion protein.

[0184] The NanoBRET™ TE Intracellular Kinase Assay K-4 (Promega, #N2520) was used to determine intracellular target binding of Fyn kinase in HEK293 cells (ATCC®, Catalog No. CRL-1573) transiently transfected with the Fyn-NanoLuc® fusion vector (Promega, #NV1411) and thus expressing the Fyn-NanoLuc® fusion protein. The tracer was used at a final concentration of 0.33 μM and the cells were treated with the compounds for 2 hours. Emission values ​​were measured at 450 nm and 610 nm (GloMax® Discover, Promega) to determine the raw BRET ratio value of each sample. Compounds that specifically bind to the intracellular target protein-NanoLuc® fusion will result in a decrease in the BRET signal and a lower BRET ratio value.

[0185] result Compound 3 showed an IC of 1.5 μM against Fyn-NanoLuc® fusion protein transiently expressed in HEK293 cells. 50 Binding values ​​are shown.

[0186] Example 59: Inhibition of FYNB-induced TAU(Y18) phosphorylation (cell-based assay) HEK293 cells (Human Embryonic Kidney 293) were plated on a poly-D-lysine 12w microplate at 6 × 10 5Cells were seeded at 1000 x 1000 and allowed to grow adherently in medium DMEM / 10% FBS at 37°C with 5% CO2. After 24 hours, cells were transfected to overexpress either the constitutively active form of human FynB and Tau protein (isoform 0N4R) by an optimized Lipofectamine® 3000 transfection protocol (Life Technologies™). Non-transfected samples (negative controls) were included in all experiments. 24 hours after transfection, cells were treated by adding fresh medium containing diluent (DMSO final concentration 0.1%) or test compound. Incubation was performed for 6 or 24 hours at 37°C with 5% CO2. At the end of the incubation, the medium was removed and the cell lysate obtained by adding M-PER lysis / protease / phosphatase inhibitor cocktail was transferred to an Eppendorf tube, sonicated and stored at -80°C. Protein content was measured by the Bradford method. Lysates were analyzed either by Tau phosphorylation (tyrosine 18-Fyn mediated) and by customized ELISA assays for total Tau determination.

[0187] result After 6 h of treatment, compound 3 concentration-dependently inhibited FynB-induced Tau(Y18) phosphorylation (IC of 0.131 μM). 50 ). The compounds maintained their inhibitory activity after 24 hours of treatment, with an average inhibition rate of 95% at 1 μM. A non-significant but moderate effect on total Tau protein was observed.

[0188] Example 60: Inhibition of VEGF-induced VEGFR (Y1175) phosphorylation (cell-based assay) HUVEC-C cells (human umbilical vein endothelial cells from ATCC) were cultured in 24W microplates at 6x10 4Cells / well were seeded and allowed to adhere and grow in F12K medium + 0.1 mg / ml heparin + 0.05 mg / ml ECGS + 10% FBS at 37°C with 5% CO2. After 24 hours, the medium was removed and starvation was induced overnight in F12K medium + 0.1 mg / ml heparin + 0.5% FBS (starvation medium). At the end of the incubation, the cells were cultured by medium replacement and with diluent (DMSO final concentration 0.1%) or test compound (10 -8 M~10 -5 Treatment of cells was performed by adding fresh starvation medium with or without VEGF (range of M). After 1 h, VEGF stimulation (final concentration 50 ng / ml) was added to each sample, except for the "basal-no stimulation" sample, and the plates were then incubated for 5 min at 37°C with 5% CO2. At the end of the incubation, the medium was removed and cell lysates were obtained by adding M-PER lysis / protease / phosphatase inhibitor cocktail. The lysates were then transferred to Eppendorf tubes, sonicated, and stored at -80°C.

[0189] Lysates were analyzed by Western blot for determination of VEGFR phosphorylation (tyrosine 1175) and total receptor amount. Densitometric analysis of sample lanes was performed by ImageQuant TL software (GE Healthcare Life Sciences). Each sample value was normalized by its respective actin and the resulting data was used to calculate the inhibitory effect of compounds relative to the stimulation control (absence of inhibitor).

[0190] result Compound 3 showed complete inhibitory activity against VEGFR phosphorylation at the Y1175 residue, starting at a concentration of 0.01 μM.

[0191] Example 61: Gene expression analysis in rat articular chondrocytes under inflammatory conditions (IL-1β stimulation) Primary rat articular chondrocytes were obtained from the lower and upper limbs of Sprague-Dawley rats according to the protocol used by Berenbaum and colleagues (Berenbaum F, Thomas G, Poiraudeau S, Bereziat G, Corvol MT, Masliah J. Insulin-like growth factors counteract the effect of interleukin 1 beta on type II phospholipase A2 expression and arachidonic acid release by rabbit articular chondrocytes. FEBS Lett 1994;340:51-55). All studies involving animals were performed in accordance with the Guide for the Care and Use of Laboratory Animals adopted and published by the National Institutes of Health.

[0192] Purified chondrocytes were resuspended in DMEM glutaMAX 10% and plated into 96× well plates for toxicity analysis and 6× well plates for gene expression analysis.

[0193] Then, for toxicity analysis, the cells were treated with different compounds for 24 and 48 hours. At the end of the incubation period, the medium was removed and replaced with a 10:1 mixture of DMEM glutaMAX 10%-MTT (2mg / ml) for 1 hour at 37°C in a cell incubator. After this incubation, precipitated salts were dissolved with 100μl of DMSO and the plates were read at 540nm. Toxicity analysis was performed to determine the maximum non-toxic concentration of each compound used in the gene expression assay.

[0194] For gene expression analysis, 10 days after plating, the medium was changed and replaced with DMEM GlutaMAX I 0.4% to synchronize the cells. The cells were then co-treated with different concentrations of test compounds and IL-1β at a final concentration of 2 ng / ml in DMEM GlutaMAX I 0.4% for 6 and 24 hours. The concentrations of test compounds used were selected based on toxicity data.

[0195] At the end of the incubation, the supernatant was discarded and the cells were washed with cold PBS 1X and scraped with 200 μl of RNA lysis buffer 1X (Nucleic Acid Purification Lysis Solution, Applied Biosystems).

[0196] Total RNA was purified using an ABI Prism™ 6100 Nucleic Acid PrepStation (Applied Biosystems) according to the manufacturer's instructions.

[0197] Total RNA was retrotranscribed using the High-Capacity cDNA Archive Kit (Applied Biosystems-Thermo Fisher Scientific) according to the manufacturer's instructions.

[0198] Specific probes and primers for real-time PCR were obtained from Applied Biosystems (Thermo Fisher Scientific) as Assays-on-Demand™, while the probe and primers for the endogenous control 18S were PDAR (Pre-Developed TaqMan® Assay Reagents-Applied Biosystems-Thermo Fisher Scientific).

[0199] Gene expression of the most relevant pro-inflammatory markers and matrix degrading enzymes that are upregulated in osteoarthritis was analyzed.

[0200] The assay was designed to amplify target cDNA without amplifying genomic DNA.

[0201] Gene expression analysis of IL-1β, IL-6 and ADAMTS-5 was performed at 6 h incubation, while gene expression analysis of MMP3, MMP13 and COX2 was performed at 24 h incubation. For each compound, the maximum concentration tested was dependent on the toxicity results obtained in primary rat chondrocytes.

[0202] For relative quantification of gene expression, data analysis was performed following the specific instructions of Applied Biosystems, normalizing the 18S amplification values. [Table 15]

[0203] result As shown in Table 15, most of the compounds of the present invention, which were demonstrated to inhibit gene expression of the studied pro-inflammatory (IL-1β, IL-6, COX2) and degradative (ADAMTS-5, MMP3, MMP13) markers, in particular compound 3, inhibit gene expression induced by IL-1β stimulation at submicromolar concentrations.

[0204] Example 62: Inhibition of cartilage degradation in a bovine in vitro model Nasal septum cartilage was obtained from 8-month-old bulls at a local slaughterhouse.

[0205] The tissue was sprayed with 70% ethanol and immediately placed in sterile PBS containing antibiotic-antimycotic stabilized solution (PBS-AASS). Small punches (2 mm diameter, 1 mm thickness) were cut to obtain them. Sections were washed with sterile PBS-AASS and transferred to DMEM 10%+AASS in 96× well plates (one piece per well). After 48 hours, cartilage was stimulated with white DMEM+0.1% BSA+AASS containing 10 ng / ml IL-1α in the absence or presence of the study compound.

[0206] Compound concentrations used in this analysis were selected according to toxicity results obtained in primary rat chondrocytes over 48 h of incubation.

[0207] After 48 hours of stimulation, the culture medium was collected and stored at −80° C. Cartilage punches were digested with papain in phosphate buffer (0.05M pH 6.5 containing 2 mM N-acetyl-L-cysteine ​​and 2 mM EDTA) at 65° C. for 2 hours.

[0208] Glycosaminoglycans (GAGs) were determined by colorimetric assay using 1,9 dimethylmethylene blue (DMB).

[0209] Digested cartilage samples were diluted in PBS-BSA 1%. To 100 μl of diluted sample or standard, 100 μl of DMB 2X was added. After 5-20 min incubation, samples were read at 590 nm (Titertek Multiscan Plus).

[0210] Cartilage degradation induced by IL-1α was expressed as follows: GAG (medium) / total GAG (medium + cartilage) x 100 [Table 16]

[0211] result As shown in Table 16, most of the compounds of the present invention that were demonstrated to inhibit IL-1α-induced cartilage degradation, especially compounds 3, 13, 15 and 34, were able to completely inhibit GAG release (95-100% inhibitory effect).

[0212] Example 63: Description of the "in vivo" pharmacological activity of the compounds of the present invention The compound of formula (I) has been shown to be a potent analgesic in models of acute inflammatory pain. The efficacy of the compound of formula (I) was tested for its analgesic efficacy in the following in vivo animal models of inflammatory pain:

[0213] Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats CFA injected intradermally into the hind paw of rats induces persistent inflammation and hyperalgesia. Compound 3 was injected into the right hind paw of male Wistar rats with the same bolus containing 50 μg of Mycobacterium tuberculosis in 100 μL of liquid paraffin (CFA). 18 hours after challenge, mechanical pain thresholds were determined using a Randall-Selitto apparatus and the values ​​obtained were compared with those obtained before CFA injection. Measurements of hyperalgesia were repeated 24, 42 and 48 hours after CFA injection.

[0214] result Figures 1 and 2 show the results obtained in the CFA-induced inflammatory pain model for compound 3. The results demonstrated that compound 3 given by local (intradermal, id) administration is a highly potent inhibitor of CFA-induced hyperalgesia. The compound injected at a maximum concentration of 3 μM (i.e., 140 ng / paw) completely restored pain behavior in CFA-inflamed animals and did not modify normal pain sensation in naive animals not challenged with CFA.

[0215] Example 64: Pharmacokinetics Compound 3 was characterized by a suboptimal pharmacokinetic profile when given by the systemic route. From the oral route, its absolute bioavailability is about 12% in mice and 6% in rats. However, the lack of significant metabolism in rats and the associated local analgesic effect described above make compound 3 particularly suitable for the local treatment of OA by intra-articular injection.

[0216] Compound 3 administered as a suspension (phosphate buffer 150 mM pH 7, 0.5% HPMC, 0.1% Tween 80) to the knee joint of rats demonstrated depot-like long-term persistence in the synovial fluid and articular tissues (cartilage and synovial fat) for at least 14 days.

Claims

1. N-Phenylcarbamoyl Compounds of Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof In the formula, A is a group of the following formula: 【Chemistry 2】 and X is 5- or 6-membered heteroaryl rings, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO-, (phenyl)CO-, and 5- or 6-membered saturated heterocyclic rings. an optionally substituted group selected from the group consisting of Y is an optionally substituted 5- or 6-membered heteroaryl ring; B is, Phenyl, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocycle, azaspiro (C ７ ~C １０ ) alkyl and saturated (C ３ ~C ６ ) Cycloalkyl-NH- an optionally substituted group selected from the group consisting of R １ and R ２ are each independently hydrogen, (C １ ~C ３ ) is a group independently selected from alkyl and halogen.

2. X, 5- or 6-membered heteroaryl rings, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, (5- or 6-membered heteroaryl)CO-, (phenyl)CO-, and 5- or 6-membered saturated heterocyclic rings. is an optionally substituted group selected from the group consisting of The N-phenylcarbamoyl compound according to claim 1.

3. The N-phenylcarbamoyl compound of claim 2, wherein the 5- or 6-membered heteroaryl ring is pyrazine, pyridine or pyrimidine.

4. The pyrazine, pyridine or pyrimidine is (C １ ~C ３ 4. The N-phenylcarbamoyl compound of claim 3, which is substituted with one or more substituents selected from the group consisting of 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, morpholin-1-yl, and cyano.

5. X, (C １ ~C ３ ) alkyl, hydroxy (C １ ~C ３ ) alkyl and (C １ ~C ３ ) alkyl)CO- The N-phenylcarbamoyl compound according to claim 2, which is 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl substituted with one or more substituents selected from:

6. The N-phenylcarbamoyl compound of claim 5, wherein the one or more substituents are selected from the group consisting of ethyl, acetyl and 2-hydroxyethyl.

7. 3. The N-phenylcarbamoyl compound of claim 2, wherein X is an optionally substituted (5- or 6-membered heteroaryl)CO-.

8. The N-phenylcarbamoyl compound of claim 7, wherein the optionally substituted (5- or 6-membered heteroaryl)CO- is selected from the group consisting of (pyridine)CO- and (pyrimidine)CO-.

9. 3. The N-phenylcarbamoyl compound of claim 2, wherein X is (phenyl)CO-, optionally substituted with one or more substituents.

10. The N-phenylcarbamoyl compound according to claim 9, wherein the (phenyl)CO-, optionally substituted with one or more substituents, is substituted with one or more substituents selected from the group consisting of halogen, (1-isopropylazetidin-3-yl)oxy, 4-methylpiperazin-1-yl and 1-methylpiperidin-4-yl.

11. 2. The N-phenylcarbamoyl compound of claim 1, wherein Y is an optionally substituted 5- or 6-membered heteroaryl ring.

12. The N-phenylcarbamoyl compound of claim 11, wherein the optionally substituted 5- or 6-membered heteroaryl ring is an unsubstituted pyrazine.

13. R １ is hydrogen, methyl, fluoro or chloro; R ２ But, R １ and independently are hydrogen or fluoro.

14. 3. The N-phenylcarbamoyl compound of claim 2, wherein B is an optionally substituted phenyl.

15. The optionally substituted phenyl is substituted with one or more substituents selected from the group consisting of (C1-C3)alkyl, R'SO2-, R'R''N(C1-C3)alkyl, R'NH(C1-C3)alkyl, trifluoromethyl, difluoromethyl, halogen, R'R''NSO2-, (C3-C6)cycloalkyl, C3-C6)cycloalkyl-NH-, and NR'(C3-C6)cycloalkyl-; 15. The N-phenylcarbamoyl compound of claim 14, wherein R' and R'' are each independently (C 1 -C 3 ) alkyl.

16. Phenyl is CH ３ SO ２ --, --CH ２ N (CH ３ ) ２ , C.H. ３ , C.F. ３ , C.H.F. ２ , Fluoro, -SO ２ N (CH ３ ) ２ 16. The N-phenylcarbamoyl compound according to claim 14 or 15, which is substituted with one or more substituents selected from the group consisting of (N-ethyl)aminocyclopropyl.

17. 3. The N-phenylcarbamoyl compound of claim 2, wherein B is a 5- or 6-membered heteroaryl ring selected from pyridine and oxazole, and is optionally substituted.

18. B is one or more hydroxy (C １ ~C ３ ) alkyl, CF ３ , (C １ ~C ４ ) alkyl, cyano (C １ ~C ３ ) alkyl and (C ３ ~C ６ ) Cycloalkyl-SO ２ 20. The N-phenylcarbamoyl compound of claim 2 or 17, wherein the N-phenylcarbamoyl compound is a 5- or 6-membered heteroaryl ring substituted with -.

19. B is 2-cyanopropyl-2-yl, 2-hydroxypropyl-2-yl, CH ３ , C.F. ３ 18. The N-phenylcarbamoyl compound of claim 17, which is a pyridine or oxazole substituted with one or more substituents selected from the group consisting of fluoro, isobutyl and cyclopropylsulfonyl.

20. B is an azaspiro(C) selected from azaspiro[3,4]octane and azaspiro[4,5]decane; ７ ~C １０ 3. The N-phenylcarbamoyl compound of claim 2, wherein the N-phenylcarbamoyl group is aryl.

21. 3. The N-phenylcarbamoyl compound of claim 2, wherein B is an optionally substituted 5- or 6-membered saturated heterocycle.

22. The N-phenylcarbamoyl compound of claim 21, wherein the optionally substituted 5- or 6-membered saturated heterocycle is pyrrolidine.

23. The N-phenylcarbamoyl compound of claim 22, wherein the pyrrolidine is substituted with one or more (C 1 -C 3 ) alkyl groups.

24. The N-phenylcarbamoyl compound of claim 23, wherein (C 1 -C 3 )alkyl is ethyl.

25. B is an optionally substituted saturated (C ３ ~C ６ 3. The N-phenylcarbamoyl compound according to claim 2, wherein the N-phenylcarbamoyl compound is cycloalkyl-NH-.

26. The N-phenylcarbamoyl compound of claim 25, wherein the optionally substituted, saturated (C 3 -C 6 )cycloalkyl-NH- is selected from the group consisting of 4,4-(dimethylcyclohexyl)-NH- and cyclopentyl-NH-.

27. A is a group of the following formula: 【Chemistry 3】 The N-phenylcarbamoyl compound according to claim 1,

28. 28. The N-phenylcarbamoyl compound of claim 27, wherein X is an optionally substituted 5- or 6-membered heteroaryl ring.

29. The N-phenylcarbamoyl compound of claim 28, wherein the optionally substituted 5- or 6-membered heteroaryl ring is an optionally substituted pyrazine.

30. The N-phenylcarbamoyl compound of claim 27 or 28, wherein B is an optionally substituted phenyl.

31. The N-phenylcarbamoyl compound of claim 30, wherein the optionally substituted phenyl is substituted with CF 3 .

32. The N-phenylcarbamoyl compound of claim 1, selected from the group consisting of: 1) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 2) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 4) 4-(1-(ethylamino)cyclopropyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 5) 2-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 6) 2-methyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)oxazole-4-carboxamide, 7) 2-fluoro-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)benzamide, 8) 4-(cyclopropylsulfonyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 9) N-(3-(2-fluoro-5-(6-isobutylnicotinamido)phenethyl)-1H-pyrazol-5-yl)pyrimidine-2-carboxamide 10) N-(4-fluoro-3-(2-(5-((2-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide 11) 2-(2-cyanopropan-2-yl)-N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 12) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 13) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 14) N-(3-(2-(5-((3,5-dimethylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 15) N-(4-fluoro-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 16) N-(4-chloro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 17) N-(3-(2-(5-((2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 18) N-(5-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenethyl)-1H-pyrazol-3-yl)picolinamide, 19) N-(3-(2-(3-(4-fluorobenzamido)-1H-pyrazol-5-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 20) N-(4-methyl-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-6-azaspiro[3.4]octane-6-carboxamide, 21) 3,3-diethyl-N-(4-methyl-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)pyrrolidine-1-carboxamide 22) 3,3-diethyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)pyrrolidine-1-carboxamide 23) N-(3-(5-(3-(4,4-dimethylcyclohexyl)ureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-((1-isopropylazetidin-3-yl)oxy)benzamide, 24) N-(3-(5-(3-cyclopentylureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)benzamide, 25) N-(3-(5-(3-(4,4-dimethylcyclohexyl)ureido)-2-methylphenethyl)-1H-pyrazol-5-yl)-4-(1-methylpiperidin-4-yl)benzamide, 26) N-(4-fluoro-3-(2-(3-((2-methyl-6-(morpholinomethyl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 27) N-(3-(2-(3-((6-(((2S,6R)-2,6-dimethylmorpholino)methyl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 28) N-(4-fluoro-3-(2-(3-((2-methyl-6-(pyrrolidin-1-ylmethyl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 29) N-(3-(2-(3-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 30) N-(4-fluoro-3-(2-(3-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 31) N-(4-fluoro-3-(2-(3-((6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 32) (S)—N-(3-(2-(3-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide, 33) 3-(difluoromethyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 34) N-(3-(2-(5-((2-acetyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, 35) 3-(isopropylsulfonyl)-N-(4-methyl-3-(2-(5-((3-methylpyridin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 36) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-((3-methylpyridin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)isonicotinamide, 37) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(N,N-dimethylsulfamoyl)benzamide, 38) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-8-azaspiro[4.5]decane-8-carboxamide, 39) N-(3-(2-(5-((6-cyano-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-fluorophenyl)-4-((dimethylamino)methyl)-3-(trifluoromethyl)benzamide, 40) N-(4-fluoro-3-(2-(5-((2-methylpyrimidin-5-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 41) 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 42) N-(4-fluoro-3-(2-(3-((6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 43) N-(2-fluoro-5-(2-(5-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 44) N-(2-fluoro-5-(2-(3-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 45) N-(5-(2-(3-((6-(4-ethylpiperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzamide, 46) N-(2-fluoro-5-(2-(3-((6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl)amino)-1H-pyrazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 47) 4-((dimethylamino)methyl)-N-(3-(2-(5-(4-morpholinobenzamido)-1H-pyrazol-3-yl)ethyl)phenyl)benzamide, 48) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(methylsulfonyl)benzamide, 49) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, and 50) 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)isonicotinamide.

33. 33. The N-phenylcarbamoyl compound of claim 32, selected from the group consisting of: 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 6) 2-methyl-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-5-(trifluoromethyl)oxazole-4-carboxamide, 8) 4-(cyclopropylsulfonyl)-N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)picolinamide, 13) N-(4-fluoro-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 15) N-(4-fluoro-3-(2-(5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide, 34) N-(3-(2-(5-((2-acetyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)ethyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide, and 49) N-(4-methyl-3-(2-(2-(pyrazin-2-ylamino)thiazol-5-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide.

34. The N-phenylcarbamoyl compound according to claim 33, which is compound 3) N-(4-methyl-3-(2-(5-(pyrazin-2-ylamino)-1H-pyrazol-3-yl)ethyl)phenyl)-3-(trifluoromethyl)benzamide.

35. A pharmaceutical composition comprising the N-phenylcarbamoyl compound (I) according to any one of claims 1 to 34 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

36. An N-phenylcarbamoyl compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 34 for inhibiting both Fyn and VEGFR2 kinases, wherein the inhibition of both Fyn and VEGFR2 kinases occurs in the treatment of a disease / disorder / pathology in which both kinases are involved; The disorder / disease / condition is selected from the group consisting of: Osteoarthritis, eye diseases, such as intraocular neovascular disorders, e.g. age-related macular degeneration, diabetic macular edema and other ischemia-related retinopathies, or immune-mediated corneal graft rejection; skin disorders, such as psoriasis or rosacea; acute or chronic pain; lung diseases, such as acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and systemic sclerosis (SSc); and cancers, such as metastatic colorectal cancer, non-squamous non-small cell lung cancer, metastatic renal cell carcinoma, recurrent glioblastoma multiforme, gynecological malignancies, metastatic breast cancer.

37. The N-phenylcarbamoyl compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 36, wherein the acute or chronic pain is selected from neuropathic pain, inflammatory pain, osteoarthritic pain, and ocular pathological pain.

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