TWI324926B - Monocyclic heterocycles as kinase inhibitors - Google Patents

Description

IX. Description of the Invention [Technical Field] The present invention relates to a compound which can inhibit protein tyrosine kinase activity of a growth factor receptor such as c-Met and which can be used as an anticancer agent. Pharmaceutical compositions comprising such compounds are also useful in the treatment of diseases other than cancer, and such diseases are associated with signaling pathways that operate through growth factors and anti-angiogenic receptors such as 'c-Met.

[Prior Art] Hepatocyte growth factor (HGF) (also known as dispersing factor (SF)) is known to induce most pleiotropic effects in normal and proliferating cells due to its ability to disintegrate colonies in vitro. Pleiotropic) reaction between leaf-derived cytokines (Sonnenberg et al.,··. CeH 5/〇, 123:223-235, 1 9 9 3 ί Matsumato eta 1., Cr it. Rev. Oncog. 3:27 -54, 1 992; and Stoker et al., Nature 327:239-242, ® 1 987 ). These reactions are known to include: proliferation of epithelial and endothelial cells, separation of epithelial cell colonies into individual cells, stimulation of epithelial cell motility [motogenesis], cell survival, and induction of cell morphogenesis (Μ〇ten) Sano et a 1 ·, Ce// 6 7 : 90 1 -90 8,1 9 9 1 ), and promote the onset (Stella, et al-, «/· Ce// βίο/., 1 2:1 3 5 7-62, 1 999 and Stuart, et al., /«/. ·/· £jc/7. corpse fli/i, 81:17-3 0, 2 000 ), which are the basis of the transfer Important process. It has also been reported that HGF promotes angiogenesis (Bussolino et al,, Ce// 5/<?/· 1 1 9: 629-64 1, 1 992 ). In addition, HGF plays an important role in the regenerative 'wound healing of the group -5- (2) 1324926 and the normal embryonic process (which are both dependent on cell motility and proliferation). HGF initiates these physiological processes through high affinity binding to its associated receptor (Met protein tyrosine kinase receptor, a proven proto-oncogene) (Park et al., /Voc·· Wai Λ Sc ί. 5^ 84:6379-83,1987 and Bottaro et al., ie/7ce 251:802-4, 1991). The mature form of Met consists of a highly glycosylated external subunit and a/5-unit with extensive extracellular functional sites, a penetrating membrane segment, and a cytoplasmic tyrosine kinase functional site. Ligand engagement induces Met dimerization leading to the production of autophosphorylated activated receptors. Activation of Met promotes message-conduction tandem reactions, as indicated by the transphosphorylation of key cytoplasmic tyrosine residues responsible for complementing most of the effect proteins (Furge et al., Oncogewe 19: 5582-9, 2000). These include the p85 subunit of PI3-kinase, phospholipase Cr (Gaul et al., 19:1509-18, 2000), Grb2 and She adaptor proteins, protein phosphatase SHP2 and Gabl. The latter adaptation protein has emerged as the docking molecule of the main gene expression direction, and becomes a tyrosine phosphorylated in response to ligand occupancy (Schaeper et al., J. Cell Biol. 1 49:1 4 1 9 -32, 2000; B arde 11 ieta 1 ·, O « coge π e 1 8 : 1 1 3 9 - 4 2,1 9 9 9 and S achset al., J. Cell. 5 ζ· o/. 1 5 0 :1 3 7 5 - 8 4, 2 0 0 0 ) » Other signaling molecules have been confirmed in HGF-stimulated cells (especially Ras, MAP kinase, STATs, ERK-1, -2, and FAK) Activation (Tanimura et al., Oncogene 17:57-65, 1 9 9 8; Lai et al., J. Biol. C he m. (3) 1324926 275:7474-80,2000 and Furge et al., Owcogewe 19:5582-9, 2000). The role of most of these molecules in the message has been fully confirmed in cell proliferation.

Met (also known as hepatocyte growth factor receptor (HGFR)) is mainly expressed in epithelial cells, but has also been shown to be expressed in endothelial cells, myoblasts, hematopoietic cells, and motor neurons. Excessive expression of HGF and activation of Met have been implicated in the onset and progression of many different types of tumors and the promotion of transgenic disease. Preliminary evidence linking Met to cancer has been supported by the confirmation of a mistranslational mutation in the kinase's functional site that makes individuals susceptible to papillary renal cell carcinoma (PRC) and hepatocellular carcinoma (HCC) (Lubensky et al) ., A mer. J. Pathology, 155:517-26, 1 999 ). Mutated forms of Met have been used in ovarian cancer, childhood HCC, gastric cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, colorectal metastasis (Christensen et al 1., Cancer Res. 63:7345-55, 2003 Lee eta 1 ,O « coge « e 1 9 : 4 9 4 7 - 5 3,2 0 0 0 and D ire η zoeta 1., • Ca/ice/· 1 : 1 47-54,1 995 ) Obtained confirmation. In addition, further evidence supporting the role of Met in cancer is based on the overexpression of H GF and Met receptors in various tumors, including thyroid, ovarian and pancreatic cancers. In liver metastasis of colorectal cancer, it has also been confirmed to be enlarged (R 〇 n g e t a 1., C a « c e ; Λ e ί · 5 5 : 1 9 6 3 - 1 9 7 0 , 1 9 9 5 ;

Rong et a 1., Cancer Res. 5 3:5 3 5 5 - 5 3 60, 1 993 ; Kenworthy eta 1.,r. · C or ncer 6 6 : 2 4 3 - 2 4 7,1 9 9 2 And S carpi η oet

Al.5 J. Pathology 1 8 9:5 70-5 7 5, 1 999 ). T P R - M e t (an activated form similar to BCR / Abl in C M L) has been published and confirmed to appear in 1324926

Human gastric cancer (PNAS 88: 4892-6, 1991). In patients with invasive breast cancer and in recent studies of non-small cell lung cancer, the expression of the receptor or ligand is a sign of a decrease in the survival rate, further linking Met to the progression of the tumor ( Camp et al., Cancer 86: 2259-65, 1999 and Masuya et al., Λ Cfl; 7ce; 90: 1555-62, 2 004). In general, most human tumors and mesenchymal-derived tumor cell lines unduly exhibit HGFR and/or HGh.

Numerous experimental data support the role of HGF and Met in tumor invasion, growth, survival, and progression (and ultimately metastasis). Preclinically, the transgenic expression of HGF causes a metastatic phenotype (Takayama et al., 94:701-6, 1997) and the expanded/overexpressed Met automatically transforms NIH-3T3 cells (Cooper et al., «/. 5 : 2 62 3 - 8, 1 986 ) ° Biological agents such as ribozyme enzymes, antibodies and antisense RNAs with HGF or Met have been shown to inhibit tumorigenesis (Stabile et a 1., Gene Th erapy, 11:325-35, 2004; Jiang et al., Clin.

Cancer Res. 9:4274-81, 2003; and Genentech US 6,2 1 4,344,200 1 ). Therefore, selective, small molecule kinase modulators targeting Met are expected to have therapeutic effects in the treatment of cancer, in which the activation of Met receptors is in the growth and progression of primary tumors and secondary metastases, Played a key role. SUMMARY OF THE INVENTION OBJECT OF THE INVENTION -8 (5) 1324926 The present invention relates to a compound (R2)r R3 丫丫, R1 having the following formulas 1 and 11 and which can be used for treating cancer.

DESCRIPTION OF THE INVENTION The present invention provides a formula I and a hydrazine compound as defined above, a pharmaceutical composition such as a compound, and a method for using a compound as a medicament for the treatment of cancer. As used herein, the term "alkyl" as used alone or as part of another group refers to a radical derived from a monovalent alkane (hydrocarbon) containing 1 to! A group of 2 carbon atoms unless otherwise stated. Preferred alkyl groups are lower alkyl groups having from 1 to 1 carbon atom. The alkyl group is an optionally substituted linear, branched or cyclic saturated hydrocarbon group. The alkyl group can be substituted at any feasible point of attachment. An alkyl group substituted with another alkyl group is also referred to as a "branched alkyl group". Examples of alkyl groups include: methyl, ethyl 'propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl Base, octyl, 22,4-trimethylpentyl, decyl, decyl, undecyl, dodecyl, and the like. Examples of the substituent include, but are not limited to, one or more of the following groups: an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a -CN' aryl group, a heteroaryl group, a halogen group (such as F, Cl). , Br, I), haloalkyl (such as 'CCl3 or CF3), hydroxy, alkoxy 'alkylthio, aminyl' -COOH' -COOR, -C(0) R, -OCOR, amine, Amine (6) 1324926 Formamyl (-NHCOOR- or -OCONHR-) 'Urea (-NHCONHR-) or sulfhydryl (-SH). As used herein, the term "alkenyl", whether used alone or as part of another group, refers to a straight, branched or cyclic ring containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Hydrocarbon atomic group. The alkenyl radical can also be substituted at any feasible point of attachment. Examples of the substituent of the alkenyl group include those which have been listed as an alkyl group in the foregoing.

As used herein, the term "alkynyl", alone or as part of another group, refers to a straight, branched or cyclic ring containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Hydrocarbon atomic group. The alkynyl group can also be substituted at any feasible point of attachment. Examples of the substituent of the alkynyl group include those which have been listed as an alkyl group in the foregoing. The number below the symbol "C" indicates the number of carbon atoms that a particular group can contain. For example, "(^.6 alkyl) means a straight or branched saturated carbon chain having 1 to 6 carbon atoms; examples thereof include: methyl, ethyl, n-propyl, isopropyl, n-butyl Base, second butyl, isobutyl, tert-butyl 'n-pentyl, second pentyl, isopentyl, and n-hexyl. Depending on the context of the article, "Ci-6 alkyl" may also mean a Ci-6 alkyl group bridging two groups; examples of which include: propane-1,3-diyl, butane-1,4-diyl, 2-methylbutane-I,4-diyl Etc. "C2.6 alkenyl" means a straight or branched carbon chain having at least one carbon-carbon double bond and 2 to 6 carbon atoms; examples of which include: vinyl, propenyl, isopropenyl , butyl ketone 'isobutyring group, pentenyl group, and hexyl group. Depending on the context of the article, "C2-6 alkenyl" may also refer to a C2-6 enediyl group bridging two groups: Example package-10-(7) 1324926 includes: ethylene·1,2-diyl (vinyl), 2-methyl-2-butyl-1,4-diyl, 2-hexene-1,6 -diyl and the like. "C2.6 alkynyl" means having at least one carbon-carbon oxime bond and 2 to 6 carbon atoms Chain or branched carbon chain; examples thereof include: ethynyl, propynyl 'butynyl, and hexynyl. In this context, "cycloalkyl" is used either alone or as part of another group. An alkyl species containing from 3 to 15 carbon atoms without alternating or resonating the double bond between the carbon atoms. It may contain from 1 to 4 rings. # Exemplary groups include: cyclopropyl, cyclobutene Base, cyclopentyl, cyclohexyl, adamantyl, etc. The cycloalkyl group can be substituted at any feasible point of attachment. Examples of substituents include one or more of the following groups: halogen (such as F, Br) Or C1), a hydroxyl group, an alkyl group, an alkoxy group, an amine group, a nitro group, a cyano group, a decyl group, an alkylthio group, and any substituent described in the aforementioned alkyl group moiety. The words "alkoxy" or "alkylthio", used alone or as part of another group, are preceded by an oxygen linkage (· ® 〇-) or a sulfur linkage (-S·) linkage, respectively. Alkyl as described herein, whether used alone or as part of another group, "alkoxycarbonyl" The term refers to an alkoxy group bonded through a carbonyl group. The alkoxycarbonyl radical is represented by the formula -C(0)OR, wherein the R group refers to a linear or branched C!.6 alkyl, cycloalkyl group. Or aryl or heteroaryl. As used herein, the term "alkylcarbonyl", alone or as part of another group, refers to an alkyl group bonded through a carbonyl group. In this context, either alone or The term "alkylcarbonyloxy" as part of another group refers to an alkylcarbonyl group bonded through an oxygen linkage. -11 - (8) i324926

As used herein, the term "aryl" as used alone or as part of another group refers to a monocyclic or bicyclic aromatic ring, for example, phenyl, substituted phenyl, and the like, and A fused group, for example, a naphthyl group, a phenanthryl group or the like. Thus an 'aryl group' may contain at least one ring having at least 6 atoms, up to 5 such as a ring (which contains up to 22 atoms) and alternating between adjacent carbon atoms or suitable heteroatoms Double bond of (resonance). The aryl group may be optionally substituted by one or more groups including, but not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy 'amine carbamoyl, alkoxycarbonyl, nitro , alkenyloxy, trifluoromethyl, amine, cycloalkyl, aryl, heteroaryl, cyano, alkyl-S (0) „(!« = 0, 1, 2), or fluorenyl. As used herein, the term "aralkyl" as used alone or as part of another group refers to an aryl group as described above which is bonded through an alkyl group as hereinbefore described. One example of an aralkyl group is a benzyl group. As used herein, the term "amino" as used alone or as part of another group refers to -ΝΗ2-. The amine group may be optionally substituted by one or two identical or mutually different substituents, such as alkyl, aryl, aralkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cyclohexane A heterocycloalkylalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a thioalkyl group, a carbonyl group or a carboxyl group. These substituents may be further substituted with a carboxylic acid, any alkyl or aryl substituents listed herein. In some systems, the amine group can be substituted with a carboxy or carbonyl group to form a mercapto or amine mercapto derivative. As used herein, the term "heteroaryl" as used alone or as part of another group, 12-(9) 1324926, refers to a substituted or unsubstituted 5 or 6 membered monocyclic group, 9 or A 10-membered bicyclic group, and a 1 to 14 membered tricyclic group, which contain at least one hetero atom (〇, S or n) in at least one ring. Each hetero atom-containing ring of a heteroaryl group may contain one or two oxygen or sulfur atoms and/or from j to 4 nitrogen atoms. The prerequisite is that the total number of hetero atoms in each ring is 4 or less and each ring contains At least one carbon atom. The fused ring constituting the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and oxygen atoms may be oxidized arbitrarily and the nitrogen atom may be arbitrarily quaternized. The bicyclic or tricyclic heteroaryl group must include at least one fully aromatic ring 'but the other fused ring may be aromatic or non-aromatic. The heteroaryl group can be attached at any feasible nitrogen or carbon atom position of any ring. The heteroaryl ring system may contain hydrazine, 2 or 3 substituents selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano 'hydroxyl , alkoxy, sulfanyl, =0, -C02H, -c (=0) H, -C〇2-院, -C(=0)alkyl, phenyl, ® benzyl, phenethyl , phenoxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclic, heteroaryl '-NR'R", -C(=〇) NR, R'', -C〇2NR , R", -C(=0) NR, R,, -NR, C02R', -NR, C( = 〇)r", -so2nr'r", and -nr'so2r" 'where each R 'and r' are independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R' and R" are taken together to form a heterocyclic or heteroaryl ring. Monocyclic heteroaryl groups Examples include: pyrrolyl, pyrazolyl, indolinyl, imidazolyl, oxazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, furyl, thienyl, Examples of β-bicyclic heteroaryl groups such as oxadiazolyl, pyridyl-13-W4926 do) 'oxazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like Including: fluorenyl, benzothiazolyl, benzodiazolyl, benzoxazolyl, benzothienyl, dark porphyrin, tetrahydroisomorpholinyl, iso-loxalinyl benzimidazolyl, Benzopyridinyl, pyridazine basic and ketone, chromonyl, oxacillin, benzopipetanyl, fluorenyl, quinoxalinyl, oxazolyl, pyrrolopyridyl, furan a pyridine group, a dihydroisoindolyl group, a tetrahydro D quinolyl group, etc. Examples of the tricyclic heteroaryl group include: carbazolyl, benzindenyl, linalyl, If "steep base, Ordinary, saturated, or partially unsaturated, as used herein, or as part of another group, "heterocyclic". A monocyclic system 'containing 5 to 7 soil members comprising carbon atoms and selected from nitrogen, sulfur and/or oxygen. Preferably, the heterocyclic ring is a 5- or 6-membered monocyclic ring and contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen and/or sulfur. The heterocyclic ring may be optionally substituted' to mean that the heterocyclic ring may be substituted at one or more substitutable ring positions by ~ or a plurality of groups independently selected from the group consisting of alkyl (preferably lower alkyl) , hospital oxygen (preferably low-grade alkoxy), nitro, single-yard amine (preferably lower-grade amine), dialkylamine (preferably di-lower alkylamine), cyano, yl, halogen Alkyl (preferably trifluoromethyl), alkyl fluorenyl, amine carbonyl, monoamine amino group, dialkylaminocarbonyl, alkyl guanamine (preferably lower alkyl guanamine), alkoxy An alkyl group (preferably a lower alkoxy-lower alkyl group), a oxime group (preferably a lower alkoxycarbonyl group), an alkylcarbonyloxy group (preferably a lower alkylcarbonyloxy group), and an aryl group (preferably a phenyl group) ): The aryl group is optionally substituted with a -14-(11) 1324926 halo group, a lower alkyl group, and a lower alkoxy group. Examples of heterocycles are: isoxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, piperidyl, piperazinyl, hexahydropyridyl, fenofyl and three Azolyl. The heterocyclic ring can be attached to the parent structure through any carbon atom or a hetero atom on the heterocyclic group which can form a stable structure. "The term heteroatom J refers to 〇, S or N, which are selected on an independent basis. It should be noted that any #hetero atomic system with an imperfect valence is considered to have a hydrogen atom. To fill up its valence. "Halogen j or "halo" refers to chlorine, desert, fluorine or iodine, which are selected on an independent basis. When a monofunctional group is "protected", it means that the group is in a modified form to exclude unwanted side reactions at the protected position. Consider the technical level of this skill and refer to standard textbooks such as Greene, T.W. et al., /Voiecn've Growpi /«

Wiley, Ν·Υ, (1991), by this specification, can identify ® protecting groups for the compounds of the present invention. The term "patient" as used in this article covers all mammalian species. Suitable examples of the salts of the compounds of the present invention and inorganic or organic acids include: hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, fumarate, And phosphate. It is not suitable for pharmaceutical use, but may be used, for example, as free orally purified salts of free compounds I or II, and their pharmaceutically acceptable salts. In general, the invention encompasses compounds having formula 1 or II -15- (12)

Or their mirror image isomers 'non-image, is a hydrate, a solvate or a pharmaceutically acceptable salt, wherein: R1 represents hydrazine, alkyl, substituted alkyl, cycloalkyl, substituted Cyclosyl-arylalkyl, substituted arylalkyl 'aryl, substituted aryl, decyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted a heteroaryl group, a heterocyclic group, a substituted heterocyclic group, a heteroarylalkyl group, a substituted heteroarylalkyl group, a heterocycloalkyl group, or a substituted heterocycloalkyl group; each R 2 independently represents a halogen, a halogen Cyano, n〇2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclic group, substituted heterocyclic group, aralkyl group, substituted aralkyl group, heterocycloalkyl group, or substituted heterocycloalkyl group; B shows 0, NR8, NR8CH2, S 'SO, S 〇2, or CR9R10; v indicates NRH or -(CR37R38) p_, the prerequisite is: when v shows N, W represents alkyl or cycloalkyl; W and X each independently show c or N·, Y is selected from 0, S and NR12; Z show - CRI3R 14, or -(CR13R14) |NR15-; 1 shows 0 to 2; -16- (13) where η is not I to 4 (if both W and X are C), 〇 to 3 (if 乂 and ~ ^ N) And 〇 to 2 (if X and w are both N); P shows 1 to 4; R 3, 5 ——^,...'. , ..., ^ and ^ are independently selected from the group consisting of hydrazino, alkenyl substituted alkenyl, alkynyl, substituted, benzyl, cycloalkyl via BV / φ AA · ^ Substituted cycloalkyl, aryl, substituted aryl; aryl-substituted heteroaryl, heterocyclyl, and substituted heterocyclic R4 are selected from aryl, substituted aryl The prerequisites are: (3) if R4 is a phenyl group (〇R4 is not simultaneously substituted by a hydroxy group and a guanamine group, if the base, heteroaryl group, substituted heterocyclic heterocyclic group, and substituted heterocyclic fluorenyl group are: And (11) R4 is not substituted by -NRS〇2R-, wherein r is alkyl or (b) if R4 is pyridyl, R4 is not simultaneously substituted with hydroxy and methoxy; and (e) if R4 is a pyrimidinyl group which is not substituted by =0; R9 and R1Q are independently selected from the group consisting of an anthracene, a halogen, an alkyl group, a substituted alkyl group, a bad group, a substituted group, a substituted cycloalkyl 'aryl group, a substituted Aryl, heteroaryl 'lightly substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; RU is selected from the group consisting of an anthracene, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted burn Alkynyl, substituted alkyne Base 'CN, Ν02 or S02NH2;

Rl3 and R14 are independently selected from the group consisting of hydrazine, halogen, alkyl, substituted alkyl-17-(14) 1324926, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted Cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, or together form a carbon having from 3 to 8 atoms Ring or heterocycle; A is selected from the following:

Wherein D represents S or 〇; m represents 0 to 6; R16, R", Ri*, Ri9, r2, r2 丨, r22 r23, r24 r2; R26 and R27 are independently selected from H'halogen, NR3QR31, 〇 R32 'C〇2R33 ' conr34r35, so2r36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, - CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocycloalkyl; R28 and R29 are independently selected from H, alkyl, substituted An alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, or a carbocyclic or heterocyclic ring having 3 to 8 atoms; wn r32, r33, r34' r35 And r36 are independently selected from the group consisting of h, hydroxy, substituted, decyl, substituted, alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, Aryl, lightly substituted aryl, heteroaryl, substituted heteroaryl 'heterocyclyl, substituted -18-(15) J324926 heterocyclic, heterocyclic or substituted heterocyclic Base; and R37 and R38 are each H, halogen, or a hospital base. In some systems of the ryokan, RI shows substituted or unsubstituted (such as fluorophenyl), substituted or unsubstituted c, _C4 such as, Methyl), or substituted or unsubstituted c3_c8 ring such as cyclohexyl or cyclopentyl). In certain systems of the invention, ... shows a Cl-c4 alkyl group, a halogen-based group. In certain systems, 'R4 indicates that the optionally substituted benzene is a 5 or 6 membered nitrogen-containing heteroaryl group (such as pyridyl, pyrazolyl H-based). According to one system of the invention, B shows hydrazine, NHCH2, CH (OH): Y is not 0 or S and Z is -cr13r14 or -NR15, and 丨, R14, and R15 are shown.

In certain systems of the invention, any substituted pyridinium is illustrated, wherein the substituent is alkyl, alkenyl, alkynyl, halo, cycloheterocycloalkyl, -NR39COR4G, -NR39C(0)2R4 . , -NR or -C ( Ο ) NR43R44, wherein R3 9, R4 0, R41 ' R42, R4: independently H, lower alkyl, substituted lower alkyl, hydroxyalkane, ring-based, Substituted ring-based, heterocyclic, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted, heteroaryl, substituted heteroaryl, or -NR43R44 One base. According to some systems of the invention, A is represented by -NR4IR42, a substituted phenyl group (alkyl (or a halogen or a pyrrole ch2 or a medium, an R13 azine or a pyridinyl group, a 41r42, 5 and R44 group, an amine) Substituted heteroarylheterocyclohexane-19-(16) 1324926 _NR39COR40, -c (〇) NR43R44, halogen, C 丨-c4 alkyl, _C = C-R45, -C = C-R46, aryl, Or a pyridine substituted with a heteroaryl group, wherein r45 and R46 are alkyl, hydroxyalkyl, aminalkyl, cycloalkyl, heterocycloalkyl, -C(0)R47'-NR39COR4, aryl or heteroaryl Or the pyridine is substituted with an aryl group such as a 'phenyl group, and the aryl group may be C0NH2, methyl, amine ethyl, hydroxyethyl, -CONHCH2CH2NHCH3, or C Η 2 C Ο N Η 2 in any step. Alternatively, the pyridine may be substituted with pyridyl or hexahydropyranyl. In accordance with certain systems of the invention, preferred substituents for any substituted pyrimidine β include -NR41R42, or -nr39co2R4() Wherein R41 and R42 are preferably hydrazine or methyl, and R3 9 and r4 are preferably η or alkyl. The present invention further provides a compound or pharmaceutically acceptable compound or π as defined above. A pharmaceutical composition of an acceptable carrier. Optionally, the pharmaceutical carrier may further comprise at least one additional anticancer agent formulated as a fixed dose. The present invention also provides a method of treating a proliferative disease via modulation of Met kinase. 'It comprises administering a therapeutically effective amount of a compound of formula I or n as defined hereinbefore to a mammal in need of treatment. In another system, the invention provides another treatment for proliferative diseases via modulation of Met kinase. A method comprising administering a therapeutically effective amount of a compound of formula I or U as hereinbefore defined together with (simultaneously or continuously administered) at least one other anticancer agent, to a mammal in need of treatment, eg certain compounds of formula I and II It can be prepared according to the following Schemes 1-14. It is easy to prepare -20-8 (17) 1324926 by the synthesis method well known to those skilled in the art. The solvates of the compounds of the formulae I and 11 ( For example, hydrates are also encompassed within the scope of the invention. Methods of solvation are generally known in the art. Thus, the compounds of the invention may be free or hydrated. The form of the material can be prepared by the method exemplified by the following scheme. The general route for the preparation of pyridine and pyrimidine described in the present invention is exemplified in Scheme 1 » The appropriately substituted pyridine or pyrimidine 1 can be used in a base (such as In the presence of sodium hydride, sodium hydroxide or potassium carbonate, the functionalized phenols 2, 4 φ and 8 are treated to give the desired ethers 3, 5, and 9. In methanol, aqueous HC1 is used. The acetamide protecting group ' of compound 3 is removed to give a critical intermediate 5. Another possible method is a reduction reaction of the nitro group introduced by the compound 9' via a zinc powder and ammonium chloride or an Adams' catalyst, under hydrogenation conditions, An aniline 5 is obtained. The analogs 6 and 7 can then be deuterated by 'for example, 'isocyanate, ruthenium chloride compound' or by using a carboxylic acid and a coupling agent [such as benzotriazol-1-yl hexafluorophosphate). Oxime (trimethylamino) scale® (BOP reagent), bromopyridinium tripyrrolidinium (PyBroP), tetrafluoroboric acid 6>-(1Η-benzotriazol-1-yl)tetramethyl A quaternary urea (TBTU) was prepared to treat aniline 5 and was prepared. By treating aniline 5 with an appropriately substituted isothiocyanate, thiol thiourea 6 can be formed (Υ = S, Z = ΝΗ ) 〇 (18) 1324926 Process]

1

NHAc 1N aqueous HCl/methanol (1:1), reflux

Zn, NH4CI methanol/THF or H2_ Pt〇2_ methanol

T = CRI9 or NL = leaving group, such as halogen or N〇2 Two different metameric aminopyrimidine analogs 14 and 19 can be prepared by using the synthetic routes listed in Schemes 2 and 3. The PMB-protected aminopyrimidine 11 (derived from commercially available 2,4-dichloropyrimidine [10, Aldrich]) can be converted to ether 12 via the same chemistry as shown in Scheme 1. . Removal of 13 PMB using trifluoroacetic acid and methoxybenzene yields compound 14» (19) 1324926

p-CH3OC6H4CH2NH2 Atdnch Process 2 ci PMB,

11 1,>: NaH, DW1F 2· H2. Pt02, ethanol

PMB = P"CH3OC6H4CH2

Similarly, PMB-protected aminopyrimidine 16 (derived from commercially available 4,6-dichloropyrimidine [15, butyl (:1 VIII 11^1^3)) can be converted to ether 17 (in the PMB deprotection step) Thereafter) (Scheme 3). The amine 17 is subjected to double Boc (third butoxycarbonyl) protection with an excess of ditributyl dicarbonate, after hydrogenation with an Adam catalyst (A dams ' cata 1 yst ), The aniline 18 can be obtained. After the deuteration or thiourea formation step is carried out by the compound 18 and the Boc protecting group is removed under acidic conditions, the amine 19 can be obtained. (20) (20) 1324926 Scheme 3

15 16 2.TFA> methoxybenzene 17 TCI America PMB - p-CH3OC6H4CH2

Using the synthetic route shown in Scheme 4, an amine hydrazine derivative 26 can be prepared which is based on a chemistry similar to that described in the references cited below: Chung, HA et al. J. //ere /·C/ie/w. 1 999, 3 6, 905-9 1 0 , and Bryant RD et al. J. qc//c CAew. 1 99 5,32,1 473- 1 476, their disclosure The content is incorporated herein by reference. The 4,5-dichloropyridazin-3-(2//)-one (20, Aldrich) can be protected, for example, with a tetrahydropyran (ΤΗΡ) group to give the intermediate 21. Treatment of compound 2 with an appropriately substituted phenol and a base (i.e., sodium hydride) followed by reduction of the nitro-containing intermediate under catalytic hydrogenation conditions affords aniline 22. After removal of the THP group under acidic conditions, the protection of the anilino group of 22 (protected as bis(trimethyltrimethyl ester) (Cbz)) affords compound 23. The desired leaving group can be introduced into the compound 24 by treating the compound 23 with trifluoroacetic anhydride (TFA A ) or phosphonium chloride or phosphonium bromide in the presence of a base such as triethyl or diisopropylethylamine. 3-position. Substituting the leaving group X of compound 24 with an appropriately substituted -24-(21) 1324926 amine followed by removal of the Cbz group affords intermediate 25. The aniline 25 can be converted to the desired 3-aminopyridazine analog 26 using the chemistry shown in Scheme N3 above. Process 4

20 Aidrich

THP

THP = tetrahydrofuran 1.xs PhCH20C(0)CI EtsN, DMAP, CH,a, [ H0I/dioxine

Using the synthetic route shown in Schemes 5 and 6, a 2-aminopipipyridine derivative can be prepared. The aniline 27 obtained from the chemistry described in Scheme 1 can be converted to the intermediate 28 after heating with copper powder and potassium carbonate in benzylamine (Scheme 5). Under the conditions of catalytic hydrogenation, the protecting group of the benzyl group is removed by using a carrier supported on carbon to obtain an aminopyridine 29. In the presence of a coupling agent, the intermediate 28 or -25-(22) 1324926 2 9 ' can be treated with isothiocyanate 30 or isocyanate 32 to obtain mercaptothiourea 3 1 and mercapto urea 3 3, respectively. And guanamine 3 Bu flow 5

In a related approach 'using 3·chloroperoxybenzoic acid (m-CPBA) in chloroform' can convert 2·chloropyridine intermediate 36 (obtained according to Scheme 1) to N - Oxide (see, W02004/002410) (Scheme 6). Treatment of compound 3 7 with an appropriately substituted amine provides intermediate 38. Reduction of the N-oxide of compound 38 with, for example, triphenylphosphine, followed by removal of the acetamide protecting group under acidic conditions provides aniline 39. Using the chemistry described in Schemes 1-5, the conversion of aniline 39 to the desired analog 40 can be accomplished. 8 -26- (23) 1324926

In another possible route in which a compound associated with 40 is available, the aminopyridines 47 and 48 are prepared according to the synthetic sequence exemplified in Scheme 7. For the purposes of this, a two-step procedure involving the use of thiopurine chloride followed by ammonia in methanol is used to convert 4-chloropyridine carboxylic acid (41, TCI America) to 4-chloropyridine. Formamide. The intermediate 42 is coupled with the 4-aminophenol derivative 43 in the presence of a base (such as potassium t-butoxide) to give the pyridine carbenamide derivative 44. The intermediate 44 is deuterated or subjected to a guanylurea formation reaction to give intermediates such as 45 and 46. Treatment of pyridine carbenamide derivatives 45 and 46' with bis(trifluoroacetoxy)-iodobenzene, pyridine and water (in DMF) or bromine and potassium hydroxide (in water) Promote Hofmann rearrangement to produce the desired 2-amino-based steep derivative 47 and 48 ° -27- (24) 1324926

TCI America Process 1, SOO7 r 2.7NNH3 in Methanol

Deuteration or thiourea formation

Ph 丨(OCF3>3.pyridine. H20, DMF or l Br2. koh, h2o, dioxane and then AcOH

g 8-l〇 Compounds 53, 57 and 62 containing thiazole can be widely used in the process, 8)

The synthetic route shown is prepared. Substituting aniline/phenol 50 for the leaving group of 49 (or 5 4 (Scheme 9), respectively, intermediate 3 1 can be obtained with zinc powder and ammonium chloride in a THF-methanol mixture, 5 丨 and 55 nitro Substituent reduction, aniline 52 and 56 should be obtained separately. The reaction of converting aniline 52 and 56 to the desired compound 5 3 and 57 can be accomplished by the chemistry described above. -28- (25) 1324926 Scheme 8

L = leaving group, such as C1 or Br Ri = 0, S or NH (RJ)n

Zn, NH^CI, THF-methanol-

R’ = 0 or NH

Zn, NH4C1 THF-methanol

The nitro intermediate 60 can be obtained by reductive amination of aldehyde 58 with an appropriately substituted aniline 59 using the method described in WO 2004/00 1 059, which is incorporated herein by reference in its entirety. 1 0 ). Then, using the chemistry similar to that described in Sections 8 and 9, the desired aminothiazole derivative 62 can be obtained. (26) 1324926 Scheme 1 〇

By the chemistry shown in Scheme 11, various substituents can be incorporated at the 3-position of the pyridine nucleus. For this purpose, 4-chloro-3-iodopyridine (63, Tabanella, S. eta 1. Or g. Biomol. Che m. 2003, 1, 42 5 4-426 1 ) can be obtained in the presence of a base. (For example, diisopropylethylamine (Hunig's base)), coupled with 4-nitrophenol derivative 8, gives the desired iodide derivative 64. Then, the iodide derivative 64 can be subjected to various coupling reactions by an organic metal medium, and examples thereof are shown in the scheme φ Π. An amine (R"R'NH), a substituted alkyne 66, an aryl boronate 67' vinyl stannane, and an alpha, cold-unsaturated ester in the presence of a palladium or copper catalyst To treat the iodide 64, the intermediate 65' 68-71 can be obtained separately. For example, zinc powder and ammonium chloride (in a THF-methanol mixture), the nitro group of the compound 65 and 6 8-7 1 can be obtained. The radicals are reduced and the resulting aniline intermediate can be deuterated by the chemistry shown in Schemes 1-5 above.

Intermediate 7 1 can then be converted to alpha, no-unsaturated guanamine 7 3 (Scheme 12). Compound 72 derived by acid-promoted hydrolysis of ester 71 can be in the presence of a coupling agent (such as, but not limited to, EDCI, TBTU, DCC -30-(27) 1324926), with various amines (R"R 'NH' is coupled to produce the desired amide intermediate 73. The reduction of the nitro group at 73 and the subsequent oximation of the necessary aniline intermediate can be accomplished by the chemistry shown in Scheme 1-5 above.

C!

S6

Pd(PPh3)4 Cui, Et3N THFi reflow

Ar-B(OR)2 67 i^SnBUs Pd(PPh3)4. Pd(PPh3)4, Pd(OAc)2 Na2〇〇3, CsF, Cul, NBu3 Dioxane/h2o B3N, dmf DMF, 100 0C 80 °C 100 °c (

(28) 1324926 Process 1 2 /-Bu〇2〇

N〇2

Intermediate 74 can also be further modified to produce alkynylamines 76 (Scheme 13). The methanesulfonate 75 can be obtained by methanesulfonating the alkynyl alcohol 74 with methanesulfonium chloride in the presence of a base such as Hunig's base. Substitution of the methanesulfonyl group of compound 75 with various amines (R"R'NH) provides the alkynylamines 76. The reduction of the nitro group of 76 can be accomplished by the chemistry shown in Schemes 1-5 above and subsequent The deuteration reaction of the necessary aniline intermediate.

Process 13

The 3-aminopyridine derivatives 79 and 80 can be prepared according to the synthetic route described in Scheme 14. For this purpose, 4-chloro-3-nitropyridine (77, Lancaster Synthesis Ltd.) can be coupled with 4-aminoindole in the presence of a base such as sodium hydride in DMF to give nitrate Base intermediate 78. The intermediate 78 can be converted to the desired compound 79 and 80 using the chemistry previously described. The amine substituents of 79 and 80 can also be modified by -32- (29) 1324926 - for example, via a hospital base. Modification by brewing, cyclization or sulfonation. Process] 4

77 Lancaster Synthesis Ltd

Substituents can be introduced at the 5- or 3-position of the 2-aminopyridine ring by using the alkoxide intermediates 8 3 and 8 6 ', respectively (Schemes 15 and 16). The 2,methanamine derivative 81 can be converted to the 2-aminopyridine derivative 82 by the Huffman recombination method described in the above Scheme 7. Iodination of the 5-position of compound 82 can be accomplished in acetonitrile-isopropanol mixture using iodosuccinimide to provide the desired iodide intermediate 83. Another possible way is to pass the 4-step procedure (including the use of n-butyllithium in THF at low temperatures and the subsequent addition of iodine) to give 4-chloropyridin-2-ylaminecarboxylic acid a third Butyl ester (84, CB Research and Development Inc.) was converted to 4·chloropyridine·3_iodopyridine·2_ylamine carboxylic acid tert-butyl vinegar (85). Removal of 85##B〇c (amine carboxylic acid terpene vinegar) protecting group by refluxing aqueous hydrogen bromide followed by methylpyrrolidone (NMP) in the presence of diisopropylamine (Hernigen) In the middle of the coupling with the 4-nitrophenol derivative 8 at an elevated temperature (30) 1324926, an iodide intermediate 86 can be obtained. The iodide intermediates 83 and 84 can be further processed using chemistry similar to that shown in Scheme 11 above.

Process 15

Process 1 6

According to the synthetic sequence shown in Scheme 17, a methylene-linked (B = CH2) analogs 93 and 94 can be prepared. At low temperatures, methylmagnesium bromide and t-butyllithium and 2-chloroisonicotinaldehyde can be used successively (Frey, L. F. et al. Tetrahedron)

ZeH. 2001, 42, 6815-6818), Treatment of Compound 88 (derived from deprotection of 4-bromoaniline derivative 87) affords intermediate 90. Oxidation of a 90 ring with 3-chloroperoxybenzoic acid (m-CPBA) followed by substitution of the chloro substituent with an amine (R'NH2) followed by oxidation with zinc and ammonium formate (in methanol) The intermediate is reduced to obtain an intermediate 91. -34- (31) 1324926 Although propylamine is used as the nucleophilic amine (R ' jy H 2 ), the allyl group can be removed from the amine 9 I using a money catalyst in an ethanol-water mixture. Group. The 9-inch kinky base can be removed by a different method. For example, compound 91 is hydrogenolyzed in the presence of a palladium catalyst and the iV-Boc group on the aniline is deprotected under acidic conditions (HCI in methanol). Alternatively, the intermediate may be hydrogenolyzed by acidic deuteration in the presence of a palladium catalyst under acidic acidic conditions (trifluoroacetic acid in dichloromethane 0) by deuteration of the alcohol of 91. The #-Boc protecting group was removed to give compound 92. Then, the intermediate 92 can be deuterated by the chemistry shown in the above Scheme I - 5 to obtain the desired compounds 9 3 and 94.

-35- 8 (32) 1324926

Process 1 7

Nh2

R' = Η, 3-dimethylaminopropyl

According to the synthetic route shown in Schemes 18 and 19, heterocyclic oxime derivatives 〇〇 and 105 can be prepared. For this purpose, in a two-step procedure (using commercially available 2-(3-methoxyallyl)malonic acid (£)-dimethyl ester as a starting material), 2 嗣 is obtained. Methyl-1-phenyl-1,2·-nitropyrrolidine-3-decanoate (97) (Scheme 18). Thus, treatment of compound 95 with aniline at room temperature provides intermediate 96 which can then be cyclized in the presence of a base (e.g., sodium hydride) in dimethyl hydrazine to yield 97. The intermediate 97 is hydrogenolyzed under basic conditions to give 2,keto-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (98). The carboxylic acid 98 can then be subjected to 8-36-(33) 1324926 (such as 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxyl groups in the presence of a coupling agent. Benzotriazole (HOBt), in DMF, is coupled with an aniline derivative 99 to provide the desired compound 100. Process 1 8

9

NaH DMSO rt

By a two-step procedure in which commercially available 6-bromopyridinecarboxylic acid (101) is in the presence of a palladium (ruthenium) catalyst and sodium carbonate with phenyl-1,3,2-dioxaboron Coupling of diox aborinane 102 (Aldrich) followed by oxidation of the necessary intermediate 1 at elevated temperature provides the pyridyl oxide intermediate 104 (Scheme 1 9). The intermediate 104 is coupled with the aniline derivative 99 to give the desired compound 159. -37- (34)I324926 Process]9 ho2c

Aldrich 101

CH2CI2 Na2HP04 60 °C

m-CPBA )C/O102

Na2C〇3, DME-H20 H02C ethanol

Pd(PPh3)4,100〇C

103

The compounds of formula I and formula can be used to treat a variety of cancers including, but not limited to, the following cancers:

(a) Carcinoma, including: bladder, chest, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, neck, thyroid, prostate, and skin (including squamous cell carcinoma) Tumors of tumors (b) Hematopoietic tumors of the lymphoid system, including: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma (Hodgkin's) Lymphoma ), non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma: (c) Hematopoietic tumors of the myeloid lineage, including: acute and chronic myeloid leukemia, myelodysplasia Syndrome and pre-myeloid leukemia (35) 1324926 (d) Tumors at the beginning of the interlobes, including: fibrosarcoma and rhabdomyosarcoma; (e) Tumors of the central and non-vertebral nervous systems, including: astrocytoma' neuroblastoma , glioma and schwannomas; and (f) other tumors' include: melanoma, germ cell tumor, teratoma, osteosarcoma, pigmented dry skin, horny echinoderma Thyroid follicular cancer and Kaposi's sarcoma. # Given that protein kinase plays a key role in general cell proliferation, its inhibitors can act as reversible cytostatic agents and can be used to treat any course characterized by abnormal cell proliferation, for example, benign Prostatic hypertrophy, familial adenoma, polyposis, fibrone on neuroma, arteriosclerosis, pulmonary fibrosis, arthritis, psoriasis, spheroid nephritis, angioplasty or restenosis after vascular surgery, formation of hypertrophy, Inflammatory bowel disease, transplant rejection, endotoxic shock, and mold infection. Compounds of Formulas I and 11 that act as modulators of apoptosis can be used to treat ® cancers (including but not limited to, the cancer types listed above), viral infections (including but not limited to: herpes virus, poxvirus , African lymphocytoma virus, Sindbis virus (Sindbis virus) and adenovirus), prevention of AIDS progression in HIV-infected patients, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, by Autoimmune mediators of spheroid nephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, with AIDS Related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal cord-39- (36) (36) 1324926 muscle atrophy and cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, and Cardiovascular infarction, stroke, and reperfusion-related septic injury, arrhythmia, arteriosclerosis, toxin-induced or alcohol-related liver disease, blood disease (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the muscle and bone system (including, but not limited to, osteoporosis and arthritis), sinusitis allergic to aspirin, Bladder fibrosis, multiple sclerosis, kidney disease and cancer pain. Formula I and indole compounds modulate the extent of intracellular RN A and DN A synthesis. Thus, such agents are useful for treating viral infections (including, but not limited to, HIV, human papilloma, herpes virus, poxvirus, African lymphoma virus, neo-Drbes virus, and adenovirus). Formula I and hydrazine compounds are useful for chemoprevention of cancer. The term "chemical prevention" is defined as the inhibition of the development of invasive cancer by blocking the initiation of a genetic mutation event or by blocking the progression of a malignant pro-cell that has suffered damage or inhibiting the recurrence of a tumor. Formula I and hydrazine compounds are also useful for inhibiting tumor angiogenesis and metastasis. The term "anticancer agent" includes any of the known agents for treating cancer, including: 17α-ethinyl estradiol, diethylhexene female Alcohol, anthrone, prednisone, Fluoxymesterone, Dromostanolone propionate, decanolactone, Megestrolacetate, methyl Methylprednisolone, methyltestosterone's prednisolone, Triamcinolone, chlorotris-40- (37) 1324926 p-methoxytrianisene 'hydroxyl Progesterone

Hydroxy progesterone), Amionglutethimide, Es tramuestine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex, interstitial metalloproteinase inhibitors, VEGF inhibitors (including those who are anti-VEGF antibodies, such as Avastin®), and small molecules such as ZD6474 And SU666 8, Van Talaniib, BAY-43-9006, SU 1 1 248, CP-547632 and CEP-7055 are also included. Genentech's anti-Her2 antibody (such as Hereeptin) can also be used. Suitable EGFR antibodies include: gefitinib, erlotinib', and cetuximab. Pan Her inhibitors include: canertinib, EKB-569, and GW-572-016. Also included are: Src inhibitors, as well as Casodex® (Bicalutamide, Astra Zeneca), Tamoxifen's MEK-1 kinase inhibitor, ΜΑPK kinase Inhibitors, ΡΙ3 inhibitors, and PDGF inhibitors (such as imatinib). Also included are anti-angiogenic and anti-angiogenic agents which, by interrupting the flow of blood to the solid tumor, deprive the cancer cells of their nutrients and cause the cancer cells to stand still. Castration can also be used, which can also prevent androgen-dependent cancers from proliferating. Also included are inhibitors of IGF1R, non-receptor inhibitors, and receptor tyrosine kinases, as well as inhibitors of integrin signaling. Other anticancer agents include: microtubule stabilizers such as paclitaxel (commercial-41 - (38) 1324926 called Taxol®), docetaxel (trade name Taxotere®), Τ Ο - methylthiomethyl Paclitaxel (disclosed in U.S. Patent No. 5, 6 4 6 J 7 6), 4-desylidene-4-methylcarbonate paclitaxel, 3, tert-butyl-3,-N-butoxycarbonyl-4 - Deacetyl- 3'-dephenyl-3'-N-debenzylidene-4-0-methoxycarbonyl-paclitaxel (disclosed in USSN 09/712,352, November 14, 2000) , C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, epothilone D, Deoxy Epothilone A, Deoxy Epothilone B, [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*,] 2R*, 16S*]]-7 -1]-dihydroxy- 8,8,10,12,] 6-pentamethyl-3-[l-methyl-2-(2-methyl-4-thiazolyl)vinyl]-4-nitrogen Hetero-17-oxabicyclo[14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514), [ IS-[ 1R*,3R* (E) , 7R*,10S *, 11R*, 12R*, 16S* -3-[2-[2.(Aminomethyl)-4-thiazolyl]-1-methylvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl -4,17-Dioxabicyclo® [14.1.0] heptadecane-5,9-dione (disclosed in U.S. Patent No. 6,262,094) and derivatives thereof; Agent. Also suitable are: CDK inhibitors; anti-proliferative cell cycle inhibitors; epidophyllotoxin; anti-tumor-forming enzymes; topoisomerase inhibitors; methotrexate; Mit (mitoxantrone): platinum coordination complex (such as cisplatin and carboplatin): biological response modifier; growth inhibitor; anti-hormone therapeutic; leucovorin; special complex Lacy ( Tegafur); and hematopoietic growth (39) (39) 1324926 Other cytotoxic agents include: melphalan, hexamethyl melamine (he X amethy 1 me 1 amine ), thiotepa, rossose (cytarabin), Idatrexate, trimetrexate, dacarbazine, L-aspartame, camptothecin 'topodine' Topotecan), bicalutamide, flutamide, leuprolide, pyridobenzopyrene derivatives, interferon' and interleukins. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as a tablet, a lozenge, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup or It is a tincture. The composition intended for oral administration can be prepared according to any method known to those skilled in the art for the manufacture of a pharmaceutical composition, and if the composition may contain one or more agents selected from the group consisting of: sweeteners, Flavoring agents, colorants, and preservatives provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulation and disintegrating agents (eg 'microcrystalline cellulose, crosslinked carboxylates Methylcellulose sodium, corn starch, or alginic acid); binders (eg, starch, gelatin, polyvinylpyrrolidone or gum arabic); and lubricants (eg, magnesium stearate, stearic acid or talc) ). The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract and thus Provides a continuous effect over the longer 8 -43- (40) 1324926 period. For example, a water-soluble taste masking substance such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed; or a time delaying substance such as ethylcellulose 'acetate-butyrate cellulose. The formulation for oral administration may also be in the form of a hard capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin: or in the form of a soft capsule, wherein The ingredients are mixed with a water-soluble carrier such as polyethylene glycol or an oily substrate (for example, ® peanut oil, liquid paraffin or olive oil). Aqueous suspensions contain the active materials together with excipients suitable for use in the manufacture of aqueous suspensions. If the excipient is a suspending agent, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl-cellulose, sodium alginate 'polyvinyl-pyrrolidone, tragacanth and gum arabic The dispersing or wetting agent may be a natural phosphatidyl ester, for example, lecithin, or a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), or an epoxy epoxide and a long a condensation product of a chain aliphatic alcohol (for example, hepta-(ethylene)oxyhexadecanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example, polyoxygen) Ethylene sorbitan monooleate) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (for example, ethyl or propyl paraben), one or more colorants, one or more flavoring agents, and one or more sweetening agents (such as sucrose, Saccharin or aspartame). The oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (for example, -44 - (41) 1324926 peanut oil, olive oil, sesame oil or coconut oil), mineral oil (such as liquid paraffin). The oily suspensions may contain a tackifier such as beeswax, hard paraffin or wax alcohol. A sweetening agent as described above, as well as a flavoring agent, may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxymethoxybenzene or alpha-tocopherol. Dispersible powders and granules suitable for use in the preparation of aqueous suspensions by the addition of water, containing the active ingredient together with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as exemplified above. Other excipients, such as sweeteners, flavoring agents, and colorants, may also be present. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The pharmaceutical compositions of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, for example, olive oil or peanut oil; mineral oil, for example, liquid paraffin; or a mixture thereof. Suitable emulsifiers may be natural phosphatidic acid esters such as 'soy lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides (eg 'sorbanoic acid monooleate'); A condensation product of a partial ester with ethylene oxide (for example, polyoxyethylene sorbitan monooleate). These emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs can be formulated with sweetening agents (for example, glycerol, propylene glycol, sorbitol or sucrose). If it is a formulation, it may also contain a lubricant, a preservative, a flavoring agent, a coloring agent and an antioxidant. The pharmaceutical compositions of this invention may be in the form of a sterile aqueous solution for injection. -45- (42) 1324926 Among the acceptable excipients and solvents, water, Ringer's solution (R i n g e r s s ο 1 u t i ο η ) and isotonic sodium chloride solution can be used. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion wherein the active ingredient is dissolved in the oil phase. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. Then, the oily solution is introduced into a mixture of water and glycerin' and processed to form a microemulsion. The injectable solution or microemulsion can be introduced into the bloodstream of the patient by topical bolus injection. Further, it is also advantageous to use the solution or microemulsion in such a manner that the circulating concentration of the compound of the present invention can be maintained constant. In order to maintain a fixed concentration, a continuous intravenous delivery device can be utilized. An example of a device is the Deltec CADD-PLUS. ΤΜ. Model 5400 intravenous pump. The pharmaceutical compositions of this invention may be in the form of a sterile, aqueous injectable or oily suspension for administration by muscle and subcutaneous administration. The suspension can be formulated according to known techniques using the appropriate dispersing or wetting agents and suspending agents ® as previously described. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a non-toxic, parenteral acceptable diluent or solvent, for example, in the form of 1,3 butanediol . In addition, it is customary to use sterile, non-volatile oils as a solvent or suspension matrix. For this purpose, any non-irritating, non-volatile oil may be employed, including: synthetic mono- or diglycerides. Further, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of formula I and II can also be administered in the form of a suppository for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-46-(43) 1324926 stimulating excipient which is solid at ordinary temperatures but liquid at the rectal temperature, thus It will melt in the rectum and release the drug. The materials include: cocoa butter, glycerinated gelatin, deuterated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol - for topical administration, emulsifiable concentrates may be used. Ointments, gels' solutions or suspensions, etc. (For the purposes of this application method, the topical application method should include #口口液液和漱液液). The compounds of the present invention can be administered nasally via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, in the form of transdermal patches well known to those skilled in the art. In order to be administered in the form of a transdermal delivery system, the dosage usage must of course be continuous rather than intermittent throughout the dosage regime. The compounds of the present invention may also be delivered in the form of a suppository using a base such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and polyethylene glycol. Fatty acid esters. When a compound of the invention is administered to a human patient, the daily dose is usually determined by the prescribing physician, and the daily dose is usually associated with the age, weight, sex, and response of the individual patient. The severity of the symptoms of the patient varies. If the conjugated product is formulated as a fixed dose, it will employ a compound of the invention in the aforementioned dosage range and other pharmaceutically active agents or therapies within the approved dosage range. The formula I and the guanidine compound may also be administered sequentially, in association with known anticancer agents or cytotoxic agents, when the formulation of the combination -47-(44) 1324926 is inappropriate. The present invention is not limited in the order of administration, and the formula I and the guanidine compound can be administered before or after administration of a known anticancer or cytotoxic agent. Analysis The pharmacological properties of the compounds of the invention can be confirmed by several pharmacological analyses. The compounds of the present invention and their salts have been subjected to the Φ pharmacological analysis exemplified below.

Met kinase analysis

Final concentration of reagent substrate mixture Storage solution Tris-HCl (1M, pH 7.4) 20 mM MnCl2dM) 1 mM DTT (1M) 1 mM BSA (100 mg/ml) 0.1 mg/ml polyGlu4 / tyr (10 mg/ml ) 0.1 mg/ml ATP (1 mM) ΙβΜ γ-ATP (10//Ci//zl) 0.2 μ. Ci/ml -48- 8 (45) 1324926

Buffer enzyme mixture 20 Ail 1MDTT 4 " 1 GST/Met enzyme (3.2 mg/ml) =10ng/rxn 200^1 lMTris-HCl » pH7.4 appropriate amount 12 m] buffer 20 //1 100mg/ml BSA 20 ml H2O

The culture mixture used for Met kinase analysis contains synthetic receptors polyGlu: Tyr (4:1), ATP, ATP-r-33P, and buffers containing Mn++ and/or Mg+' DTT, BSA, and Tris buffers. Agent. The reaction was incubated at 27 ° C for 60 minutes and the reaction was terminated by the addition of trichloroacetic acid (TCA) to a final concentration of 4%. TCA pellets were collected into GF/C microplates (Packard using Filtermate Universal Harvester (Packard Instrument Co., Meriden, CT)

Instrument Co., Meriden, CT) > and the filter was quantified using a TopCount 96-well liquid state flash counter (Packard Instrument Co., Meriden, CT). A dose response curve was made to determine the concentration required to inhibit 50% of kinase activity (IC5Q). The compound was dissolved in dimethyl hydrazine (DMSO) at 10 mM and evaluated in six concentrations, four times each. In the analysis, the final concentration of DMSO was 1%. Using nonlinear regression analysis, IC5G値 was derived and the dispersion coefficient (SD / average 値, n = 6) = 6%. Preferred compounds of the invention inhibit the Met kinase IC5 〇値 between 〇.〇1 to 1 0 0 v 。. The best compound has an IC 5 〇値 less than 0 · 5 V Μ. (46) The present invention also encompasses a medicament for use in the aforementioned uses, including control of cancer, inflammation and arthritis, comprising at least one of Formula 1 and a hydrazine compound as defined above or at least one pharmaceutically acceptable acid plus Salt-forming; also includes the use of a compound of formulas I and II as hereinbefore defined for the preparation of a medicament having activity against the proliferative diseases described above, including cancer, inflammation and/or arthritis. The following examples and preparations are illustrative of the manner in which the invention may be made and used, and are intended to be illustrative and not limiting. As a matter of course, there are other systems that are also in accordance with the spirit and scope defined by the scope of the patent application of the present invention. [Embodiment] The present invention can be further illustrated by the following working examples (which are preferred systems of the present invention). All reactions were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere. All evaporation and concentration operations were carried out under reduced pressure in a rotary evaporator. Commercially available reagents were used directly without further purification. The solvent is a commercially available anhydrous grade and is used directly, not dried or purified. Flash chromatography was performed on sand (Emerck Kieselgel 60, 0.040·0·060 mm). Reverse phase (RP) HPLC was performed on a Phenomenex Luna C18 S5 4.6 mm x 50 mm layer column or YMC S5 ODS 4.6 x 50 mm layer. The column is coming. In each case, a linear gradient of 4 minutes (1 〇〇% A : (47) 1324926 0% B to 0% A : 100% B ) was used, along with the following mobile phase systems: A = 90% water / methanol + 0.2 % Η 3 P 0 4 ; B = 9 0 % Methanol / water + 0.2 % Η 3 Ρ 0 4, flow rate = 4 m L / min, and detected at 2 2 0 nm. Prepare the reverse phase (RP) HPLC using a linear gradient elution (using 10% methanol, 90% water, 0.1% TFA (solvent A), and 90% methanol, 10% water, 0.1% TFA (solvent B) ) and detected at 220 nm and on a layer column of one of the following: A - Shimadzu S5 ODS-_ VP 20 x 100 mm layer column, flow rate = 20 ml / min; B - YMC S5 ODS 30 x 100 mm layer column, flow rate = 20 ml / min; C -Phenomonex 30 x 250 mm layer column, flow rate = 10 ml / min; D - γMC S5 ODS 20 x 250 mm layer column, flow rate = 10 ml / min; £1 YMC S10 ODS 50 x 500 mm layer column, flow rate = 50 ml / min; or F - YMC S10 ODS 30 x 500 mm layer column, flow rate = 20 ml / min

All final products were characterized by 4 NMR, RP HPLC, electron spray ionization (ESI MS) or atmospheric pressure ionization (API MS) mass spectrometry. The 1H NMR spectrum was obtained on a 500 MHz JEOL or 400 MHz Bruker instrument. The l3C NMR spectrum was recorded at 100 or 125 MHz. The magnetic field strength is expressed in 6 units relative to the absorption peak of the solvent (one part per million, ppm), and the weight of the absorption peak is expressed as follows: s, single peak; d, doublet: dd, double peak Doublet; dm, doublet of multiplet; t, triplet; q, quartet; br s, broad singlet; m, multiplet. The following abbreviations are used for commonly used reagents: Boc or BOC: amine Formic acid-51 - (48) 1324926

Third butyl ester; Fmoc: 9H-fluorenylmethyl carbamate; TEA: triethylamine; NMM: methylmorpholine: Ms: methanesulfonyl; DIEA or DIPEA: diisopropylethylamine or Herni Hunig's base ; NMP : N-methylpyrrolidone; BOP reagent: benzotriazol-1-yloxyindole (trimethylamino) hexafluorophosphate; DCC: 1,3 -dicyclohexyl Carbodiimide; EDCI: 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; RT or rt: room temperature; tr: residence time; h: hour; mi η: Minutes; # PyBroP: bromopyridinium hexafluorophosphate; TBTU: bismuth tetrafluoroborate-(1H-benzotriazol-1-yl)tetramethyltetraurea; DMAP: dimethylaminopyridine; HOBt or HOBT: benzotriazole; Na(OAc) 3BH: sodium triethoxy borohydride; H〇Ac: acetic acid; TFA: trifluoroacetic acid; LiHMDS: bis(trimethylmethyl fluorenyl) hydrazine Lithium amine; DMSO: dimethyl sub-milling; MeCN: acetonitrile: MeOH: methanol: EtOAc: ethyl acetate; DMF: dimethylformamide; THF ··tetrahydrofuran; DCE ·· 1,2-dichloroethane ; Et20 · · diethyl ether; DCM · · dichloromethane®; w-CPBA: 4-chloroperoxy Benzoic acid. Example 1

(4-Fluorophenyl)(4-(pyridin-4-yloxy)phenyl)propanediamine Amine -52- (49) 1324926

A) 4-(4-Aminophenoxy)pyridine 4-chloropyridine was treated with 4-aminophenol (Aldrich, 2.1 g, 20.0 mmol) and sodium hydroxide Nine (2.0 g '50.0 mmol). A solution of hydrochloric acid φ salt (Aldrich, 3_0 g' 20.0 mmol) in dimethyl sulfoxide (40 mL) was added and the mixture was heated at 1 ° C for 18 hours. The mixture was cooled to room temperature, poured into an ice-water mixture (30 g) and extracted with diethyl ether (3 X 150 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to afford 4 <RTI ID=0.0>(4-</RTI> <RTIgt; 1H NMR (DMSO-d6) δ 8.38 ( dd, 2H, J = 5.5, 1.5 Hz) » 6.83 -6.79 ( m, 4H ) &gt; 6.63 - 6.5 9 ( m, 2H) &gt; 5.13 ( br s, 2H) ; MS ( ESI+) Φ m/z 187.2 ( M + H ) + 〇

B) 3-(4-Fluorophenylamino)-3-ketopropionic acid

Add monoisopropylethylamine (8.4 mL, 48 mmol) and 4-fluoroaniline (Aldrich' 3.6 mL '38 mmol) to 3·Chloro-3-ketopropionic acid (Aldrich' 5.0 mL' 40 Methyl) a solution of Ot under dichloromethane (1 mL mL (50) 1324926). The reaction mixture was stirred overnight at room temperature and then quenched with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with chloroform (3×1 00 m L). The combined organic extracts were dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> 1 Η NMR ( CDC13 ) δ 9.30 ( br s, 1 H ) ' 7.55 ( m, 2H ) , 7.05 (t, 2H, J = 8.8 Hz) 5 4.28 ( q, 2H, J = 7.2 Hz) , 3.49 • ( s, 2H) &gt; 1 .35 ( t, 3H, J = 7.1 Hz ) ; MS ( ESI+ ) m/z 226.1 1 ( M + H ) + . The above ester was dissolved in 100 mL of ethanol and cooled to 〇 °C. A 1 N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was stirred at 0 ° C for one hour. The reaction solution was concentrated under vacuum to remove ethanol. The aqueous solution was extracted with ethyl acetate (50 mL) and then acidified using 1N aqueous hydrogen chloride. The aqueous solution was extracted with ethyl acetate (5×100 mL). The combined organic extracts were dried <RTI ID=0.0> NMR( OMSO-d6) 6 12.9 ( br s, 1H) &gt; 10.3 ( br s, 1H) « 7.59 (

m, 2H) &gt; 7.16 (t, 2H, J = 8.9 Hz) &gt; 3.34 (s, 2H); MS (ESI+) m/z 1 98.43 ( M + H ) + . C) #-(4-Fluorophenyl)(4-(pyridin-4-yloxy)phenyl)propanediamine with 3-(4-fluorophenylamino)-3-ketopropionic acid ( 99〇^,0.50 -54- (51) 1324926 mmol), DIPEA (1 1 3 y L, 0.65 mmol) and TBTU (209 mg, 0.65 mmol) to treat 4-(4-aminophenoxy) shame A solution of steep (93 mg '0.50 mmol) in DMF was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to remove DMF and the residue obtained was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The ethyl acetate layer was washed with aq. EtOAc EtOAc (EtOAc)EtOAc. 1HNMR(DMSO-ί/¢)(5l0.30 (s, 1Η) &gt; 10.24 ( s, 1 Η ) &gt; 8.43( dd, 2H, J = 5.5, 1.5 Hz) &gt; 7.70 ( d, 2H, J = 9. 1 Hz) , 7.63-7.60 (m, 2H), 7.17-7.14 (m, 4H) &gt; 6.89 (dd, 2H, J = 5.5, 1.5 Hz) » 3.46 ( s, 2H ) ; MS ( ESI+ m/z 365.9 ( M + H ) + » Example 2

-3- (2-(4-Gas 1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenylphenyl)ethionyl)thiourea

N〇2 -55- (52) 1324926 A) 4-Chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine with potassium carbonate (〇·72 g' 5·2 mmo丨) Treatment of 4,6-dichloropyrimidine (Aldrich, 0. 74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Aldrich, 0.79 g, 5.0 mm 〇l) and DMF (10 ml) The mixture 'and was heated at 8 01:' for 3 hours. The mixture was cooled&apos; diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over magnesium sulfate and concentrated to give a crude product as a yellow solid. The crude product was triturated with isopropyl ether to give 4-chloro-6-(2-fluoro-4-n-phenoxy)pyrimidine (1.3 g' 94%) as a yellow solid. 1 H NMR ( DMSO-^β ) 5 8.80 ( s, 1 Η ) ' 8.5 1 ( dd, 1 H, J = 8.6, 2.5 Hz) &gt; 8.31 (d, 1H, J = 9.1 Hz) &gt; 7.87 ( d, 1 H, J ^ 9.1 Hz ) - 7.84 ( s, 1 H ) °

B) 4-Chloro-6-(2-amino-2-fluorophenoxy)pyrimidine was treated with Raney nickel (1.5 g, aqueous slurry) to treat 4-chloro-6- a solution of (2-fluoro-4-nitrophenoxy)pyrimidine (1.3 g, 4.8 mm 〇i) in methanol (120 mL) and under hydrogen blanket (from latex balloons), in a chamber The reaction mixture was stirred for 3 hours at warming. The catalyst was filtered off, the filtrate was concentrated, and the obtained residue was dissolved in dichloromethane and water. The dichloromethane layer was separated, dried (MgSO4) and concentrated. The obtained crude product was purified by flash chromatography on silica gel using (53) 1324926 1 - 2% methanol / dichloromethane as eluent. 6-(2-Amino-2-fluorophenoxy)pyrimidine (600 mg, 52%). 'H NMR (DMSO-heart) δ 8.64 ( s, 1 Η) , 7.39 ( s, 1 Η) , 6.9 7 ( dd, 1 Η, · / = 8.8, 8.8 Hz) ' 6.46 ( d, 1 H, J = 13.1, 2.5 Hz ) « 6.38 ( dd, 1H, 7 = 8.6, 2.5 Hz ) , 5.44 ( br s, 2H ) ; MS ( ESI+ ) m/z 2 4 0 · 0 4 ( M + H ) + ° ❿ C) 1 -(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)thiourea 4-fluorophenyl To a mixture of NaSCN (0-27 g, 3.3 mmol) and ethyl acetate (12 mL) was added and the mixture was stirred at room temperature for 3 min. This mixture was added to a solution of 4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine in 1:1 ethyl acetate/dichloromethane (5 mL), and The resulting mixture was stirred overnight at room temperature. The mixture was concentrated and the residue obtained was dissolved in ethyl acetate / water. The ethyl acetate layer was separated, washed with brine, dried (MgSO4) and evaporated. The title compound (0.85 g, 65%) was obtained. NMR (DMSO-i/d) 5 12.40 ( s, 1 Η ) &gt; 11.81 ( s, 1 Η ) - 8.67 ( s, 1 H ) , 7.90 ( dd, 1 H, J = 12.1, 2.0 Hz ) &gt; 7.62 ( s, 1 H ) , 7.47-7.41 ( m, 2H) , 7.38-7.35 (m, 2H) - 7. 1 7 ( t, 2H, J = 8.8 Hz ) -57- (54) 1324926 ,3.8 1 ( S5 2H) ; MS ( ESI+) m/z 434.8 (M + H) +. Example 3

1-(2-(4-Fluorophenyl)ethenyl)-3-(4-(pyridin-4-yloxy)phenyl)sulfide is 4-(4-aminophenoxy)pyridine ( The title compound was prepared by a procedure similar to that described for the preparation of the compound of Example 2, Compound A. Yield: 10%. 'H NMR(CDC13) &lt;5 12.3 (s, 1Η) &gt; 8.63 ( s, 1 Η ) &gt; 8.49( d, 2Η, J = 6.2 Hz ) &gt; 7.71 ( d, 2H, J = 8.9 Hz ) &gt; 7.3 1 -7.27 ( m, 2H ) &gt; 7.14-7.09 ( m, 4H ) &gt; 6.90 ( dd, 2H, J = 4.8, 1.4 Hz ) , 3.73 ( s, 2H) ; MS (ESI+) m/ z 382.2 (M + H) +. Example 4

(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)(4-fluorophenyl)propanediamine-58- 8 1324926 with DIPEA (24ν I, 0.14 mmol) and TB Butyl U (46 mg, 0.14 mmol) to treat 4· chloro-6-(2-amino-2-fluorophenoxy)pyrimidine (29 mg, 0.12 mmol, Compound B of Example 2), 3 A solution of (4-fluorophenylamino)-3-ketopropionic acid (26 mg, 0.13 mmol, compound B of Example 1) in DMF (1·5 m1). The reaction mixture was stirred overnight at rt EtOAc (EtOAc) (EtOAc) The title compound (35 mg, 78%) was obtained as a white solid. NMR (DMSO·heart) δ 10.49 ( s, 1Η ) &gt; 1 0.25 ( s, 1 Η ) , 8.65 ( s, 1 Η ) , 7.78 (d, 1H, J = 12.1 Hz) , 7.63 - 7.5 7 ( m, 3H • 7.40-7.34 ( m, 2H ) &gt; 7.16 ( t, 2H, J = 8.8 Hz) , 3.48 (s, 2H ) ; MS ( ESI+) m/z 419.12 ( M + H) + . Lu Example 5

N7-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-indole-(4-fluorophenyl)propanediamine with 2Μmethylamine/THF (0.2 mL) to treat #-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-γ-(4-fluorophenyl)propanediamine ( -59- 8 (56) 1324926 100 mg, 0.42 mmol, Example 4) a solution of n-butanol (3 mL), and heated in a small glass bottle with a screw cap at 80 ° C for 12 hours. The mixture was concentrated and purified using preparative HPLC (methanol gradient eluting with 0.1% TFA). The product-containing fractions were lyophilized to give the title compound (60 mg, 34%). 'H NMR(DMSO-i/6) δ 10.58 ( s, 1 Η )&gt; 10.36 ( br s, 2Η ) &gt; 8. 1 9 ( br s, 1 H ) &gt; 7.76 ( d, 1H &gt; Φ J = 12.1 Hz) , 7.64 - 7.62 ( m, 2H ) , 7.36 - 7.27 ( m, 2H) , 7.15 (dd, 2H, J = 8.8, 8.8 Hz) , 5.95 ( br s, 1H ), 3.49 ( s, 2H ) , 2.80 ( s, 3H ) ; MS ( ESI+) m/z 4 14.16 (M + H + ). Example 6

3-(2-Fluoro-4-(3-(4-fluorophenylamino)-3-ketopropylamino)phenoxy)pyrimidin-4-ylaminecarboxylic acid tert-butyl ester a

A) #-(2,4,6-Trimethoxybenzyl)-6-chloropyrimidin-4-amine (57) 1324926 Under ^乞' will be ^-dichloropyrimidine^八丨心丨^丨^, 10.0 mmol ), 2,4,6 · Trimethoxybenzylamine hydrochloride (2.3 3 g, 10.0 mmol) &gt; DIPEA (4.8 mL - 27.7 mmol), and n-butanol (50 m L The mixture was heated for 2 hours. The mixture was cooled, diluted with water (.200 mL) and the precipitated product was collected on a &lt;RTI ID=0.0&gt;&gt; The product was washed with ice water and diethyl ether and dried in vacuo to give a white solid (: 2.8 g, 90%). NMR ( DMSO-heart)^ 8.28 ( s, 1H ), 7.3 8 ( s, 1 Η ) &gt; 6.49 ( s, 1 Η ) * 6.25 ( s, 2Η ) » 4.34 ( s, 2H ) , 3.77 ( s, 9H).

B) 6-(2-Fluoro-4-nitrophenoxy)pyrimidine-4-amine (2,4,6-trimethoxybenzyl)-6-chloropyridinium at 160 ° C a mixture of 4-amine (2.2 g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and 2-methoxyethyl ether (50 m L) was heated 6 〇 hour. The reaction mixture was cooled to room temperature and poured into water (200 mL). The resulting solid was collected, washed with 2M aqueous sodium carbonate and water, and then vacuum dried on a flat-bottomed funnel. The crude product was treated with TFA (20 mL) (40 mL EtOAc). The reaction mixture was concentrated and the residue was taken crystalljjjjjjjjj The ethyl acetate layer was separated, dried (MgSO.sub.4), dried, and purified using flash chromatography using 1-2% methanol/dichloromethane as eluent. Purification of the crude product gave 6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-amine (440 mg &lt;RTI ID=0.0&gt; 'H NMR ( OMSO-d6) 5 8.3 1 ( dd, l H, J = 10.4, 2.5 Hz) ' 8.14 ( dd,]H, = 9.8, 2.0 Hz) , 8.04 ( s, 1 H ) - 7.6 1 ( Dd, 1H, J = 8.3, 8.3 Hz) 7.07 ( s, 2H ), 6.02 ( s, 1 H ) : MS ( ESI+) m/z 251.15 ( M + H) + .

C) 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylaminecarboxylic acid tert-butyl ester 6-(2-fluoro-4-nitrophenoxy group) at room temperature a mixture of pyrimidine-4-amine (43 9 mg, 1.2 mmol), B0C20 (261 mg, 1.2 mmol), • DMAP (10 mg), and THF (10 m) was stirred for 1 hour then in vacuo It was concentrated to give a crude product. Purification of the product by flash chromatography (using 1-2%MeOH/dichloromethane as eluent) afforded 6-(2-fluoro- 4- phenylphenoxy)pyrimidine as a white solid. Tert-butyl 4-aminocarbamic acid (110 mg '26%). 4 NMR ( DMSO-c/tf ) δ 10.59 ( s5 1Η ) , 8.39 ( dd, 1 Η, J = 8.8, 1.1 Hz) &gt; 8.32( dd, 1 H, J = 10.3, 2.4 Hz ) ' 8.15 ( ddd , 1 H, J = 9.1, 2.5, 1.0 Hz ) - 7.67 ( dd, 1H, J = 8.8, 8.8 Hz) - 7.45 ( s, 1H ) &gt; 1 .44 ( s, 9H ) ; MS(ESI+) m /z 3 49.0 8 ( MH ). -62- (59) 1324926

D) 6-(4-Amino-2-fluorophenoxy)pyrimidin-4-ylaminocarbamic acid tert-butyl ester treated with Pt02 for 6-(2-fluoro-4-nitrophenoxy)pyrimidine _4_T-butyl carbamic acid carboxylic acid (11 mg, 0.031 mmol) in methanol (2 mL), and the mixture was stirred under hydrogen (from a latex balloon) for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give 3-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamic acid tert-butyl ester (8 mg, 81%). 4 NMR (DMSO-i/6) 5 1 0.62 ( s, 1 Η ), 8.43 ( d,1 Η, = 2.5 Hz ) &gt; 8.36 ( ^d, 1H, J = 9.8, 2.5 Hz) &gt; 8.36 ( dd , 1 H, J = 9.8, 2.5 Hz) ' 8.20-8.17 (

m, 1H ) &gt; 7.71 ( dd, 1H, J )* 1.48 ( s, 9H ). 8.8, 8.8 Hz)

7.49 ( s, 1 HE) 6-(2-Fluoro-4-(3-(4-fluorophenylamino)-3-ketopropylamino)phenoxy)pyrimidin-4-ylaminocarboxylic acid The third butyl ester was prepared by a procedure similar to that described in the preparation of Compound C of Example 1, from 3-butyl 4-(4-amino-2.fluorophenyloxy)pyrimidin-4-ylaminecarboxylate (8 mg, 0.025 mmol) and (4-fluorophenylamino)-3-ketopropionic acid (6 mg, 0.031 mmol, compound B of Example 1), TBTU (11 mg &gt; 0.034 mmol), DIP EA (6//L, 0.030 mmol). The title compound (10 m, 80%) was obtained as a white solid. 1 Η NMR ( DMS Ο - heart) (5 1 0 · 4 8 ( s, 1 Η ) , 10.46 ( s, 1 Η ) &gt; 10.25 ( s, 1 Η ) &gt; 8.39 ( s, 1H ) &gt; 7.74- 7.77 ( m, 1 H ) , 7.62 ( d: 1 H, J = 5.5 Hz ) , 7.61 (d, 1 H, J = 4.9 Hz ) , 7.3 6-7.3 0 ( m, 2H ) , 7.17-7.13 ( m , 2H ) &gt; 3.48 ( s, 2H ) &gt; 1 .46 ( s, 9H ) ; MS ( ESI+ ) m/z 500.12 ( M + H) + .

Example 7

6-(2-Fluoro-4-(3-(4-fluorophenylamino)-3-ketopropylamino)phenoxy)pyrimidin-4-yl(methyl)aminecarboxylic acid tert-butyl ester

Ch3 A) 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl(methyl)aminecarboxylic acid tert-butyl ester in an ice bath, 6-(2-fluoro-4-) The solution of the third butyl nitrophenoxy)pyrimidin-4-ylaminecarboxylate (Compound C of Example 6, 44 mg, 0.13 -64- (61) 1324926 mmol) in anhydrous DMF (1 mL) was cooled. The spent was treated with 60% sodium hydride (44 mg, 0.16 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was treated with iodomylmethane (1 0 # L s ^ 1 5 mmol) and taken at 0-5 ° C for 1 Torr. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with ice (10 mL) and extracted with ethyl acetate (2×1 () mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the product as a pale yellow solid (3 5 mg, 74%) &lt;1&gt;H NMR (DMSO-Heart) &lt;5 8.5 7 (d, 1 H, J = 1.1 Hz) ' 8.37 (dd, 1 H, J = 9.8, 3.0 Hz), 8 · 1 9 (ddd, 1 H, J = 9.1, 2.5, 1.0) &gt; 7.7 1 ( dd, 1 H, J = 8.8, 8.8 Hz ) &gt; 7.66 ( s, 1H ) ' 3.38 ( s9 3H ) - 1 .5 1 ( s, 9H ) »

B) 6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl(methyl)aminecarboxylic acid tert-butyl ester treated with Pt〇2 (10 mg) 6-(2-fluoro group a mixture of 1,4-nitrophenoxy)pyrimidin-4-yl(methyl)aminecarboxylic acid tert-butyl ester in 1:1 ethanol/methanol (2 mL) and under hydrogen blanket (from latex vapour) The ball was stirred for 2 hours. The reaction mixture was filtered and concentrated to give the desired compound (30 mg, 75%). MS (ESI+) m/z 3 65.1 3 (M + H) +. -65- (62) 1324926 C) 6-(2-Fluoro-4-(3-(4-fluorophenylamino)-3- ketopropenyl)phenoxy)pyrimidin-4-yl The (meth)carbamic acid tert-butyl ester is a procedure similar to that described in the preparation of the compound C of Example 2, from 6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl (Methyl)-tert-butyl butyrate (30 mg, 0.068 mmol), 4-fluorophenylethyl fluorene chloride (Lancaster, 15 mg, Ο. 8 8 m mo 1 ) and N a CN (9 mg, • The title compound was prepared from 0.11 mmol (m. The title compound (30 mg, 83%) was obtained as a white solid. 'H NMR (DMSO-heart) (5 1 2.4 0 (s,

1Η ) &gt; 1 1 .79 ( s, 1 Η ) &gt; 8.5 5 ( s, 1 Η ) &gt; 7.86 ( dd, 1H, J = 12.1, 2.5 Hz ) , 7.54 ( d,1 H, J = 1.1 Hz &gt; 7.45-7.35 (m, 4H), 7.20-7.14 (ddd, 2H, J = 8.8, 8.8, 2.1 Hz) 3.81 ( s, 2H ) &gt; 3.36 ( s, 3H ) &gt; 1 .49 ( s , 9H) ; MS (Scent ESI+) m/z 5 3 0.09 (M + H) +. Example 8

Η H

H 1-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)thiourea- 66-(63) 1324926 6-(2-Fluoro-4-(3-(4-fluorophenylamino)-3) was treated with 4M HCl (3 mL in 1,4-dioxane) -ketopropionylamino)phenoxy)pyrimidin-4-yl(methyl).-tert-butyl carbamate (Example 7, 25 mg &gt; 0.04 7 mmol), stirred at room temperature for 4 hours And concentrated in vacuo. The residue obtained was dissolved in saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer was separated, dried (MgSO4) and concentrated in vacuo. The title compound (10 mg, 50%) was obtained as a white solid. 4 NMR (DMSO-heart) δ 12.37 (

s,lH) ,11.77 (S,1H) » 8.09 ( s, 1Η ) - 7.82 ( d, 1H, J = 11.6 Hz) ' 7.41-7.35 (m,5H) ,7.32-7.28 (m,lH), 7.1 9-7.14 ( m, 2H ) &gt; 3.81 ( s, 2H ) , 2.78 ( s, 3H); MS ( ESI+) m/z 430.07 ( M + H ) + . Example 9

1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4.fluorophenyl)ethenyl)thiourea-67- (64) 1324926

N〇2 A) 6-(V, tert-butoxycarbonyl)amino-4-(2-fluoro-4-nitrophenoxy)pyrimidine

6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-amine (Compound B of Example 6, 150 mg, 0.60 mmol), B0C20 (277 mg, 1.26) A mixture of mmol), DMAP (5 mg) and THF (20 mL) was stirred for 2.5 hours. The reaction mixture was concentrated under vacuum to give a crude material. The title compound (180 mg, 67%) was obtained as a white solid. h NMR (DMSO-d6) δ 8.62 ( d, 1 Η &gt; J = 1.0 Hz) , 8.42 - 8.3 9 ( m, 1 H ), 8.2 1 (ddd, 1H, J = 9.1, 2.5, 1.0 Hz) &gt; 7.77 ( dd, 1H, J = 8.8, 8.8 Hz ) &gt; 7.49 ( d, 1 H, J = 1.1 Hz ) &gt; 1.49 ( s, 1 8H ); MS ( ESI+ ) m/z 451.12 ( M + H ) +.

B) 6-(Di-tert-butoxycarbonyl)amino-4-(4-amino-2-fluorophenoxy)pyrimidine-68-(65) 1324926 Treated with Pt20 (35 mg) 6-(brother Di-tert-butoxycarbonyl)amino-4-(2-fluoro-4-nitrophenoxy)oxime (175 mg, 0.38 mmol) in toluene (5 m L) and methanol (3 m L ) The resulting mixture was stirred under a blanket of hydrogen (from a latex balloon) and the reaction mixture was stirred for 15 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo, and the residue obtained was purified by flash chromatography (using 1-10% methanol/dichloromethane as eluent) on cerium oxide. Purification gave the product as a white y color (110 mg, 68%). 4 NMR (DMSO-heart) 0 8.56 ( s, 1Η ) &gt; 7.1 7 ( s, 1Η ) &gt; 6.97 ( dd, 1H, J = 8.8, 8.8 Hz) ' 6.46 ( dd5 1H, J = 12.6, 2.5 Hz &gt; 6.38 ( dd, 1 H, J = 8.8, 2.5 Hz ) , 5.40 (s, 2H) , 1.89 ( s, 18H).

C) 1-(4-( W · bis 3 -butoxycarbonyl 6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)-3 -(2-(4-Fluorophenyl)ethinyl)sulfide gland using the procedure of Preparation of Compound C of Example 2, similar procedure, from di-tert-butoxycarbonyl)amino-4-(4- Amino-2-fluorophenoxy)pyrimidine (20 mg, 0.048 mmol), 4-fluorophenylethylidene chloride (Lancaster, 10 mg, 0.062 mmol), and N a SCN (9.5 mg, 0.062 mmol) (In ethyl acetate / dichloromethane) to give the title compound. The title compound (23 nig, 7 7 ) was obtained as a white solid. EtOAc (EtOAc) %). 'H NMR ( DMSO-i/fi ) δ 12.40 ( s, 1 Η ) &gt; 1 1 .79 ( s, 1 Η ) &gt; 8.5 9 ( s, 1 Η ) &gt; 7.88 ( dd, 1 Η, J = 12.5, 1.8 Hz) &gt; 7.46-7.41 (m, 2Η) , 7.38-7.35 (m, 3H ) » 7. 1 7 ( dd, 2H, J = 8.8, 8.8 Hz ) , 3.81 (s, 2H), 1 .47 ( s, 1 8H ) ; MS ( ESI4 ) m/z 6 16.12 ( M + H ) +. φ D) 1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)thiourea at room temperature Next, 1·(4-(di-tert-butylcarbonyl 6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl) A mixture of thiourea (18 mg, 0.029 mmol) and 4M HCl (1.5 mL in dioxane) was stirred for 18 hours and then concentrated to give a crude product. The crude product was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was separated, dried (MgSO.sub.4), EtOAc (EtOAc) Φ* gives a standard compound (1 2 mg -9 9%) in white solid form. 1H nmr ( DMSO- d6 ) δ 12.38 (s, 1H ) j 11.77 (s, 1H ) ' 8. 〇5 ( s, 1H ) , 7 • 83 (dd, 1H, J = 1 2. 3, 1.8 Hz ) &gt; 7.41- 7. 35 ( m, 3H ) , 7 • 3 1 (dd, 2H, «7=8 • 8 , 8.8 Hz) * 7.17 ( t, 1H, J = 8.8 Hz ) 9 7.02 ( :s, : 2H ), 5 .89 ( s ,1 H) &gt; 3.8 1 (s,2H) ; MS (ESI+) m/z 416.06 (M + H) + 〇1324926

Example 1G H2N n

f - (4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-indole-(4-fluorophenyl)propanediamine

Α)-(4-(brother #-di-tert-butylcarbonyl 6-aminopyrimidin-4-yloxy). 3-fluorophenyl)fluorophenyl)propanediamine is used in the same manner as in Example 1. A similar procedure as described in the preparation of Compound C, from 6-(#,iV-di-t-butoxycarbonyl)amino-4(4-amino-2-fluorophenoxy)pyrimidine Example 9 Compound Β, 20 mg, 0.048 mmol), 3-(4-fluorophenylamino)-3-mercaptopropionic acid (Compound B of Example 1, 14 mg * 0.072 mmol), DIPEA (12&quot; L, 0.069 mmol) of the mixture formed in DM F, the title compound can be prepared by flash chromatography on cerium oxide (using 15-50% ethyl acetate/hexane as eluent). The title compound (2 3 mg, 80%) ° 'H NMR ( DMSO-^6 ) δ 10.47 ( s5 1 Η ), 10.24 ( s, 1 Η ) · 8.58 ( d, 1 Η, J = 1 Hz ) , 7.77 (dd, lH, -71 - (68) 1324926 J = 12.9, 1.8 Hz) &gt; 7.63 - 7.60 ( m5 2H ) &gt; 7.3 7- 7.3 6 ( m, 2H) &gt; 7.32 ( s, 1 H ) - 7.1 5 ( t, 2 H , J = 8.8 H z ) &gt; 1.47( s, 18H) ; MS ( E S1+ ) m/z 600.17 ( M + H) + . B) 〆_(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenylfluorophenyl)propanediamine is similar to that described in the preparation of the compound D of Example 9. Procedure φ, from; V-1-(4-(di-tert-butylcarbonyl 6-aminopyrimidin-4-yloxy)-3-fluorophenyl)-#-3-(4·fluorophenyl) The title compound (13 mg, 98%) was obtained as a white solid. NMR (DMSO-A) δ 10.42 ( s, 1 Η ) ' 1 0.24 ( s, 1H ) &gt; 8.03 ( s, 1H ) &gt; 7.73 ( d, 1H, J = 11.0 Hz) , 7.61 ( dd, 2H, J = 9.2, 4.9 Hz ) , 7.3 3 -7.3 0 ( m, 1 H ) - 7.2 8- 7.23 ( m, 1H ) - 7.18-7.13 ( m, 2H ) , 6.89 ( s, 2H ) , 5.80 ( s, 1H ), 3.47 ( s, 2H) ; MS ( ESI+ ) m/z 400.09 ( M + H) + . Example 1 1

1-(4-(6-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3.fluorophenyl-72-(69) 1324926 )-3- (2-(4-fluoro Phenyl)ethinyl)urea

A) #-(4-Methoxybenzyl)-6-chloropyrimidin-4-amine 4,6-dichloropyranidine (Aldrich, 3-6 g, 24.2 mmol),

A mixture of 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), and n-butanol was heated to reflux for 3 hours. The mixture was concentrated, and the obtained residue was purified mjjjjjjj The ethyl acetate layer was separated, washed with EtOAc EtOAc m. 4 NMR ( 7.25 ( d, 6.56 ( s, DMSO-ί/δ ) (5 8.29 ( s, 1 Η ) - 8.13 ( br s, 1 Η ) 2H, J = 8.2 Hz ) , 6.90 ( d, 2H, J = 8.2 Hz) 1 H ) , 4.48 ( s, 2H ) , 3.75 ( s, 3H ).

B) #-(4-Methoxybenzyl)-6-(2-fluoro-4-nitrophenoxy)pyrimidine-4-amine in a sealed pressure bottle at 1 60 ° C #-(4-Methoxybenzyl)-6-chloropyrimidin-4-amine (2.3 g, 9.2 mmol), 2-fluoro-4-nitro-73- 8 (70) 1324926

A mixture of the base acid (1.45 g, 9.2 mmol), DIPEA (15 mL), and 2-methoxyethyl ether (75 mL) was heated for 5 hrs. The mixture was cooled, poured into EtOAc (EtOAc)EtOAc. After vigorous stirring for 10 minutes, the insoluble matter was filtered off. The ethyl acetate layer was washed with a saturated aqueous solution of sodium carbonate (100 mL), brine (3×100 mL) and evaporated. The title compound ( 1.75 g, 7 6%) was obtained as a brown solid. </ br> NMR ( DMSO-i/i) δ 8.32 ( dd, 1H, J =10.2 , 2.0 Hz ) , 8.15 ( d, 2H, J = 9.2 Hz ) , 8.05 ( br s, 1H ) , 7.61 ( dd, 1H, J = 8.4, 8.4 Hz ) ' 7.26 ( d, 2H, J = 8.5 Hz ) &gt; 6.9 1 ( d, 2H, J = 8.5 Hz ) &gt; 6.14 ( br s, 1H ) '4.48( br s, 2H ) , 3.74 ( s, 3H ).

C) (4-Methoxybenzyl)·6-(4-Amino-2-fluorophenoxy)pyrimidine-4-amine with ammonium chloride (0.22 g, 4.1 mmol) and zinc powder (&lt;&gt; 20 ren, 0.27 g, 4.2 mmol) for the treatment of #-(4-methoxyloxy)-6-(2.fluoro-4-n-phenoxy)pyrimidin-4-amine (150 mg, 0.41 mmol A solution of 1:1 methanol / ΤΗ F (20 mL). The reaction mixture was stirred at room temperature for 1 hour. An additional portion of zinc powder (150 mg) was added to -74-8 (71) 1324926 to the mixture, and the reaction mixture was stirred at room temperature for 1 hour and at 7 CTC for 20 minutes. The mixture was filtered to remove the inorganic solid, concentrated in vacuo, and the residue obtained was partitioned between ethyl acetate and brine. The title compound (145 mg, 99%) was obtained eluted eluted eluted NMRC DMSO-i^) &lt;5 8.1 0 ( br s, 1 Η ) , 7.76 ( br s, 1 H ) , 7.2 1 ( d, 2H, J = 8.6 Hz), • 6.88 ( d, 3H, J = 8.6 Hz ), 6.44 ( dd, 1H, J = 12.7, 2.0

Hz) , 6.36 ( dd, 1H, J = 8.3, 2.3 Hz ) , 5.79 ( s, ] H ), 4.41 ( br s, 2H ) - 3.73 ( s, 3H ) ; MS ( ESI+ ) m/z 341.18 (M + H) +.

D) 2-(4-Fluorophenyl)ethenyl isocyanate

Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq.) was added to 4-fluorophenylacetic acid chloride (Lancaster, 0.794 ml, 5.79 mmol, 1.0 eq.) in toluene (16 m EtOAc) at room temperature. In solution. The reaction mixture was shielded from light and heated to reflux. After 60 minutes, the mixture was cooled to room temperature and filtered (Acrodisc &gt; PTFE 0.2 / / Μ) to obtain a 0.36 M solution of 2-(4-fluorophenyl)ethenyl isocyanate in toluene. It can be used directly without purification E) 1-(4-(6-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluoro75 8 (72) 1324926 phenyl)-3 -(2-(4-Fluorophenyl)ethenyl)urea was treated with 2-(4-fluorophenyl)ethenium isocyanate in 0.36 M solution (0.72 mL, 0.26 mmol) in toluene. a solution of 4-methoxybenzyl)·6·(4-amino-2-fluorophenoxy)pyrimidine-4-amine (88 mg, 0.26 mmol) in THF (2 mL) The reaction mixture was stirred for 1 hour at room temperature. The title compound (25 mg '93%) was obtained as a white solid. NMR (DMSO-i/(5) &lt;5 11.00 (s, 1H) &gt; 10.50 (s, 6.88), 8_09 (s, 1H), 7.85 (br s, 0.5H) &gt; 7.66 (d, 1H, J = 12.6 Hz) &gt; 7.36-

7.15 ( m, 9.5H ) , 6.88 (d, lH, "7 = 8.1Hz), 5.91 (s, lH ) '4.42 (br s, 2H) , 3.72 (s, 2H), 3.71 (s, 3H); MS ( ESI+) m/z 520.1 4 (M + H) +. Example 1 2

Using -(4-(6-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)(4-fluorophenyl)propanediamine as the compound of the example Preparation of C is a similar procedure from; V·(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidine--76- 1324926 4 -amine ( Compound C of Example 11, 200 mg '0.59 mmol), 3-(4-fluorophenylamino)-3-ketopropanoic acid (Compound B of Example 1, 128 mg '0.65 mmol), TBTU (228 The title compound was prepared in mg <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The obtained crude product was purified by EtOAc (EtOAc m. ) - 7.85 ( s, 1 Η ) - 7.72 ( dd, 1H, J = 9.1, 5.0 Hz) &gt; 7.62 ( dd, 2H, J = 8.8, 5.0Hz ) &gt; 7.31-7.21 (m, 4H ) , 7.15 ( dd, 2H, J = 8.8, 8.8 Hz) &gt; 6.88 ( m, 2H ) , 5.90 ( s, 1 H ) &gt; 4.42 ( br s, 2H ) , 3.71 ( s, 3H ) , 3.46 ( s, 2H MS ( ESI+ ) m/z 520.1 4 (M + H) +. Example 1 3

H2N N 1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

A). Procedure for V-(3-fluoro-4-hydroxyphenyl)acetamide-77-(74) 1324926 1 948,7(7,1 3 63 ), from commercially available 2-fluoro- The title compound was prepared from 4-nitrophenol. Nitrophenol (5.73 g, 36.5 mmol) and acetic anhydride ( 3.72 g' 36.5 mmol) were dissolved in acetic acid (20 mL), then Pt 〇 2 (150 mg) was added. The reaction mixture was shaken for 24 hours under a hydrogen atmosphere (50 psi) at room temperature. The resulting precipitate was collected by vacuum filtration, and the filter paper was washed with acetic acid (25 mL). The filtrate and the washing solution of φ hydrazine were concentrated in vacuo to give the title compound (2·0 g). The solid remaining on the filter paper was treated with methanol to dissolve the product and filter out Pt02. The filtrate was concentrated in vacuo and EtOAcqqqqqqqqq WNMRC DMSO-heart) 59.83 (s, 1 Η ) , 9.51 ( s, 1 Η ) , 7·50 ( dd, 1 Η, "/= 13.6, 2.5

Hz) , 7·03 ( d, 1H, "7 = 8.5Hz) « 6.84 ( dd, 1H, J = 9.3,

9.3 Hz), 1.98 (s, 3H); MS ( ESI+) m/z 1 70.23 ( M + H

B) #·(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamidine 4,6-dichloropyrimidine (1.50 g, 10.0 mmol) at 701: , #-(3-Fluoro-4-hydroxyphenyl)acetamide (1.70 g, 10.0 mmol), K2C03 (1.8 g &gt; 13.0 mmol), and DMF (15 mL) mixture (75) 1324926

The object was heated for 1.5 hours. The mixture was concentrated to half its original volume and allowed to cool in an ice bath. The mixture was treated with water (100 mL) to precipitate a product, and the product was collected by vacuum filtration. The product was washed with EtOAc (EtOAc)EtOAc. A NMR (DMSO-i/d) δ 10.26 ( s, 1 Η ) · 8.6 7 ( s, 1 Η ) &gt; 7.78 ( dd, 1H, J = 12.6, 2.0 Hz) · 7.56 ( s: 1H) &gt; 7.3 7-7.3 0 (

^ m, 2H ) &gt; 2.08 ( s, 3H ) ; MS ( ESI+) m/z 2 82.1 0 ( M + H , +

C) #-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamide

#-( 4_( 6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamidamine (1.0 g, 3.5 mmol) in a sealed pressure flask at 100 ° C A mixture of about 7 M of NH3 (5 mL) in methanol was heated for 2 hours. The mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was separated, washed with brine, dried (sodium sulfate) and concentrated. The title compound (175 mg, 20%) was obtained as a brown solid. . 4 NMR ( DMSO-^d ) ό 10-17 ( s, 1H ) &gt; 8.02 ( s, 1H ) · 7.70 ( dd, -79- (76) 1324926 1H, J = 13.2, 2.2 Hz) &gt; 7.26 ( Dd, 1H, J = 8.8, 2.2 Hz), 7.22 ( dd, 1H, J = 8.8, 8.8 Hz), 6.89 ( br s, 2H ), 2.05 ( s, 3H ) ; MS ( ESI+ ) m/z 263.1 5 ( M + H ) +.

NH2

D) 6-(4.Amino-2-fluorophenoxy)pyrimidine-4-amine;V-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl) A mixture of acetaminophen (175 mg, 0.67 mmol), 1M HCl (6 mL), and methanol (2 mL) was refluxed for 3 hours. The reaction mixture was cooled, made basic with aqueous sodium carbonate and extracted with ethyl acetate (2×25 mL). The combined extracts were dried (MgSO.sub.sub.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsubsub s, 1H ) ' 6.89 ( dd, 1H, J = 9.0, 9.0 Hz ) , 6.80 ( br s, 2H ) , 6.43 (dd, 1 H, J = 12.7, 2.8 Hz ) &gt; 6.35 ( dd, 1 H, J = 8.8, 2.2

Hz), 5.67 (s, 1H), 5.34 (brs, 2H). E) 1-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea as in Example I above 1 , from 6-(4-Amino-2-fluorophenoxy)oxime-4-amine (92 mg, 0.42 mmol) and 2·(4-fluorophenyl)ethenyl isocyanate The title compound was prepared as a solution of EtOAc EtOAc (EtOAc: EtOAc: EtOAc: The obtained crude product was purified by tanning with 1:1 ethanol/water and absolute ethanol. The title compound (1 〇〇 mg, 60%) was obtained. By extracting the combined filtrate and washing with ethyl acetate, the second batch of the less pure product (45 mg &gt; 2 7%) oiHNMRCDMSO-^) δ 10.99 ( s, 1 Η ) - 10.50 (s, 1 Η ) , 8.01(s,1 Η ) &gt; 7.65 ( dd, 1H, J = 12.6, 2.1 • Hz) - 7.33 ( dd, 2H, J = 8.1, 6.0 Hz ) - 7.28 ( dd, 1H, J = 8.6, 2.0 Hz) &gt; 7.22 ( dd, 1H, J = 8.8, 8.8 Hz ) , 7.17-7.1 2 ( m, 2H ) &gt; 6.89( br s, 2H ) - 5.80 ( s, 1H ) &gt; 3.71 ( s, 2H) ; MS ( ESI+ ) m/z 400.09 ( M + H ) + . Example 1 4

A^_(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)(4-fluorophenyl)propanediamine

A) 2-Chloro-4-(2-fluoro-4-nitrophenoxy)pyrimidine-81 - 8 (78) 1324926 2,4-dichloropyrimidine (Aldrich, 0.74) at loot: g,

A mixture of 5 - 〇 mmol), 2-fluoro-4-n-nitrophenol (Avacado, 0.79 g, 5.0 mmol) 'K2C03 (0.76 g &gt; 5.5 mmol), and DMF (50 mL) was heated for 2 hours. The mixture was cooled and diluted with a saturated sodium hydrogen carbonate solution (100 mL) and then extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO.sub.sub.sub.sub.sub.sub.sub. . The title compound was obtained as a white solid (yield: 7 1 g, 5 3). %). 1 Η NMR (DMSO-heart) δ 8.76 ( dd, 1H, J = 6.0, 1.6 Hz) ' 8.43 ( dt5 1H, J = 9.8, 2.2 Hz ) &gt; 8.23 ( dd, 1H, J = 8.8, 1.6 Hz ) &gt; 7.80( dt, 1 H, J = 9.8, 2.2 Hz ) &gt; 7.48 ( dd, 1 H, / = 6.0, 2.2 Hz ).

B) AN (4-methoxybenzyl)-4-(2-fluoro-4-n-phenoxy)pyrimidin-2-amine 2-Chloro-4-(2) at 100 °C -fluoro-4-nitrophenoxy)pyrimidine (0.66 g, 2.44 mmol), 4-methoxybenzylamine (〇·34 g' 3.45 mmol), K2 C Ο 3 ( 〇. 3 7 g, 2 · 6 6 g ) ' and DMF (15 (79) 1324926 mL) were diluted and extracted with ethyl acetate (100 mL). The organic phase was washed twice with saturated sodium bicarbonate solution and water, respectively. The organic material was dried (MgSO.sub.4) and concentrated to give crude material. The title compound (2 7 5 m g ' 2 9 %) was obtained as a pale yellow solid (yield: EtOAc). 'H NMR ( DMS O-i/d ) &lt;5 8.40-8.21 (m, 2H) ' 8.16 ( dd, 1 H, J = 8.8, 1.7 Hz ) ' 7.98 (br s, 0.5H) , 7.73 - 7.55 (

m, 1.5H), 7.16( br s,1H) * 6.85-6.71 (m, 3H) 1 6.37 (s,1H) , 4.43 (br s, 1H) ' 3.95 ( br s, 1 H ) ' 3.69( s , 3H).

% 〇#-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyridin-2-amine is similar to that described in the section C of the compound of Example 的Procedure, using strontium powder (475 mg, 7.3 mmol) and chlorinated money (387 mg, 7.3 mm 〇l) (in 20 mL of 1:1 THF / methanol), #- (4-methoxyl group) The title compound was prepared by the reduction of -4-(2-fluoronitrophenoxy)pyrimidine-2-amine (270 mg, 0.73 mmol). Flash chromatography on silica sand (using 1-3% methanol/dichloromethane as the eluent) gave the title compound as a brown film. 1H NMR (-83-(80) 1324926 DM SO-i/6) δ 8.01 (s, 1 H) &gt; 7.65 (br s. 0.5 H) &gt; 7.49 C br s, 0.5H ) &gt; 7.08 ( brs , 1 H ), 6.83 (br s , 2H ) , 6. 8 1 ( m . 1 H ) , 6.69 (br s , 2H ) , 6. 39 ( br s, 0.5H ) &gt; 6.3 1 ( br s, 0.5H ) &gt; 1 5.0 1 ( m, 1 H ), 5.26 (br s , 2H ) , 4. 2 4 ( br s, 1H ) , 3. 95 ( brs 1 H ) , 3.6 1 ( s, 3H) ; MS ( ESI+ ) m/z 34 1 . 1 6 ( M + H ) + . φ D) #-(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-A^-(4-fluorophenyl)propanedifluoride The amine was subjected to a procedure similar to that described in the preparation of the compound C of Example 1, from ΑΓ-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyran Diethylamine (34 mg, 0.10 mmol), 3-(4-fluorophenylamino)-3-ketopropionic acid (Compound B of Example 1, 22 mg ' 0.11 mmol), TBTU (39 mg The title compound was prepared from EtOAc (EtOAc:EtOAc) The title compound (35 mg, 6 1%) was obtained as a white solid. NMR ( DMSO-i/6 ) δ 10.47 ( br s,lH) &gt; 1 0.26 ( s, 1 H ) &gt; 8. 1 5 ( s, 1 H ) &gt; 7.77 ( m, 3H ) • 7.61 ( m , 2H ) , 7.3 5 -7.2 5 ( m, 2H ) &gt; 7.15 ( dd, 2H, J = 8.8, 8.8 Hz) , 6.81-6.73 (m, 2H) &gt; 6.24 ( s, 1H ) &gt; 4.32 ( Br s, 1 H ) , 3.96 ( br s, 1 H ) , 3.68 ( s, 1H ), 3.48 ( s, 2H ) ; MS ( ESI+) m/z 520.14 ( M + H) + . Example 1 5 -84- (81) 1324926

^(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetamid)urea

Treating #-(4-methoxybenzyl) with a solution of 0.36M of 2-(4-fluorophenyl)ethenyl isocyanate in toluene (Example Compound D, 0.31 mL '0.1 1 mmol) 4-(4-Amino-2-fluorophenoxy)pyrimidine-2-amine (Compound C of Example 14, 3 4 mg, 0 · 10 mmol) in THF (1 mL) The solution was stirred at room temperature for 1 hour. The title compound was obtained as a white solid. m. 1Η NMR (DMSO-heart) δ 10.47 ( s, 1 Η ) , 10.26 ( s, 1 Η ), 8.15 ( s, 1 Η ) , 7.76 ( d, 1H, J = 12.6 Hz) , 7.61 ( dd, 3H, J = 9.1, 5.0 Hz ) &gt; 7.29 ( s, 2H ) &gt; 7.31-7.21 (m, 3H )&gt; 6.8 1 ( s, 3H ) &gt; 6.24 ( s, 1H ) &gt; 4.32 ( s, 1 H ) , 3.96 (s, lH), 3.68 (s, 3H) &gt; 3.48 ( s, 2H ) ; MS ( ESI+ ) m/z 520.1 4 ( M + H ) + . Example I 6 -85- (82) 1324926

F H2N ( 4- ( 2-aminopyrimidin-4-yloxy)-3-fluorophenyl)-#- (4-fluorophenyl)propanediamine

#-(4-(2-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-(4-fluorophenyl)propane at 85 °C Indoleamine

A solution of the fluorobenzene (52 mg, 0.48 mmol) in TFA (1 mL) was stirred for 6 hr. Under vacuum, the TFA was removed and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was washed with brine, dried (MgSO4) and evaporated. The title compound (1 2 mg, 6 3%) o' was obtained as a white solid. HNMRCDMSO-A) &lt;5 11.00 (s,1 Η ) , 10.51 ( s, 1 Η ) &gt; 8.02 ( s, 1Η ) &gt; 7.66 ( dd, 1 H, J = 12.6, 2.0 Hz ), 7.42-7.3 1 ( m, 2H ) &gt; 7.3 2- 7.2 7 ( m, 1H ) , 7.23 ( t,

2H, J = 8.6 Hz ) , 7.16 ( t, 2H, J = 9.1Hz) &gt; 6.91 ( s, 2H )-3.73 ( s, 2H ) ;MS(ESI+)m/z400.11 (M + H)+ . Example 1 7 -86 - 8 (83) 1324926

1-(4-(2-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluoro.phenyl)ethenyl)urea

A procedure similar to that described in Example 16 was followed by 1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3- (2-(4-Fluorophenyl)ethinyl)urea (Example 15, 20 mg, 0.039 mmol). The title compound (&gt; 〇 mg, 62%) was obtained as a white solid. 'H NMR ( DMSO-Jtf) δ 11.01 ( s, 1H) &gt; 1 0.52 ( s, 1 H ) &gt; 8.20 ( d, 1 H, J = 6.0 Hz ) , 7.70 (dd, 1H, · / = 12.1 , 2.0

Hz) , 7.3 6-7.3 0 ( m, 6H) &gt; 7.16 ( dd, 2H, J = 8.8, 8.8 Hz) &gt; 6.45 ( d, 1 H, J = 6.1Hz) &gt; 3.73 ( s, 2H ) MS ( ESI+ ) m/z 400.09 ( M + H ) +.

-87- (84) 1324926 W -( 3 -Fluoro-4 -( 2 -( 2 ·morpholylethylamino)pyridin-4-yloxy)phenyl)-Λ^-(4_Fluorine Phenyl) propylenediamine, hydrochloride

CH3 A) iV-( 4-(2-chloropyridine-4-yloxy)-3-fluorophenyl)acetamide

At 100. (:, #-(3-Fluoro-4-hydroxyphenyl)acetamide (Compound A of Example 13, 1.33 g, 7.87 mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24 g, 7.87 mmol), a mixture of K2C03 (1.6 g' 11.8 mmol), and DMF (25 mL) was heated for 9 hours. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate. Ester and saturated sodium bicarbonate solution. Wash the ethyl acetate phase with brine, dry (magnesium sulfate) and concentrate. Perform rapid chromatography (using 30-80% acetic acid / hexanes as a decanting agent) The title compound (1.6, DMSO-7.89-7.64 (m, 1H, 2.06 ( s, 3H) 8 ' 7 3%) (s, ih ), 9 ( m, 2H ) D6 ) δ 10.24 ( s, 1H) &gt; 8.65 ) '7.56 ( s, 1 H ) &gt; 7.46-7. j ;MS ( ESI+ ) m/z 28 1 . 1 6 ( M + H ) +

(85) 1324926 B ) TV-(4-(1-Oxidation 2-chloropyridin-4-yloxy)·3-fluorophenyl)acetamide in the chamber, in the prison & under the dish&gt; 4-(2-Chloropyridine. -4 -oxy)· 3-fluorophenyl)acetamide (0.98 g - 3.5 mmol), m-chloroperoxybenzoic acid (&gt;90%, 1, 3 The mixture of g, 7.6 mmol) and CHC13 (50 m L) was stirred for 60 hours. The title compound (0.89 g &gt; 8 7%) was obtained as a pale yellow solid. 1 Η NMR (DMSO -d6 ) (5 10. ,25 ( s, 1H ) , 8. 34 ( d, 1 Η, J = Ί. 1 Hz ), 7.80 (d, 1 H, J = 13.2 Hz ) , 7 . 49 ( d, 1H, J = 3, .3 Hz ), 7.33 (d, 2Η, J r = 4.9

Hz), 7.02 (dd, lH, J = 7.1, 3.3 Hz) &gt; 2.06 (s, 3H) MS (ESI+) m/z 295.04 (M-H).

C) #-(3-Fluoro-4-(1.Oxidation 2-(2-morpholineethylamino)pyridin-4-yloxy)phenyl)acetamidine #-(4-( 1-Oxo-2-chloropyridin-4-yloxy)-3.fluorophenyl)acetamidamine (205 mg, 0·62 mmol), 4-(2-aminoethyl)morpholine (Aldrich A mixture of 169 mg, 1.30 mmol) and absolute ethanol was heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo, and the obtained residue was taken with water (3 mL) and applied to 1 〇 g 8 (86) 1324926

Vairan C-l 8 filter cartridge. The filter cartridge was eluted with water and 30% methanol (in water). Fractions containing the desired product were collected and concentrated to a volume of 5 mL and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) NMR (DMSO-heart) δ 10.22 ( s, 1 Η ) -7.84 ( d, 1 Η, 7 = 6. 1 Hz ) &gt; 7.77 ( dd, 1 H, J = 13.2, 2.2

Hz ) &gt; 7.3 1 ( dd, 1Ή, J = 8.8, 2.2 Hz ) ' 7.2 4 ( t,1 H,/ = 8.8 Hz), 6.41(m,lH) &gt; 6.1 3 ( dd, 1 H, J = 5.5 , 2.2 H z ), 5.81 ( d,1H, J = 2.2 Hz) , 3.60-3.52 ( m, 4H )-3.3 1 -3.28 ( m, 2H ) , 2.38 ( t, 2H, J = 7.1 Hz ) &gt; 2.34 (

m, 4H ) , 2.06 ( s, 3H ) ; MS ( ESI+) m/z 405.22 ( M + H \ +

D) (3-Fluoro-4-(2-(2-norfosylethylamino)pyridin-4-yloxy)phenyl)acetamidamine, trifluoroacetate at 135 ° C 'will (3-fluoro-4-(2-oxo-2-(2-morpholine)ethylamino)pyridin-4-yloxy)phenyl)acetamide (1 mg, 0.26 mmol), and A mixture of triphenylphosphine polymer (1.4-2.0 mmol/g) and DMF (2 mL) on polystyrene (500 mg) was stirred for 15 hours. The mixture was filtered to remove the resin and used DMF and ethyl acetate

Wash the resin. The filtrate and washings were combined and concentrated. The title compound (45 mg, 46%) NMR (OMSO-d6) δ NMR ( OMSO-d6) δ NMR ( OMSO-d6) δ 10.33 ( s, 1 Η ) &gt; 8.02 ( d5 1H, J = 6.6

Hz) , 7.84 ( dd, 1H, J = 13.2, 2.0 Hz) - 7.39-7.31 (m, 2H ) &gt; 6.52 ( s, 1 H ) &gt; 6. 1 0 ( s, 1 H ) , 3.83 (brs , 4H) * 3.64 ( m, 2H ) , 3_28 (m, 6H) · 2.08 ( s, 3H ) ; MS( ES1+ ) m/z 3 7 5.1 2 ( M + H ) +.

E ) 4-(4-Amino-2-fluorophenoxy)( 2 ·folphitylethyl)pyridin-2-amine, hydrochloride

(3-Fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)acetamide trifluoroacetate (40 mg), methanol (1 mL), And a mixture of 6M HCl (0.2 mL) EtOAc (3 mL). 4 NMR (DMSO-heart) 5 11.12 (br s, 1H) ' 8 85 (br s, 1 Η ), 7.95 ( d, 1 Η, J = 7.2 Hz) , 7.08 ( dd, 1 Η, J = 8.8, 8.8 Hz ), 6.65-6.63 (m, 2H) &gt; 6.54 ( d, 1H = J = 8.3 Hz) , 6.3 1 ( br s, 1 H ) , 3.85 ( m, 6H ) , 3.33 (m, 6H ) ; MS ( ESI+) m/z 3 73.1 4 ( MH). (88) 1324926 F) Λ&quot;- ( 3 -Gasyl-4-( 2· ( 2 · 福 咐 乙 乙 乙 ) ) ) The base oxy)phenyl)-V-(4-fluorophenyl)propanediamine is a procedure similar to that described for the preparation of the compound C of Example 1, from 4-(4-amino-2-fluoro) Benzyloxy)-AN ( 2 ·morpholinoethyl) anthracene-2-amine • chlorate (15 mg, 0.043 mmol), 3-(4-fluorophenylamino)-3 Ketopropionic acid Compound b of Example 1, 1 0 m g, 0.0 5 2 mmol), TBTU (17 mg, 0.052 mmol), DIPEA (φ 3 0 # L) 'and DMF (1 mL) mixture, to prepare the title compound. The crude product was purified by preparative HPLC (Shimadzu S5 VP-ODS 20 x 1 00 mm). The title compound (10 mg, 40%) was obtained as a white solid. 'H NMR ( DMSO-A ) &lt;5 10.37 ( s, 1 Η ) , 10.05 (s, lH) * 9.90 ( br s, 1H ) » 7.90 ( d, 1H, J = 6.1 Hz ) &gt; 7.75 ( d, 1H, J = 13.2 Hz) - 7.5 8-7.5 5 ( m, 2H ) , 7.5 3 - 7.5 0 ( m, 1H) - 7.40 ( d, 1H, J = 8.8 Hz) - • 7.24 ( t, 1H, J = 8.8Hz ) &gt; 7.08-7.03 ( m, 3H ),6,39 ( d, 1 H, J = 6.1Hz) , 6.11 (s,1H) ,3.8 0 - 3 . 8 1 ( m,4 H ) , 3.67-3.65 ( m5 2H) &gt; 3.47 ( br s, 2H) &gt; 3.20 ( br s, 4H) ; MS ( ESI+ ) m/z 512.12 (M + H) +. Example 1 9 1324926

V-(3-Oxo-4-(deuterium D-1,4-yloxy)phenyl)·A’'3-(4-(phenylphenyl)propanediamine

A) Zinc powder (2.08 g, 31.8 mmol, &lt;10//) and ammonium chloride (1.70 g, 31.8) were successively prepared with -(3·fluoro-4-hydroxyphenyl)fluorophenyl)propanediamine. Ment) a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 〇C. Stir overnight. The mixture of the heterogeneous sentences was filtered through a thin Celite® filter pad (using methanol) and the filtrate obtained was concentrated under vacuum to give 4-amino-2-fluorophenol as a brown solid. It can be used directly without further purification (656 mg, 81%). 3-(4-Fluorophenylamino)-3-ketopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylamine (4 mL). Triethylamine (MO/zL, 1.00 mmol) was added and the solution was cooled to 0 °C. Benzotriazole-1-hexyloxyindole (dimethylamino) hydrazine (BOP reagent, 442 mg, 1.00 mmol) was added successively. The reaction solution was allowed to warm to room temperature 'then' and stirred at room temperature for 3 hours. • 93-(90) 1324926 The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate a product. The title compound (2 1 1 mg '69%) was obtained as a white solid. NMR ( CD3OD ) ο 7.6 1 - 7.5 7 ( m, 2 Η ) , 7.51 (dd, 1Η, J = 13,2.5 Hz), 7.08-6.99 (m, 3H) * 6.88 (t, 1H, J = 9.4 Hz &gt; 3.51 (s, 2H); MS ( ESI+ ) m/z 307.44 ( M + H ) + .

B) (3.Fluoro-4-(pyridin-4-yloxy)phenyl)(4-fluorophenyl)propanediamine in the order of (3-carbyl-4-phenyl)-A ^-(4-Nitrophenyl)propanediamine (31 mg, 〇.1〇mmol), copper(II) acetate (27 mg' 0.15 mmol), D to H-1,4-pyruic acid (25 mg , 0'20 mmol), and pyridine (16 &quot; L, 0.20 mmol) were placed in a pressure tube. Dichloromethane (0.5 mL) was loaded into the tube and sealed. The reaction solution was heated at 120 ° C for 5 hours. The reaction mixture was filtered through a silica gel (using 5% methanol / ethyl acetate). After concentration. The crude product was purified by preparative HPLC. The appropriate fractions were concentrated to remove methanol and the resulting aqueous solution was made basic with saturated sodium bicarbonate (5 mL). The aqueous solution was extracted with ethyl acetate (3 X 10 mL) and the organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The product was treated with 4N HCl (in dioxane) and concentrated. The title compound (8 mg, 2 1%) was obtained as a yellow solid. 'H NMR ( CD3OD ) occupies 8.31 (d, 2H, J = 6.1 Hz), 7.72 ( dd, 1H, J = 12.7, 2.4 Hz), 7.49-7.46 ( m, 2H ) -94- (91) 1324926 • 7.2 7 - 7.2 5 ( m: 1 Η ) &gt; 7. 1 5 ( t, 1 H, J = 8.8 Hz ) , 6.97 (t, 2H; J = 8.7 Hz), 6.85 ( dd, 2H; J = 5.1, 1.2 Hz), 3.46 ( s, 2H ) ; MS ( ESI+) m/z 3 84.2 1 (M + H) +. Example 2 0

• /V, (4-(2-(chloro)pyridin-4-yloxy)-3-phenyl)-A^-(4-fluorophenyl)propanediamine

A) 2-Fluoro-4-aminophenol in a 50 psi H2 hydrogen atmosphere at room temperature, stirring platinum oxide (0.010 g) and 2·gas-based 4-nitrol (Aldrich' 1.24 g' 7.78 A mixture of mmol, 1 〇 equivalent) in methanol (100 ml). The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. 1H NMR (DMSO-heart) 68.57 (s, 1H) &gt; 6.46-6.47 (m, 1 Η ) , 6.33-6.46 (m, 1 Η) , 6.19-6.21 ( m, 1 H ) , 4.79 ( s, 2H ) ; MS ( ESI+ ) m/z 128( M + H ) + (92) 1324926

Nh2 ci

B) 4-(2-(Chloropyridin-4-yloxy)-3-fluoroaniline

Sodium hydride (60%, 0.104 g, 2.60 mmol, 1.1 eq) was added to the 2-fluoro-4-an amine group (0.30 g, 2.36 mmol, 1.0 eq.) in DMF at room temperature (6.5 mL) in the resulting solution, and the reaction mixture was stirred for 30 minutes. 2-Chloro-4-nitropyridine (Aldrich, 0.374 g, 2.36 mmol, 1.0 eq.) was added and the reaction mixture was warmed to <RTIgt; The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate (3 X 70 mL). The organic extracts of hydrazine were washed with aq. EtOAc (EtOAc) (EtOAc) Further purification. NMR (DMSO-i/6) 5 8.27 (d, 1H, J = 5.7 Hz) &gt; 6.90-7.04 ( m, 3H ) &gt; 6.42-6.54 ( m, 2H ) , 5.54 ( s, 2H ) ; ESI+) m/z 23 9 (M + H) + ; HRMS (ESI+), Theory 値: 2 3 9.03 87 &gt; Measured 値: 239.0391. C) W-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)---(4-fluorophenyl)propanediamine at 2 ° C, two different Propylethylamine (〇_91 mL, 0.525 mmol, 2.5 eq.) was added to 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline-96- 1324926 (0.050 g, 0.21 mmol, 1.0 equivalents, 3-(4-fluorophenylamino)-3-ketopropionic acid (Compound B of Example 1, 0.041 g, 0.21 mmol, 1.0 eq.), and PyBroP (0-117 g, 0.252 mmol) , 1.2 eq.) in a solution of dichloromethane (1.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of sodium chloride and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound (0.0) was obtained as a solid (m.). 5 6 g, 64%). ]H NMR ( DMSO-A ) 5 1 0.61 ( s, 1H ) , 10.34 (s, 1H) , 8.36-8.38 (m, 1H), 7.91-7.93 ( m, 1H) » 7.67-7.71 ( m, 2H) « 7.46-7.48 ( m, 2H ) , 7.04- 7.26 ( m, 4H ) - 3.56 ( s, 2H ) ; MS ( ESI+) m/z 418 ( M + H ) + ; HRMS ( ESI+ ), theory 値: 4 1 8.0770, • Measured 値: 4 1 8 · 0 7 6 7. Example 2 1

Bu(4-(2-chloropyridin-4-yloxy)-3.fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)thiourea-97- (94) 1324926 4-Fluorophenylethylidene chloride (Aldrich, 0.072 mL, 0.525 mmol, 2.5 eq.) was added to the sodium thiocyanate at room temperature (〇·〇56 g' 0.6 9 5 mm ο 1,3. 3 Equivalent) in a solution of ethyl acetate (2·0 m L), and the reaction mixture was stirred for 1.5 hours to give 2-(4-fluorophenyl)ethenyl isothiocyanate. Solution (0.263 M). A solution of 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (0.050 g '0.21 mmol, 1.0 eq.) in dichloromethane (1.0 mL) The 2-(4-fluorophenyl)ethenyl isothiocyanate solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and purified using EtOAc EtOAc (EtOAc (EtOAc) Purification afforded the title compound (0·0 5 8 g, 64%). 1 Η NMR ( DMS Ο Ά ) occupies 1 2 · 4 6 ( s, 1 Η ) &gt; 11.84 (s, 1 Η) &gt; 8.35-8.33 ( m, 1H) » 8.02- 8.3 3 ( m, 1H) &gt; 6.99-7.52 ( m, 8H ) , 3.84 ( s, 2H) ; MS ( ESI+) ^ m/z 434 ( M + H) + ; HRMS ( ESI+ ), theoretical 値: 434.0542, measured 値: 4 3 4 · 0 5 4 7. Example 2 2

-98- (95) 1324926 #-(4-(2-Benzylamino)pyridin-4-yloxy)-3-fluorophenyl)-deuterium (4-fluorophenyl)propanediamine

NHBoc C!

A) T-butyl 4-(2-chloropyridin-4-yloxy)-3-fluorophenylcarbamate Add di-t-butyl succinate (0.920 g, 4.22 mmol, 4.5 eq.) to 4-(2-Chloropyridin-4-yloxy)-3-fluoroaniline (Compound B of Example 20, 0.224 g, 0.939 mmol, 1 〇 equivalent) and triethylamine (0.391 mL ' 3.00 mmol , 3.0 eq.) of the resulting solution, and the reaction mixture was stirred at 55 ° C for 14 hours. The reaction mixture was allowed to cool to room temperature and quenched with 1N HCl. The solution was extracted with chloroform (3 X 70 mL). EtOAc (EtOAc) The title compound (0.270) was obtained by EtOAc EtOAc (EtOAc) g , 8 5%). 'H NMR (DMSO 〇 δ 8.3 5 -8.3 6 Cm, 1H ). 7.55-7.57 ( m, 1H) &gt; 7.45-7.46 ( m, 1H) » 7.21-7.24 ( m, ]H) , 6.96-6.97 ( m, 2H) &gt; 1.40 ( s, 9H) ; MS ( ESI+) m/z 3 3 9 ( M + H ) + ; HRMS ( ESI+ ), theory 値: 339.0912, measured 値: 3 3 9.09 1 5 . (96) 1324926

NHBoc B) 4-(2-(benzylamino)pyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester

Add 3-(2-chloropyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester (〇.丨〇〇g, 0.295 mmol, 1.0 eq.) to d at room temperature Pp f · P d C12 (M atr i XS ci ent ific, 0 · 0 1 1 g, 0.0 1 4 8 mmol, 0.05 equivalent), dppf (0.012 g, 0.022 mmol, 0.075 equivalent), and sodium tributoxide (0.040 g, 0.414 mmol, 1.4 eq.) in a degassed solution of toluene. Benzylamine (0.045 mL, 0.414 mmol, 1.4 eq.) was added to the reaction mixture, and the obtained solution was stirred at 80 ° C for 4 hr. The reaction mixture was allowed to cool to room temperature, quenched with &lt;RTI ID=0.0&gt;&gt; The combined organic extracts were washed with 1N sodium hydroxide (70 mL), dried (MgSO4), filtered and evaporated. The title compound (0.020) was obtained by EtOAc EtOAc (EtOAc) g,1 7%). 4

NMR (CDCh) (5 7.80-7.90 (m, 1H) &gt; 7.35-7.45 ( m, 1H ), 7.19-7.24 ( m, 3H ) &gt; 6.91-6.93 ( m, 2H ) , 6.59 ( br m, 1 H) &gt; 6.10-6.20 ( m, 1 H ) &gt; 5.75 ( br m, 1 H ) &gt; 5.30-5.40 ( m, 1H ) , 4.34 ( s, 2H) , 1.46 ( s, 9H) ; MS ( -100- (97) 1324926 ESI+) m/z 410 ( M + H) + ; HRMS ( ESI+), theory 値: 4 1 0.1 8 8 0, measured 値·· 4 1 0 · 1 8 8 4.

φ C ) 4- (4-Amino-2-fluorophenyl)benzylpyridin-2-amine, hydrochloride, anhydrous HC1 in dioxane (4N, 2.00 mL, 8.00 mmol, 165 eq. Add to 4-(2-(decylamino)pyrene than B-but-4-yloxy.)-3_fluorophenylaminecarboxylic acid tert-butyl ester (0.020 g, 0.0489 mmol, 1.0 eq.), and The reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated in vacuo to give title titled <RTI ID=0.0; MS (ESI+) m/z 310 (M + H) +; HRMS (ESI+), Theory 値: 3 1 0.1 3 5 6 Measured 3: 3 1 0 · 1 3 6 4 . D) (4-(2-(Benzylamino)pyridin-4-yloxy)-3-fluorophenyl)- Λ^-(4-fluorophenyl)propanediamine at 0 ° C Diisopropylethylamine (〇.〇 14 mL, 0.08 1 mmol, 3.5 eq.) was added to 4·(4·Amino-2-fluorophenyl)benzylpyridine-2-amine•hydrochloride ( 0.008 g, 0.023 mmol, 1.0 eq.), fluorophenylamino)-3-ketopropanoic acid (Compound oxime of Example 1, 0.005 g, 0.023 mmol, 1,0 eq.), and PyBroP (0.013 g, 0.02 8) Methyl, 1.2 equivalents in a solution of (98) 1324926 formed in dichloromethane (1.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for an hour. The reaction mixture was concentrated in vacuo and purified by reverse phase HP LC chromatography (YMC-ODS-A, C-18, S10, 30 X 5 00 mm' with 20-90% aqueous methanol / 0.1 TFA 30 Minutes, gradient elution), the resulting residue was purified. The appropriate fractions were concentrated in vacuo, purified with sat. aqueous sodium bicarbonate, and the mixture was extracted with CH.sub.3 (3 X 10 mL). The combined organic extracts were dried <RTI ID=0.0>(~~~~~~~~ MS (ES1+) m/z 489 (M + H) + ; HRMS (ESI+), theory 値: 489.1738, 値: 489.1743. Example 2 3

1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

Nh2 A) 3-Fluoro-4(pyridin-4-yloxy)aniline Potassium cyanide at room temperature (30%, 0.520 g' 3.90 mmo1' -102-8 (99) 1324926 3.0 equivalent) Add to a solution of 2-fluoro-4-aminophenol (Compound A of Example 20, 0.254 g, 2.00 mmol, 1.5 eq.) in DMF (5.0 mL) and stir the reaction mixture for 15 min. . 4-Chloropyridine (Aldrich, 0,200 g, 1.30 mmol, 1.0 eq.) was added, and the reaction mixture was heated to 150 ° C for 2 hr. The reaction mixture was cooled to room temperature, quenched with 1N sodium hydroxide and extracted with ethyl acetate (3 X 50 mL). The organic extract of the combined hydrazine was washed successively with 1N aqueous sodium hydroxide (2 X 30 mL) and 10% aqueous LiCl (3 X 50 mL). The combined organic extracts were dried <RTI ID=0.0> 1H NMR (DMSO-heart) δ 8.44-8.46 (m, 2H), 6.89-7.03 (m, 1H), 6.8 7-6.88 ( m, 2H ) , 6.44 - 6.56 ( m, 2H ), 5.5 1 ( s, 2H) ; MS ( ESI+ ) m/z 205 ( M + H ) + ; HRMS (ESI+), theory 値: 205.0777, measured 値: 205.0775.

B) 1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea at room temperature in shaded light Under the conditions of irradiation, silver cyanate (0.912 g, 6.08 mmol, 1.05 equivalent) was added to 4-fluorophenylacetamidine chloride (Aldrich, 0.794 mL, 5.79 mmol, 1.0 eq.) in toluene (16 mL). In the solution. The reaction mixture was heated to reflux for 60 minutes and then cooled to room temperature. The reaction mixture was filtered (Acrodisc, PTFE 0.2 a Μ), and the thus obtained 2-(4-fluorophenyl)ethenyl isocyanate solution (0.36 Μ, 0.75 (100) 1324926) at room temperature.

m L, 0.2 7 mm ο 1,1 .1 equivalent) was added to 3-fluoro-4-(indenyl n-oxy)aniline (0.050 g, 0-245 mmol, 1.0 eq.) in dioxane (2.0 mL) In the solution formed. The reaction was stirred at room temperature for 1 hour, quenched with saturated aqueous sodium chloride and dichloromethane (3×30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound (0.043) was obtained by EtOAc (EtOAc: EtOAc, EtOAc (EtOAc) g, 46%). NMR (DMSO δ 11.06 ( s, 1 Η ) , 10.60 ( s, 1 Η ) , 8.4 7 ( s, 2H 7.77-7.80 ( m, 1 H ) , 6.9 2 - 7.4 8 ( m , 8 H ) &gt; 3.75 ( s, ;MS ( ESI+ ) m/z 3 84 ( M + H ) + ; HRMS ( ESI+ ), 値: 384.1160, measured 値: 384.1147° Example 24 -4-ylchloromethyl mixed and extracted with gel 5% A solid-d6), 2H) theory

1· (4-(2-aminopyridinium ratio D-1,4-yloxy)-3-phenylphenyl)-3-(2-(phenyl)ethenyl)urea-104- (101) 1324926

A) 4-(4-Amino-2.fluorophenoxy)·#·benzylpyridin-2-amine

Add benzylamine (9.1 mL, 83.8 mmol, 20 equivalents) to 4-(2-chloropyridin-4-yloxy)-3-fluorobenzylamine in a sealed tube (Compound B of Example 20) , 1.0 g, 4.19 mmol, 1.0 eq.), copper powder (0-266 g, 4.19 mmol, 1·〇 equivalent) and potassium carbonate (0.578 g ' 4.19 mmol' 1.0 eq.), and the reaction mixture was heated to 160 ° C 'It lasted 12 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous sodium chloride. The solution was extracted with EtOAc (3×10 mL)EtOAc. The residue obtained was purified by preparative reverse phase HPLC (YMC C-18 ODS-A S10 50 X 500 mm, eluted with 10-90% aqueous methanol (containing 0.1% TFA) for 30 minutes, gradient elution). . The obtained concentrate was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried (EtOAc EtOAcqqqqqq NMR (CD3OD) δ 7.78-7.80 ( m, 1H) * 7.2 8-7.3 0 ( m5 5H) &gt; 6.80-6.90 ( m, 1H) &gt; 6.52-6.55 ( m, 2H) &gt; 6.18-6.20 ( m , 1H) , 5.87-5.88 (m, 1H) , 4.40 (s, 2H) ; MS (ESI+) -105- (102) 1324926 m/z 3 10( M + H ) + ; HRMS ( ESI+ ), theory値:310.1356 , measured 値: 3 1 0 · 1 3 6 0.

B) 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine under hydrogen blanketing (from a balloon), palladium hydroxide on carbon at room temperature (10) %, 0.050 g) was added to 4-(4-amino-2-fluorophenoxy)-W.benzylpyridin-2-amine (0.245 g, 0.790 mmol, 1.0 eq.) in 5% HC02H-Me. 10 mL) in the solution formed. The reaction mixture was stirred for 12 hours at room temperature, filtered through Celite® and concentrated in vacuo. The residue obtained was purified by reverse phase preparative HPLC (YMC ODS-A S10 3 0 x 500 mm, eluted with 10-90% aqueous methanol (containing 0.1% TF A) for 30 minutes, gradient elution). The appropriate fractions were concentrated in vacuo. The concentrate was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with CHC13 (3 X 35 mL). The combined organic extracts were dried <RTI ID=0.0> NMR ( CD3OD ) ό 7.62-7.63 (m,1Η) &gt; 6.77-6.82 ( m, 1 H ) ,6 · 3 8 - 6 · 4 7 ( m,2 H ), 6.09-6.1 1 ( m, 1 H ) , 5 · 8 3 - 5.8 4 ( m, ih ) ; MS ( ESI+ ) m/z 220 ( M + H) + ; HRMS ( ESI+ ) ' Theoretical 値 : 220.0886 , measured 値 : 220.0877 °

-106- (D (103) 1324926 c) 1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethyl 2-(4-Fluorophenyl)ethenyl isocyanate (Example Η Compound D, 0.362 Μ, 0.351 mL, 0.127 mmol, 1.3 eq.) was added to 4-(4- Amino-2-fluorophenoxy)pyridin-2-amine (0.022 g, 0.100 mmol, 1.0 eq.) was taken in dichloromethane (2.0 mL) EtOAc. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The title compound was obtained as a solid (0.025). g &gt; 6 4%). NMR (CD3OD) &lt;5 7.62-7.67 ( m, 2H ) &gt; 7.23 -7.29 ( m, 2H ) &gt; 7.07-7.12 ( m, 2H),

6.95-6.99 ( m, 2H) &gt; 6.12-6.14 ( m, 1H) &gt; 5.86-5.87 ( m, 1 H ) , 3.6 1 ( s, 2H ) ; MS ( ESI+) m/z 3 99 ( M + H) + ; HRMS (ESI+), theory 値: 399.1269, measured 値: 399.1269. Alternatively, Example 24 can be prepared in the following manner:

H2noc A') 4-chloropyridine carbenamide formed at 80 ° C with 4-chloropyridine carboxylic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq.) and sulfinamide (30 mL) The uneven mixture was heated for 2 hours. The reaction mixture was cooled to room temperature -107- (104) 1324926 and concentrated in vacuo. The resulting residue was treated with a solution of ammonia in methanol (7N &apos; Then, the ice bath was removed, and the reaction was allowed to warm to room temperature & then was stirred for 3 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified from ethyl acetate (yield: EtOAc). 1Η NMR ( DMSO-rfi) 5 8.61-8.63 (m, 1H) , 8.21 (m.,) H)

&gt; 8.0 3 - 8.04 ( m, 1 H ) &gt; 7.76-7.83 (m, 2H); MS (ESI) m/z 1 57 (M + H) +.

B') 4-(4-Amino-2-fluorophenoxy)pyridinecarboxamide

4% Amino-2-fluorophenol (Compound A of Example 20, 0.81 g '6.4 mmol, 1.0 eq.) was treated with tributoxy oxime (0.79 g, 7.1 mmol, 1.1 eq.) at room temperature. DMF (6_5 mL) formed solution 'and the reaction mixture was stirred for 1 hour. 4·Chloropyridine carbenamide (1.0 g' 6.4 mmol' 1.0 eq.) was added and the reaction mixture was heated to U0 °C for 8 hr. The reaction solution was allowed to cool to room temperature, and the reaction mixture was quenched with water. The resulting heterogeneous solution was filtered, and the solid matter was washed with water. The solid was triturated with a small amount of methanol and diethyl ether. The title compound (1.3 g, 820 / 〇) « 'H NMR ( DMSO-^d) δ 8.49-8.50 -108- (105) 1324926 (m, lH) , 8.12 (brs, lH), 7.71 (brs, lH) · 7.35-

7.36 ( m, 1 H ) &gt; 7.1 4-7.1 6 ( m, 1 H ) - 7.01-7.06 ( m, 1 H ), 6.44-6.47 (m, 2H) , 5.53 (s, 2H) ; MS ( ESI+ ) m/z 248 ( M + H ) +.

C') 1-(2-(2-Aminomethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea 2-(4-Fluorophenyl)ethenyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 1.2 eq.) was added to 4-(4-amine a solution of 2-fluorophenoxy)pyridylcarzamide (1·86 g, 7.53 mmol, 1.0 eq.) in 10/3 DCM / φ DMF (65 mL), and the reaction mixture was stirred 1 7 hour. The reaction mixture was concentrated in vacuo and the residue obtained was redissolved in CH. The organic layer was washed with a saturated aqueous solution of sodium chloride and the organic portion was separated, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (first eluted with 1/3 hexane/ethyl acetate) and then washed with 5% methanol / CHCl3, and the appropriate fractions were taken in vacuo. The title compound (2.2 g, 69%) was obtained. 4 NMR (DMSO-i/i) 5 1 1.07 ( s, 1 Η ) &gt; 1 0.62 ( s, 1 Η ) &gt; 8.54 ( d, 1Η » J = 5.60 Hz) , 8.16-8.19 ( m, 1H ) &gt; 7.7 6-7.84 ( m, 2H ), -109- (106) 1324926 7·35·7·49 (ms 5H) , 7.16-7.23 ( m,3H) , 3.76 ( s,2H) :MS ( ESI+ ) m/z 427 ( M + H ) +. HRMS (ESP), Theory 値: 4 2 7 . 1 2 U, measured 値: 4 2 7.1 2 1 4. D') 1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloric acid salt

Bis-(trifluoroethylideneoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq.) was added to 1-(4-(2-aminopyridinyl)-4 at room temperature -yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (2.19 g, 5.14 mmol, 1.0 eq.), water (0.241 mL, 13.4 mmol, 2.6 Equivalent) and hydrazine were steep (1.62 mL, 20 mmol, 3.9 eq.) in a solution of DMF (20 mL) and the mixture was stirred for 5 hr. The reaction mixture was quenched with IN HCl and the aqueous was extracted with diethyl ether. The aqueous layer was neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer of hydrazine was washed with 10% aqueous EtOAc (EtOAc) elute The residue obtained was purified by EtOAc (EtOAc-EtOAc) elute The residue obtained was taken up in EtOAc (50 mL) EtOAc (EtOAc) The reaction mixture was allowed to warm to room temperature and stirred for 2 hours to give a s. 1.38 g, 63%). hMRCDMSO-A) 5 11.09( -110- 8 (107) 1324926 s, 1 Η ) &gt; 10.65 (s, 1H) , 7.97-8.00 (m, 1H), 7.83-7.90 (m. 3H) &gt; 7.35- 7.48 (m, 4H) , 7.15-7.21 (m, 2H), 6.70-6.72 ( m, 1H) &gt; 6.16-6.17 ( m, 1H) &gt; 3.77 ( s, 2H) ;MS ( ESI+ ) m/s 3 99 ( M + H ) +. HRMS ( ESI+): Theory 値, 399.1 269; measured 値, 3 99.1 2 5 8. C2〇H16N4〇3F2 · 1.0 HC1. Elemental analysis of 0.22 H20: Theoretical 値, C: 54.75, Η: 4·01, Ν: 12.77, Cl: 8.08; measured 値, C: 54.75, Η: 4.35, Ν: 4.35 , Cl : 8.06 . Example 2 5

H2n #- (4-(2-aminopyridinium-4-yloxy)-3-phenylphenyl)-2-yl-5-methylbenzamide at room temperature Propylethylamine (0.03 5 mL, 0.200 mmol, 2.0 eq.) was added to 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 0.022 g, 0.100 Methyl '1.0 equivalents), 2-fluoro-5-methylbenzyl acid (Aldrich '0.015 g '0.100 mmol, 1.0 equivalent), EDCI (0.021 g, 0.11 mmol, 1.1 equivalents) and HOBT (0.01 4 g, 0.1 00) Mmmol, 1 · 0 eq.) in a solution of DMF (0.7 00 mL). The reaction mixture -111 - (108) 1324926 was stirred at room temperature for 8 hours, quenched with saturated aqueous sodium bicarbonate and extracted with CH.sub.3 (3 X 10 mL). The combined organic extracts were dried <RTI ID=0.0> Purification of the obtained residue by reverse phase preparative HPLC (YMC ODS-A S10 30 X 500 mm, 30-90% aqueous methanol (containing 0.1% TFA), elution for 30 minutes, gradient elution) And the appropriate fractions were concentrated in a vacuum. The resulting concentrate was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with CHCI? The combined organic extracts were dried <RTI ID=0.0></RTI> <RTI ID=0.0> 'H NMR (CD3OD) 5 7.67-

7.80 ( m, 2H ) &gt; 7.3 6-7.45 ( m, 3H ) &gt; 7.03-7.14 ( m, 2H ), 6.1 4-6. 1 6 ( m,1 H ) - 5.89-5.90 ( m, 1 H ), 2.29 ( s, 3 H ) ; MS ( ESI+ ) m/z 3 56 ( M + H ) + ; HRMS ( ESI+), Theory 値: 3 5 6 · 1 2 1 1, measured 値: 3 5 6.1 2 0 3.

Example 2 6

(4-(2-Amino-batch steep-4-yl-gas)-3-gas-based)-·Α^·(4-oxophenyl)propanamide at 2 ° C, diisopropyl Ethylethylamine (0.105 mL, 0.604 mmol, 3.3 eq.) was added to 4·(4-amino-2-fluorophenoxy)pyridin-2-amine-112-(109) 1324926 (Compound B of Example 24) , 0.040 g, 0.183 mmol, 1.0 eq.), 3-(4-fluorophenylamino)-3-ketopropanoic acid (Compound B of Example 1, 0.054 g, 0.274 mmol, 1.5 eq.), and PyBroP ( 0.139 g, 0.298 mmol, 1.6 eq.) in a solution formed in dichloromethane (2.0 ml). The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with CH.sub.3 (3×10 mL). The combined organic φ extract was dried over sodium sulfate, passed through a celite and concentrated in vacuo. The title compound was obtained as a solid (yield from EtOAc (EtOAc: EtOAc) ·〇56 g, 77%). NMR( CD3OD ) δ Ί.61-1.6% ( m, 2Η ) ' 7.48-7.52 ( m, 2H ), 7.13-7.25 (m,lH) , 7.10-7.12 (m,lH) &gt; 6.94-6.99 ( m , 2H ) &gt; 6.1 6-6.1 7 ( m, 1 H ) &gt; 5.8 8- 5.8 9 ( m, 1H ) &gt; 3.30 ( s, 2H ) ; MS ( ESI+) m/z 3 99 ( M-H+ HRMS ( ESI+ ) ® , theoretical 値: 399.1269, measured 値: 399.1261. Example 2 7

(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)thiourea-113- (110)1324926 At room temperature, 4·fluorophenylacetamidine chloride (Aldrich, 0.017 mL,

To a solution of sodium thiocyanate (0.014 g, 0·176 mmol, 3.5 eq. A solution of 2-(4-fluorophenyl)ethenyl isothiocyanate (0.126 M) was provided. 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.01 1 g, 0.050 mmol, 1.0 eq.) was dissolved in dichloromethane (1.0 mL) 2-(4-Fluorophenyl)ethinyl isothiocyanate (0.126 Μ, 0.50 mL, 0.063 mmol, 1.3 eq.) was added, and then the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated in vacuo and was obtained by flash chromatography (Merck, 40-63 y Μ ' 2 3 0-240 mesh, eluted with 0 - 6 % methanol / CH C13) The residue was purified to give the title compound (g < 38%) </RTI> NMR (CD3OD) (5 7.85 -7.95 (m, lH) · 7.67-7.69 (m,

1 Η ) &gt; 7. 1 3-7.28 ( m, 4H ) , 6 · 9 5 - 7 · 0 〇 ( m, 2 H ) , 6.05-6.15 ( m, 1 H ) &gt; 5.90-5.91 ( m, 1H ) , 3.65 ( s, 2H ) ; MS (ESI+) m/z 415 (M + H) + ; HRMS (ESI+), Theory 値: 4 1 5.1 040, measured 値: 415.1041° Example 28

(111) 1324926 1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl) Acetyl) urea

F

A) #-( 3-fluoro-4-(1-oxo-2-(4-fluorophenylamino)pyridin-4-yloxy)-3_fluorophenyl)acetamide at 1401: #-(4-(1-Oxo-2-chloropyridin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 18 '62 mg '0.21 mmol), 4-fluoro A mixture of aniline (47 mg, 0.42 mmol) and 2-methoxyethyl ether (91 mL) was heated for 15 min. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate and brine (s), dried (MgSO4) and concentrated in vacuo. A mixture of the title compound and the starting pyridine compound (45 mg, 58%). This product was used directly in the next step without further purification. MS ( ESI+ ) m/z 3 72.1 (M + H) +.

B) (3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy) 115 @ (112) 1324926 Phenyl)acetamide at 1 3 5 °c, #-( 3 -Fluoro-4 -( 1 -oxy-2-(4-fluorophenylamino)pyridinyloxy)phenyl)acetamide (45 mg), loaded on polyphenylene bromide (200 A mixture of triphenylphosphine polymer (~3 mmol/g) and DMF (3 mL) on mg, Fluka) was heated for 48 hours. The resin was filtered off and washed with DMF and ethyl acetate. The filtrate and washings were combined and concentrated in vacuo. The title compound was obtained as a pink solid (22 mg, 51%). ). 4 NMR ( DMSO-c/e ) (5 1 0.24 ( s, 1 Η ) - 8.99 ( s, 1 Η ), 8.03 ( d, 1 H, J = 6.3 Hz ) &gt; 7.80 ( dd, 1H, J = 13.0, 2.1 Hz ) , 7.63 - 7.60 ( m, 2H ) , 7.3 6-7.29 ( m, 2H ) , 7.05 ( dd, 1 H, J = 9.1, 8.6 Hz ) - 6.44 ( dd, 1H, J = 5.5, 2.2 Hz ) &gt; 6.09 ( d, 1H, J = 2 Hz ) , 2.07 ( s, 3H ) ; MS ( ESI + ) m/z 3 5 6.7 ( M + H ) + .

C) 4-(4-Amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyridin-2-amine #-(3-fluoro-4-(2-(4-) A mixture of fluorophenylamino)pyridin-4-yloxy)phenyl)acetamide (18 mg, 0.051 mmol), EtOAc (EtOAc) The mixture was concentrated in vacuo, and the obtained residue was evaporated, mjjjjjjj The extract was dried with EtOAc (EtOAc m. 4 NMR (DMSO-heart) δ 8.97 ( s, 1 Η ) , 7.98 ( d,1 H, J = 5.8 Hz ) , 7.64-7.60 ( m, 2H ) , 7.05 ( dd, 2H, J = 9.1, 8.8 Hz ), 6.97 ( dd, 1 H, J = 9.4, 8.8 Hz ) , 6.51 ( dd, 1H, J = 1 3.3, 2.6 Hz ) , 6.40 ( ddd; 2H, J = 9.0, 6.2, 2.1 Hz)

&gt; 6.08 ( d, 1H, J = 2.0 Hz ) &gt; 5.44 ( br s, 2H ) ; MS ( ESI+ ) m/z 3 1 4.1 7 ( M + H ) + . D) 1-(3-Fluoro-4-(2-(4-fluorophenylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetonitrile 4-(4-Aminofluorophenoxy)oxyphenyl)pyridin-2-amine (11 mg, 0.035 mmol) in THF (1 niL)

The resulting solution was cooled and treated with a solution of 2-(4-fluorophenyl)ethinium isocyanate in toluene (Compound D' 250 μL, 0.070 mmol). Stir at room temperature for 2 hours. The mixture was concentrated in vacuo to give EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1 Η ) , 10.56 ( s,1Η ) ' 9.01 ( s, 1H ) &gt; 8.03 ( d, 1H, J = 5.6Hz), 7.77 ( dd, !H, J = 13.3, 2.0Hz ) &gt; 7.63-7.60 ( m, 2H ) ' 7 4 1 - 7.3 1 ( m, 5H ) &gt; 7.19-7.14 ( m, 2H ) - 7.0 5 ( dd , 1 H, J = 9.1, 8.5Hz )&gt; 6.43 ( dd, 1 H, J = 6.2, 2. 1 Hz ) &gt; 6. 1 0 ( d, 1 H, = 2' 1 • 117- (114) 1324926

Hz) ' 3.74 ( s, 2H) ; MS ( ESI+ ) m/z 493.2 ( M + H) +. Example 29

Phenyl)(4-fluorophenyl)propanediamine

Η A) #-(4-(6-(4-Benzyloxy)anilino)pyrimidin-4-yloxy)-3-

Fluorophenyl)acetamide, #-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 13 at 160 ° C, A mixture of 281 mg, 1.00 mmol), 4-nonoxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated for 45 min. The cooled mixture was treated with water (50 mL) andEtOAcEtOAc The title compound (2 0 0 m, 2 2 %) was obtained as a purple solid. 1 Η NMR (400 MHz, DMSO-i/i) &lt;5 10.19 ( s, 1H) , 9.43 ( s -118- (115) 1324926 1Η ) &gt; 8.23 ( s, 1 Η ) - 7.72 ( dd, 1 Η, J = 12.5, 2.0 Hz ) &gt; 7.44-7.42 ( m, 4H) &gt; 7.38 ( dd, 2H, J = 8.0; 6.9 Hz) &gt; 7.33-7.23 (m, 3H) , 6.98 (d, 2H , J = 9.0 Hz) , 6_07 ( s, 1 H ) &gt; 5.07 ( s, 2H ) &gt; 2.05 ( s, 3H ) ; MS (ESI+) m/z 44 5 · 1 3 ( M + H ) + .

H B) 6-(4-Amino-2-fluorophenoxy)(4-(benzyloxy)phenyl)pyrimidine-4-amine

AT-(4-(6-(4-(Benzyloxy)anilinyl)pyrimidin-4-yloxy)-3-propyl)acetamide (150 mg' 0.34 mmol), 6M HC1 (0.5 A mixture of mL) and methanol (3 mL) was heated to reflux for 2 hours. The mixture was concentrated to remove methanol and the residue obtained was purified eluted with sat. The title compound (123 mg, 90%) was obtained. NMR (DMSO-i/6): 5 9.37 ( s, 1H) , 8.24 ( s, 1H) , 7.4 6 - 7 · 3 1 ( m, 7 Η ), 6.99-6.92 ( m, 3H) &gt; 6.48 ( Dd, 1H, J = 12.5, 2.7 Hz) &gt; 6.39 ( dd, 1 H, J = 8.6, 2.7 Hz ) &gt; 5.97 ( s, 1 H ) - 5.39 ( br s, 2H ) &gt; 5.08 ( s, 2H) ; MS ( ESI+ ) m/z 403.09 ( -119 (116) 1324926 C ) Λ&quot;- ( 4-( 6-(4-benzyloxy)anilino)pyrimidin-4-yloxy)-3- Fluorophenyl)(4-fluorophenyl)propanediamine is a procedure similar to that described for the preparation of compound C of Example 1, from 6-(4-amino-2-fluorophenyl)(4- Benzyloxy)phenyl)pyrimidine-4-amine (45 mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-ketopropanoic acid (Compound B, Compound B, 24 mg' 0.12 mmol A mixture of TBTU (48 mg > 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), φ and DMF (1 mL). The title compound (56 mg - 88%) was obtained as a white solid. NMR (DMSO-i/&lt;!) δ 10.47 ( s, 1 Η ) - 1 0.27 ( s, 1 Η ) - 9.45 ( s, 1 Η ) &gt; 8.25 ( s5 1H ), 7.77 ( dd, 1H &gt; J = 12.7, 2.0 Hz ) &gt; 7 · 6 5 - 7 · 6 2 ( m, 2 H ), 7.46 ( d, 4H, J = 7.3 Hz ) , 7.40 ( dd, 2H, J = 7.6, 7.3 Hz ) &gt; 7.37-7.29 ( m, 3H) &gt; 7.17 ( dd, 2H, J = 9.0, 8.3 Hz) &gt; 7.00 ( d, 2H, J = 9.0 Hz ) &gt; 6.09 ( s, 1H ) &gt; 5.09 ( s, • 2H), 3.49 (s, 2H); MS (ESI+) m/z 582.3 (M + H)+. Example 3 0

1-(4-(6-(4-(Benzyloxy)anilinyl)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea-120-(117) 1324926 A procedure similar to that described for the preparation of the compound E of Example 11 was carried out from 6-(4-amino-2-fluorophenoxy)-.V- (4) -(Benzyloxy)phenyl)pyrimidin-4-amine (Compound B of Example 29, 45 mg '0.1 1 mmol) and a solution of 2-(4-fluorophenyl)ethenyl isocyanate in toluene ( The title compound was obtained as the title compound. The title compound (58 mg, 90%). 4

NMR (DMSO-heart) δ 11.02 ( s, 1 Η ) , 10.54 ( s, 1 Η ), 9.46 ( s, 1 Η ) &gt; 8.24 ( s, 1 Η ) &gt; 7.70 ( dd, 1H, J = 12.7, 2.4 Hz) , 7.46-7.26 ( m, 9H) &gt; 7.18 ( dd, 2H, J = 9.6, 8.3 Hz) &gt; 7.00 ( d, 2H, J = 9.6 Hz) &gt; 6.11 ( s, 1 H ) &gt; 5.09 ( s, 2H ) , 3.75 ( s, 2H ) ; MS ( ESI+ ) m/z 5 82.3 ( M + H ) + .

1-( 3-Fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea (118) 1324926

2,4-dichloropyrene (Aldrich, 1.5 g, 10.0 mmol),

A mixture of W-(3-fluoro-4-hydroxyphenyl)acetamide (0.85 g, 5.0 mmol), K2C03 (0.76 g &gt; 5.5 mmol), and CH 3 CN (1 0 0 m 1 ) was heated to reflux 2 hours. The mixture was concentrated and the residue obtained was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The ethyl acetate phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried (MgSO4) and evaporated. The title compound (1 · 1 g) was obtained as a white solid. , 78%

1H ) , 8.63 ( d, 12.6, 2.4 Hz ) &gt; ). NMR ( DMSO-i/6 ) δ 10.22 ( 1 H, J = 5.6 Hz), 7.74 (dd, 1H, J 7.34-7.26 (m, 3H), 2.01 (s, 3H).

B) (3-Fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamidine #-(4-(2-chloropyrimidine-4) -yloxy)-3-fluorophenyl)acetamidine (119) 1324926 Amine (100 mg, 0.36 mmol), 4-fluoroaniline (Aldrich, 40 mg

&lt;0.36 mmol), and a mixture of 1,4-dioxane (3 m L) were heated under reflux for 2 hours. The mixture was concentrated in vacuo and the residue obtained was purified eluting with diethyl ether. This product was dissolved in methanol, treated with EtOAc (1500) and concentrated to dryness. The mixture is concentrated on a silica gel, which is applied to a silica gel column eluting with ethyl acetate and 100:1 methanol/methanol (methanol) Mg, 3 1%) &quot;hNMRCDMSO-heart) 610.19(s,1H) * 9.61 ( s, 1 Η ) , 8.33 ( d, 1 Η, J = 5.6 Hz) , 7.71 ( d, 1H, J = 12.7Hz ), 7.40 ( s, 2H ) , 7.3 0-7.26 ( m, 2H ) , 6.86 ( dd, 2H, J = 8.3, 8.3 Hz ) , 6.50 ( d, 1H, J = 5.4 Hz) ' 2.05 ( s, 3H MS ( ESI+) m/z 3 5 7.1 3 (M + H) +.

8 C) 4-(4-Amino-2-fluorophenoxy)-W·(4-fluorophenyl)pyrimidine-2-amine #-(3-fluoro- 4-(2-(4) A mixture of -fluorophenylaminopyrimidin-4-yloxy)phenyl)acetamide (32 mg, 0.09 mmol), 6M EtOAc (2 mL) and methanol (2 mL) The mixture was cooled, diluted with ethyl acetate (20 mL), brine and evaporated. Flash chromatography on ceria (using 1% -123- (120) 1324926

For the eluent), it can be 4 6%). 1 Η NMR 1H, J = 5.5 Hz), 6.45 ( dd, 1 H, , 5.35 (br s, 2H triethylamine 30-40% ethyl acetate / hexanes) (I 5 mg , (DMSO-heart) δ 9.55 ( s, 1 Η ) , 8.25 ( d , 7.43 ( br s, 2H ) , 6.9 2 - 6.8 5 ( m, 3 H ) J = 13.5, 2.1 Hz) , 6.3 8 - 6 · 3 5 ( m, 2 H ) ); MS ( ESI+ ) m/z 3 15.17 ( M + H ) + D) 1-( 3 -fluoro-4-(2-(4-fluoro) Amino) succinyloxy)phenyl)-3-(2-(4-fluorophenyl)urea 4-(4-amino-2-fluorophenoxy) A solution of #_(4-fluorophenyl)pyrimidine-2-amine (10 mg' 0.032 mmol) in THF (1 mL) was cooled with 2-(4-fluorophenyl)ethyis. The resulting solution (Compound D of Example I1, 22 8 /z L, 0.064 mmoL) was worked up and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and made with isopropyl ether. The title compound (15 mg, 93%) was obtained as a white solid. 1H NMR (DMSO-i/6) δ 11.06 (s, 1H) &gt; 10.56 ( s, 1 H ) , 9.68 ( s,1H) &gt; 8.39 ( d, 1H, J = 5.7 Hz ) , 7_76 ( dd, 1H, J = 13.5, 2.1 Hz) &gt; 7.43 ( br s, 2H ) - 7.4 6-7.3 5 ( m , 6H ) &gt; 7.18 ( dd, 2H, J = 8.8, 8.8Hz) &gt; 6.57 ( d, 1H, J = 5.4Hz ) , 3.76 ( s, 2H) ; MS ( ESI+ ) m / z 492.0 ( M + H) Example 3 2 -124- 8 (121) 1324926

2-(4-Fluorophenyl)ethenyl)-3-(4-((2-disido-2-ylamino)thiazol-5-yl)methylamino)phenyl)thiourea

2-(Pyridin-2-ylamino)thiazole-5-carbaldehyde (0.10 g, 0.49 mmol, WO 2004/ 001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) at ambient temperature The solution of triethyl sand (0.19 mL, 1.2 mmol) in CH2C12-TFA (3:1, 4 mL) was stirred for 4 hours. The reaction mixture was concentrated in vacuo and the obtained residue was dissolved in dichloromethane and aqueous sodium hydrogen carbonate. The organic phase was washed with aq. aq. sodium hydrogen sulfate and brine and evaporated. The crude product containing the title compound and the starting aldehyde and benzene 1,4-diamine was used directly in the next step. B) 1-(2-(4-Fluorophenyl)ethenyl)-3-(4-((2.(pyridine-2-ylamino)thiazol-5-yl)methylamino)phenyl) Thiourea 4-fluorophenylethylidene chloride (7.4/zL, 0.053 mmol) was added to NaSCN (4.5 mg, 0.055 mmol) in ethyl acetate (0.5 mL) -125 - 8 (122) 1324926

The resulting mixture was stirred for 30 minutes at room temperature and at room temperature. Then, the mixture was added to a solution of the mixture obtained in the above section A) (14.5 mg) in dichloromethane (0.5 mL), and the mixture thus obtained was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography eluting with EtOAc EtOAc EtOAc The title compound of the membrane (2 mg). MS ( ESI+) m/z 493.2 (M + H) +. Example 33

1-(4-(3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4.fluorophenyl)ethenyl)urea, hydrochloride

Ν〇2 A) 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridine 4-Ethyl-3-iodopyridine at 150 ° C (1.50 g' 6.30 mmol , prepared according to Tabanella, S. et al. B io mol. Che m. 2003, 7, 4244-4261), 2-fluoronitrophenol (Lancaster, 2.0 g -126-8 (123) 1324926

A mixture of '12.7 mmol) 'DIPEA (5 mL) and NMP (10 ml) was heated. After 12 hours, more 2-fluoro-nitrophenol (〇.50 g, 3 · 18 m m ο 1 ) was added to the reaction mixture, and heating was continued for 4 hours. Most of the volatiles were removed in vacuo <RTI ID=0.0>: </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford crude. The title compound (1.0 g, mp. 4 3 % ). 1H NMR ( DMSO-d6 ) &lt;5 8.96 ( s, 1 Η ) , 8.47 ( d, 2 Η, J = 5.5 Hz) ' 8.44 ( dd, 1 H, J = 2.7, 9_2 Hz) , 7.49 ( dd, 1H, J = 8.8, 8.2 Hz) &gt; 7.07 (d, 1H, J = 5.5 Hz); MS (ESI+): m/z 3 6 1.0 5 (M + H) +.

B) 4-(2-Fluoro-4-nitrophenoxy)-3-vinylpyridine followed by CsF (169 mg, 1.12 mmol) and (Ph3P) 4Pd (3 6 mg, 0 '0 3 1 mm ο 1 ) with C u I ( 1 0 mg, 0 · 0 5 6 mm ο 1 ) to treat 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (200 mg, 0.56 mmol), a solution of tributylvinyltin (2 1 2 mg, 0 · 6 7 mm ο 丨) in DMF (1 mL), and at 451, the mixture -127- (124) 1324926 The material was heated for 1 hour. The mixture was cooled, diluted with dichloromethane (15 mL) and water (10 mL) and then shaken vigorously, then filtered and passed through Celite®. The obtained cake was rinsed with 1:1 dichloromethane/ethyl acetate, and the washings were combined with the filtrate. The solution was washed with brine, dried (MgSO4) The obtained crude product was purified by flash chromatography on ruthenium dioxide (0-2% methanol / dichloromethane) to give a semi-purified Φ product. The product was treated with 2M EtOAc (10 mL). EtOAc (EtOAc) 4 NMR ( DMSO-i/6 ) δ 9.11 ( s, 1 Η ) * 8.64 ( s, 1 Η ) , 8.51-8.48 ( m, 1 Η ) &gt; 8.24 ( d, 1H, J = 7.7Hz) &gt; 7.83- 7.79 ( m, 1H ) , 7.28 ( d, 1 H, J = 6.0Hz ) , 7.02-6.95 ( m,1H) , 6.24 ( d,1H, J = 17.6Hz) , 5.68 (d, 1 H, 1 1 .5Hz) ; MS ( ESI + ): m/z 26 1 . 1 8 ( M + H ) +.

The aforementioned hydrochloride salt can be converted to a free base in the following manner: the pyridine hydrochloride (230 mg) is stirred with sodium hydrogencarbonate (25 mL) and ethyl acetate (20 mL) until homogeneous, and separated. The ethyl acetate phase was washed with brine, dried (MgSO4) and concentrated. The title compound (190 mg) was obtained as a yellow oil.

Nh2 -128- (125) 1324926 C ) 4-(3-ethylpyridin-4-yloxy)-3-fluoroaniline using hydrogen from a latex balloon to make 4-(2-fluoro-4- A solution of nitrophenoxy)-3-vinylpyridine (80 mg '0.30 mmol) in 1:1 ethyl acetate / methanol (2 mL) was hydrogenated on 10% palladium-carbon (30 mg) for one hour . p 12 〇 (1 〇 m g ) was added to the mixture and the reaction was continued for 1 hour. The title compound (5 0 φ mg, 63%) was obtained as a yellow oil. mp NMR ( DMSO-^6) δ 8.33 ( s, 1H &gt; 8.22 (d, 1H, J = 5.6 Hz ) &gt; 6.96 ( dd, 1H, J = 8.7, 9.1Hz) * 6.50 ( dd, 1H, J = 2.0, 1.3 Hz) &gt; 6.56 ( d, 1H , J = 5.6 Hz), 6.41 (dd, 1H, J = 2.5, 6.1 Hz), 2.69 (q, 2H, J = 7.6 Hz), 1.21 (t, 3H, "/= 7.6 Hz). D) 1-(4-(3-ethylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride

Treatment of 4-(3-ethylpyridine-4-) with a 0.3 M solution of 2-(4-fluorophenyl)ethenyl isocyanate in toluene (Compound D of Example 11, 0.33 mL, 0.11 mmol) A solution of the oxo)-3-fluoroaniline (23 mg, 0.10 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2.5 hr. The mixture was concentrated in vacuo and the obtained residue was purified eluted eluted eluted The product was treated with EtOAc (1 mL) (EtOAc) (EtOAc) 1324926 compound (15 mg, 36%). 'H NMR (DMSO-c/6) &lt;5 11.04 ( s, lH) &gt; 10.57 (s, 1H) &gt; 8.4 1 ( s, 1H ) - 8.26 (d: 1H; . / = 5.6 Hz), 7.76 ( dd,1H, J = 2.0, 12.7Hz ) &gt; 7.40 -7.2 8 ( m, 4H ) , 7.19-7.14 (m,3H) &gt; 6.54 ( d, 1 H, J = 5.6 Hz ) , 3.73 ( s, 2H ) , 2.72 ( q, 2H, J = 7.6Hz ) &gt; 1.23 ( t, 3H, J = 7.6Hz ) ; MS ( ES Γ ) : m/z 412.20 (M + H)+. φ embodiment 3 4

1-(4-(2-Amino-3-ethylindole -4--4-yloxy)-3-carbyl)-3-(2-(4-fluorophenyl)ethenyl) Urea, trifluoroacetate

A) (4-chloro-3-iodopyridin-2-yl)-aminecarboxylic acid tert-butyl ester

(4-Chloro-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester (CB

Research and Development Inc., 5.0 g, 22.0 mmol) 'The solution of TMEDA (8 mL) in dry THF (100 mL) was placed under nitrogen and cooled to -7 0 ° C over 30 min. A 2.5 M solution of n-butyllithium in hexane (22.0 mL, 54.8 mmol) was added dropwise. The mixture was stirred at -7 (TC) for 1 hour, then, at -130-(127) 1324926 70 °C, I2 (14 g, 1 10 mmol) was added dropwise to anhydrous ΤΗF (1 6 m L ) The resulting solution was stirred at -7 0 t for 30 minutes, then allowed to warm to room temperature. Sodium hydrogen sulfate (1 6 g) in water The resulting solution was treated with (10 mL) and stirred for 30 min then extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The title compound (5.8 g, 78%) was obtained as a white solid (yield: EtOAc: EtOAc) HNMRCDMSO-A) δ 9.46 ( s, 1H )&gt; 8.29 ( d, 1H, J = 5.6 Hz) &gt; 7.46 ( d, lH, J = 5.0 Hz ) &gt; 1 .44 ( s, 9H ) ; MS ( ESI+ ) : m/z 352.99 (MH)+.

B) 4-Chloro-3-iodopyridin-2-amine

Suspension of (4-chloro-3-iodo-pyridin-2-yl)-aminecarboxylic acid tert-butyl ester (5.6 g, 15.8 mmol) in 48% hydrobromic acid at 10 ° C The solution was heated for 10 minutes to produce a clear solution. The mixture was cooled, crushed ice was added and made to dryness with 6M sodium hydroxide. The precipitated product was collected by a vacuum filtration method, washed with water and partially sorbed to a funnel to give a white solid. The title compound (3.7 g, 93%) eluted elute iH NMR ( DMSO- d6 ) &lt; 5 7.84 ( d, 1 H, J = 5. 1 Hz ) , 6.73 (d, lH, J = 5.6 Hz (128) 1324926 ), 6.5 1 (br s5 2H ) ; MS ( ESI+ ) : m/z 254.97 ( M + H) +

C) 4-(2-Fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine

4-Chloro-3-iodopyridin-2-amine (3.6 g, 14.2 mmol) and 2-fluoro-4-nitroindole (Lancaster, 4.5 g, 28.4 mmol), DIPEA (3.6 mL, 20· The mixture of 7 mmol) and NMP (8 mL) was placed in a glass pressure bottle and rapidly heated to 170 ° C and heated for 18 hours. The volatile components were evaporated under reduced pressure and the viscous residue was poured into ice water (150 mL). The mixture was subjected to ultrasonic treatment for 15 minutes to break up the colloidal solid, and the pH of the mixture was adjusted to 7.5 with a saturated aqueous solution of sodium hydrogencarbonate. The solid was collected by vacuum filtration and the solid was washed with water and allowed to sorb on the funnel to the extent that it was partially dried. The partially dried solid was suspended in toluene (150 mL) and concentrated in vacuo, and the procedure was repeated three times to afford a brown solid. The product was dissolved in methanol (150 mL), EtOAc (EtOAc)EtOAc. The ethyl acetate thus obtained was washed with ethyl acetate and the residue was dissolved in ethyl acetate and saturated aqueous sodium hydrogencarbonate. The ethyl acetate phase was separated and washed with brine. Then, it was dried over -132-8 (129) 1324926 magnesium sulfate. The ethyl acetate solution was treated with activated carbon, stirred at room temperature for 1 Torr, and then the activated carbon was filtered off. The title compound (3.9 g, 7 4%) was obtained. 'H NMR (DMSO-i/6) 5 8.39 (dd, 1H, J = 2.5, 10.7 Hz), 8.12 (dd, 1 H, J = 1.5, 9.2 Hz), 7.86 (d, 1 H, J = 5.6 Hz), 7.32 ( dd, 1H, J = 8.6, 8.6 Hz), 6.40 ( br s, 2H) &gt; 6.18 ( d, 1 H ) - J = 5.6 Hz ).

〇) 4-(2-Fluoro-4-nitrophenoxy)-3-vinylpyridin-2-amine

In a similar manner to that described in Step B of Example 3, via a Stille coupling reaction, 4-(2-mercapto-4-nitrophenoxy)-3.iodopyridine 2-Amine and tributylvinyltin were prepared to give the title compound. 1H NMR ( DMSO-i/6) 5 8.35 ( dd, 1H, =10.7, 3.1 Hz), 8.09 (d, 1H, J = 9.2 Hz), 7.85 (d, 1 H, J = 5.6 Hz), 7.3 1 -7. 1 5 ( m, 1 H ) , 6.54 ( dd, 1 H, J = 17.8, 11.7 Hz) &gt; 6.24 ( br s, 2H) &gt; 6.20 ( d, 1H, J = 5.6 Hz) &gt; 5.71 ( d, 1 H, J = 17.8 Hz ) , 5.46 (d, lH, «7=11.7

Hz) ; MS ( E S Γ ) : m/z 276.17 (M + H)+. -133- 8 (130) 1324926 N〇2 E) 4-(2-Fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylaminecarboxylic acid tert-butyl ester

Treatment of 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-amine (60 mg, 0.22 mmol) with B.sub.2C (140 mg, 0.64 mmol) A solution of 1,4-dioxane (0.5 mL) and third butanol (1.5 mL) was heated at 65 °C for 5 hours. The mixture was cooled and dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The title compound (50 mg, 60%) was obtained as a yellow solid (HNMRC DMSO-^) 5 9., 37 (s, 1) Η ) , 8.4 1 ( dd,1 Η, J = 1〇_7,2.5Hz) , 8.22 ( d,1 H, J = 5.6Hz) , 8.15 ( d,1H, J = 8.6Hz ) , 7.42 ( t , 1H, J = 8.6Hz ) , 6.86 ( d5 1 H, J = 5.6Hz) , 6.58 ( dd , 1H , J = 17.8 , 11.7Hz ) , 5.82 ( d,1H, J = 16.3Hz ) , 5.52 ( d , 1H, J = 11.7Hz ) « 1.42( s, 9H ) ; MS ( ESI+ ) : m/z 3 76.1 8 ( M + H ) +. -134- (131) 1324926

F) 4-butyl 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate

A solution of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridin-2-ylcarbamate (48 mg, 0.13 mmol) using hydrogen from a rubber balloon Hydrogenation was carried out for 1.5 hours on 10% carbon (10 mg) and Pt2 (5 mg). The mixture was filtered through EtOAc EtOAc (EtOAc) (EtOAc) (d, 1 Η, J = 5.6Hz), 6.95 ( dd, 1 Η, J = 8.6, 8.6Hz ), 6.50 ( dd, 1Η, J = 2.5, 1 3.2Hz ) , 6.4 1 ( dd, 1H, J = 2.5, 9.4Hz ) , 6.36 ( d,1H, J - 5.6Hz) , 5.44 ( s, 2H ), 2.67-2.62 ( m, 2H) &gt; 1.43 ( s, 9H) - 1.11 ( t, 3H, J = 7.1Hz) ; MS ( ESI+) : m/z 348.22 ( M + H ) + 〇

G) 3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)ethenyl) 135 8 (132) 1324926 Urea)phenoxy)pyridine-2 - butyl carbamic acid tert-butyl ester in a similar manner to Step D of Example 33, from 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylaminecarboxylic acid The title compound was prepared as a 3M solution (EtOAc / EtOAc) MS ( ESI+ ) m/z 5 2 7.3 1 (M + H)+.

H) 1-(4-(2-Amino-3-ethylindole It UD-4-yloxy)-3-phenyl)-3-(2-(4-fluorophenyl)acetamidine Urea, trifluoroacetate, 3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)ethyl)-ureido)phenoxy)pyridine- A solution of the tert-butyl 2- carbamic acid ester (16 mg, 0.03 mmol) was dissolved in anhydrous THF (0.5 mL). Stir for 3 hours. The title compound (5 mg, 36%) was obtained as a white solid. NMR (DMSO-d6) &lt;5 11.06 ( s, 1 Η ) &gt; 1 0.6 ( s, 1 Η ) , 7.80-7.79 (m, 4H) &gt; 7.43 -7.3 3 ( m, 4H) &gt; 7.1 6 ( Dd, 2H, J = 8.9, 8.9 Hz), 6.19 (d, lH, · / = 7.1 Hz), 3.73 (s, 2H) &gt; 2.7 1 - 2.66 ( m, 2H ) , 1.10 ( t, 3H, J = 7.1 Hz) ; MS ( ESI+ ) : m/z 427.18 (M + H), Example 3 5 8 (133) 1324926

(4-(3-(2-(4-Aminocyclohexyl-fluorenyl)ethynyl)pyridinyl-4-yloxy)-3-fluorophenyl)-3-(2-(4') Fluorophenyl)ethylidene)urea

BocHN

OTf A) 4-(Tertiary oxycarbonyl)cyclohexan-en-yl trifluoromethanesulfonate W-Boc-4 - keel cyclohexanone (AStatech inc., 213 mg, 1.0 mmol) in THF ( The resulting solution was cooled to -7 π and treated with 〇.5M KHMDS in toluene (2.4 mL, 1.2 mmol). The mixture was stirred at -70 °C for 20 minutes, and a solution of phenyltrifluoromethanesulfonimide (392 mg, 1.1 mmol) in THF # (4 mL) was added dropwise, and _7 〇 Stir at °C for 25 minutes. The mixture was quenched with aq. aq. EtOAc (EtOAc)EtOAc. The title compound was obtained as a white solid (180 mg, 52). %). i NMR (DMSO-heart) 5 5.68 ( s, 1 Η ) , 4.50 ( s, 1 Η ) , 3.82 (s, 1H ) , 2.68-2.25 ( m, 3H ) , 2 · 2 2 - 1 . 8 9 ( m, 2 H ), 1.87- 1.63 ( m, 1 H ) » 1.43 ( s, 9H ). -137- (134)1324926

BocHN B ) 4- (2-(trimethyldecyl)ethynyl)cyclohex-3-enylaminecarboxylic acid tert-butyl ester

The 4-(t-butoxycarbonyl)cyclohex-1-enyl trifluoromethanesulfonate (170 mg, 0.49 mmol), trimethyldecyl acetylene (138 &quot; L, 0.98) was rinsed with argon in a reaction flask. A mixture of mmol), triethylamine (0.68 mL) and THF (8 mL) was then taken from &lt;RTI ID=0.0&gt;0&gt; The reaction mixture was stirred at room temperature for 25 min then diluted with EtOAc EtOAc. The title compound (1 16 mg, mpjjjjjjjjjjjjjjjjjjjjj

8 1%) °1H NMR (DMSO-heart) 5 6.06 ( s, 1 Η ) &gt; 4.50 ( s, 1 Η ) , 3.76 ( s, 1 Η ) , 2.46 ( d, 1 H, J = 1 8.8 Hz ) , 2.36-2.14 ( m,2H) - 2.00- 1 .7 8 ( m, 2H ) &gt; 1.66- 1 .5 0 ( m, 1H ), 1.43 ( s, 9H) &gt; 0.27-0.05 ( m, 9H ).

BocHN C) 3-ethynylcyclohex-3-enylaminecarboxylic acid tert-butyl ester 4-(2-trimethyldecyl)ethynyl)cyclohex-3-enylamine A-138-8 (135 1324926 The solution of the acid tert-butyl ester (112 mg, 〇38 mm〇l) in THF was cooled to -15 ° C. '1 〇μ of tetrabutylammonium fluoride in THF (Aldrich, 440) /2 L' 〇·44 mmol) was treated and the mixture was stirred at -15 ° C for 40 minutes. The mixture was treated with 5% sodium carbonate (25 mL) and extracted with diethyl ether. The title compound (83 mg, 99%) was obtained eluted elute咜• NMR ( DMSO-t/i ) &lt;5 6.09 ( s, 1Η ) , 4.51 ( s, 1Η ) * 3.77 (s,lH) » 2.82 ( s, lh ) . 2.47 ( d, 1H, J = 18.3 Hz), 2.35-2.16 (m, 2H), 2.04-1.79 (m, 2H), 1.72-1.51 (m, 1H), 1.43 (s, 9H).

® D) 4-(2-(4-(2-Fluoro-4)nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylaminecarboxylic acid tert-butyl ester with triethyl Treatment of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33 '130 mg, 0.36 mmol) and #-Boc-4-acetylene with amine (2 mL) A solution of the cyclohexan-3-amine (80 mg, 0.36 mmol) in dry THF (2 mL) was evaporated and evaporated from vacuo. This solution was treated with hydrazine (triphenylphosphine)palladium (20 mg' 0.0018 mmol) and Cul (1 〇 mg, 0.054 mmol), and then heated to reflux for 2 hr. The mixture was cooled and dissolved in saturated aqueous solution of -139- (136) 1324926 and sodium bicarbonate and ethyl acetate. The ethyl acetate phase was separated, washed with brine, dried (MgSO4) The title compound (12 4 mg - 76%) was obtained as a yellow solid. H NMRCDMSOO &lt;5 8.6 8 ( s, 1 Η ) ' 8.51 ( d,1Η, J = 5.6 Hz ) , 8.43 ( dd, 1H, J = 2.5, 1 〇. 7Hz ) , 8.15 ( d, 1H, J = 9.2 Hz) , 7.49 ( dd, 1 H, J =

• 8.6, 8.6 Hz), 7.14 (d, 1H, / = 5.6 Hz), 6.85 (d, 1H, J = 7.1 Hz) &gt; 6.04-6.00 (m, 1H), 3.48-3.35 (m, 1H), 2.36-2.25 ( m,1H) , 2.17-2.04 ( m,2H) , 2.03-1.89 ( m, 1 H ) - 1.78- 1.69 ( m, 1 H ) &gt; 1.46- 1 .3 5 ( m, 1 H ) &gt; 1.36 ( s, 9H ) ; MS ( ESI+) : m/z 454.27 ( M + H ) + .

BocHN E) 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylaminecarboxylic acid tert-butyl ester in l〇 4-(2-(4-(2-Fluoro-4)nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylaminecarboxylic acid tert-butyl ester at 〇°C (110 mg &gt; 0.24 mmol), iron powder (~325, 150 mg, 2.7 mmol), ammonium chloride (280 mg, 5.3 mmol), DMF (1 mL), water (1 mL) and ethanol (1 mL) The mixture was heated for 30 minutes. The mixture was filtered through a Celite® filter pad, the filter cake was rinsed with DMF, and the filtrate was made basic with pH 8 using a solution of 14 〇 8 (137) 1324926 and sodium bicarbonate. The mixture was extracted twice with EtOAc EtOAc EtOAc m. MS ( ESI+) ·· m/z 424.27 ( M + H) +.

F) 4-(2-(4-(2)fluoro-4-(3-(2-(4-fluorophenyl)ethyl) ureido)phenoxy)pyridin-3-yl)ethynyl a 0.3 Μ solution of 2-(4-fluorophenyl)ethenyl isocyanate in toluene (Compound D of Example 11, 0.8 mL, 0.24 mmol) , to treat tert-butyl 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylaminecarboxylate (50 A solution of mg, 0_12 φ mmol) in anhydrous dichloromethane (2 mL), and the mixture was stirred at room temperature for one hour. The solvent was evaporated in vacuo and purified by flash chromatography (EtOAc-EtOAc-EtOAc) The title compound) 501^'69%). ...1^1^1^)01^50·心)5&quot;·03",1Η) 5 10.57 ( s, 1Η ) « 8.57 ( s, 1Η ) ' 8.36 ( d, 1H, J = 5.7Hz) ' 7.78 ( dd, 1H, J = 1.8, 3.1Hz ), 7 4 1 -7.29 ( m,3H ) &gt; 7.16 ( dd, 3H, J = 8.6, 8.6Hz) .6.85 ( 1H, J = 8.3Hz ) &gt; 6.70 ( d, 1H, J = 5.7Hz), • 141 - (138) 1324926 6.13-6.08 (m,1H) , 3.73 ( s, 2H) , 3.51-3.41 (m,1H) &gt; 2.38-2.27 (m , 1H) , 2.27-2.20 (m, 2H) &gt; 1.82 - 1.72 ( m, 1H ) &gt; 1.54-1.28 ( m, 2H) , 1.37 ( s, 9H) ; MS ( ESI+ ) : m/z 60 3.24 (M + H ) + G) 1-(4-(3-(2-(4-Aminocyclohex-1-enyl)ethynyl).pyridine·

4-(yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride salt 4-(2-(4-(2-fluoro) Tert-butyl 4-(2-(2-(4-fluorophenyl)ethenyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylaminecarboxylic acid A solution of (40 mg, 0.066 mol) in dry 1,4-dioxane (2 mL) was cooled to -10 &lt;0&gt;C and treated with &lt The mixture was stirred at -5 °C for 2 hours and then stirred at room temperature for 1 hour. The title compound was obtained as a yellow solid (32 mg, 84%). 'HNMRC DMSO-heart) δ 11.05 ( s, 1 Η ), 10.61 ( s, 1 H ) &gt; 8.69 (s, 1H ) , 8.44 (d, 1H, 6.1 Hz) &gt; 8.06 (d, 1H, J = 2.0 Hz ) &gt; 7.80 (dd, 1H, 12.7, 2.0Hz) &gt; 7.46-7.38 ( m, 1 H ), 7.35 (dd, 1H, 8.6, 5.6 H z ), 7.19-7.13 ( m, 1 H ) ' 6.82 (d, 1H, 5·6Ηζ), 6.17 ( s, 1Η), 3.74 ( s, 2H) &gt; 3.73-3.62 ( m, 2H ) &gt; 3.62-3.5 4 ( m, 1 H ) , 3.34 - 3.22 (m,lH) &gt; 2.3 1 (

s, 1 H ) 1.99- 1 .96 ( m, 1 H ) &gt; 1 .7 1 -1 .66 ( m, 1 H ) ; MS (ESI+ ) : m/z 5 03.1 2 ( M + H ) + . (139) 1324926 Example 3 6

φ 1-(4-( 3-( 3-( 3-(aminomethyl)azetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3_fluorophenyl) -3-(2-(4-fluorophenyl)ethenyl)urea, trihydrochloride

N〇2

A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)propan-2-yn-1-ol is 4-(2-) by vacuum/argon rinsing Fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33, 300 mg, 0.83 mmol), propargyl alcohol (Aldrich, 145/zL, 2.50 mmol), triethylamine The solution formed by (2 mL) and anhydrous THF (2 mL) was degassed and treated with Pd ( Ph3P) 4 (31 mg, 0.02 7 mmο 1 ) and CuI (10 mg, 0.054 mmol). The mixture was heated to reflux for 1 min in an argon atmosphere, then cooled to room temperature and diluted with ethyl acetate (25 mL) and water (20 mL). Wash the ethyl acetate phase with water and brine and give (140) 1324926

Dry (magnesium sulphate) and vacuum flash chromatography (purified with 0 - 3 % methyl residue) to give a pale yellow color &lt; 7 7%. 〇1H NMR (DMSO-d, 1H, J = 5. 6 Hz) , 8.43 ( 8.17 ( d, 1H, J = 9.2 Hz ), 7.04 ( d, 1H, J = 5.6 Hz), 4.28 ( d, 2H, J = 6.1 Hz); M + H ) • concentrated in fo. The desired compound (1 8 5 mgd) of the crude residue was δ 8.6 9 ( s5 1 Η ) , 8.49 ( dd, 1 Η, J = 10.7, 2.5 Hz) using the methylene chloride). ), 7.57 ( t, 1H, J = 8.6Hz ), 5.40 ( t, 1 Hs J = 6.1Hz), :MS ( ESI+ ) : m/z 2 89.1 3 (

No2 B) (1-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)propyl-# 2-ynyl)azetidin-3-yl)methyl 3-butyl 4-carbamate, 3-(4-(2-fluoro-4-nitrophenoxy)methane-3-yl)propan-2-ol-1-ol (43 mg, 0.15 mmol) And the solution of DIPEA (45//L, 0.26 mmol) in anhydrous THF (1.5 mL) was cooled to 〇t, and a whole portion of a fluorinated chlorine (15 mg, 0·11 mmo 丨) was added at a time. . After stirring at 〇 ° C for 1 hour, the mixture was concentrated under reduced pressure. Residues were treated with DMF (1.0 mL), DIPEA (45 &quot; L, 0.26 mmol) and tert-butyl 3-methyl-amino-carbamic acid (Beta Pharma Inc., 145 mg, 0.78 mmol) And stirred at room temperature for 2 hours. -144- 8 (141) 1324926 The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the ethyl acetate phase was separated and rinsed with brine. Concentrate in the middle. The title compound (3 3 mg, EtOAc (m.) 48%). 'H NMR(DMSO-i^) &lt;5 8.7 4 ( s, 1 Η ) » 8.51 (d,1Η, J = 5.6Hz) , 8.41 ( dd, 1H, J = 10.7, 2.5Hz) - • 8. 1 5 ( d, 1H, J = 9.2Hz ), 7.53 ( t, 1H &gt; J = 8.6Hz ), 7.09 ( d, 1 H, J = 6.1Hz) ' 6.86 ( t, 1H, J = 5.6 H z &gt; 3.39 ( s, 2H ) &gt; 3.24-3.14 ( m, 2H ) » 3.07-2.98 ( m, 2H )

, 2.94-2.87 (m, 2H), 2.37-2.26 (m, 1H), 1.33 (s, 9H); MS ( ESI+ ) : m/z 401.20 ( 1 00 ) , [( M-C4H9 )]+ :m /z 457.20 ( 25) , ( M + H ) +.

C) (1-(3-(4-(4)amino-2-fluorophenoxy)pyridinyl)prop-2-ynyl)azetidin-3-yl)methylaminecarboxylic acid Butane vinegar was treated with iron powder (5 〇 mg ' 〇. 〇 91 〇 〇 1) and ammonium chloride (96 mg, ! 82 〇丨 〇丨) in the same manner as in the step E of Example 35. (3-(4-(2-Fluoro-4-nitrophenoxy)pyridine 3yl)propan-2-ynyl)azetidin-3-yl)methylaminecarboxylic acid tert-butyl ester (3〇 The title compound can be prepared by reduction of mg, 〇66 mm 〇 1). This product was used directly in the next step of 8-145-(142) 1324926 without any purification. MS ( ESI + ) : m/z 3 7 1.24 ( 100 ) , 〔 ( M-C4H9 ) 〕+ : m/z 427.27(25) , ( M + H ) +

D) (1-(3-(4-(2-Fluoro-4-(3-(2-(4-fluorophenyl)ethinyl)) glyoxy)pyridin-3-yl)propyl 2-(Alkynyl)azetidin-3·yl)methyl butyl carbamic acid tert-butyl ester (1-(3-(4-(4-)-amino group) by the same procedure as in the step D of Example 33 -2 -Fluorophenoxy)pyridin-3-yl)propan-2-ynyl)azetidin-3-yl)methylaminecarboxylic acid tert-butyl ester (25 mg, 0.05 9 mmol) and 2-( The title compound was obtained as a white solid (20 mg, EtOAc, m. &gt; 5 7%). 'H NMR (DMSO-i^) &lt;5 11.04 ( s, 1 Η ), 10.58 ( s, 1 Η ) &gt; 8.63 ( s, 1 Η ) , 8.37 (d, 1H, "/= 5.5Hz ), 7.78 ( d, 1H, J = 12.6Hz ) , 7 · 4 0 - 7 · 3 3 ( m,4 H ), 7.16 ( dd, 2H, J = 8.8, 8.9Hz ) &gt; 6.89-6.87 ( m, 1H ) &gt ; 6.68 ( d, 1 H, J - 5.5Hz ) &gt; 3.73 ( s, 2H ) &gt; 3.45 ( s, 2H ) &gt; 3.26-3.24 ( m, 2H ) « 3.07-3.04 ( m, 2H ) &gt; 2.98 -2.96 ( m, 2H ) &gt; 2.3 8 -2.3 5 ( m, 2H ) , 1.32 ( s, 9H) ; MS ( -146- (143) 1324926 ESI+ ) : m/z 606.26 ( M + H ) + . E ) 1 - ( 4-( 3 · ( 3-( 3-(aminomethyl)azetidin-1-yl)prop-1-ynyl)pyridin-4-yloxy)-3_fluorophenyl )-3-(2-(4-fluorophenyl)ethenyl)urea, trihydrochloride will (Bu(3-(4-(2-fluoro)-4-(. 3-(2-() 4-fluorophenyl)ethinyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynyl)azetidine-3 · φ-yl)methylaminecarboxylic acid tert-butyl ester (20 mg , 0.033 mmol) was dissolved in dichloromethane (2 mL). The mixture was concentrated under vacuum and purified by preparative HPLC (layer A) to afford trifluoroacetate. The title compound (9 mg, 45%) was obtained as a white solid. 1 H NMR (DMSO-heart) (5 1 1.07 ( s, 1 Η ) &gt; 1 0.06 ( s, 1 Η )

• , 8.96(m,lH) &gt; 8.61 -8.52 ( m, 1 H ), 8.36-8.25 ( s, 2H ), 7.82 ( d, 1H, J = 12.2Hz ) , 7.45 -7.42 ( m, 2H ) 7.3 7 -7.3 3 ( m, 2H) - 7.18-7.14 ( m, 2H) &gt; 6.92 ( d, 1H, J = 6.1Hz) , 4.48 ( s, 2H) , 4 · 2 7 - 3 · 9 8 ( m , 2 H ) &gt; 3.76 (s, 2H), 3.30-3.20 (m, 1H) &gt; 3.16-3.00 (m, 2H); MS (ESI+): m/z 5 06.1 8 (M + H) +. Example 3 7-40 was prepared in a similar manner to that described in Example 36. (144) 1324926 Example 3 7

1-(4-(3-(3-(3-Aminobutyridin-1-yl)prop-1-ynyl)pyridin-4- φ yloxy)-3-fluorophenyl)-3-( 2-(4-Fluorophenyl)ethinyl)urea, trihydrochloride MS (ESI+): m/z 492.17 (M + H) +.

1-(3-Fluoro-4(3-(3-(hexahydropyrazin-1-yl)propanyl)pyridin-4-yloxy)phenyl)-3-(2-( 4·fluorophenyl)ethinyl)urea, trihydrochloride'H NMR (DMSO-^6) δ 11.07 ( s, 1 Η ) , 10.63 ( s, 1 Η ) &gt; 9.44 ( s, 1 Η ) &gt; 8.9 1 ( s, 1 Η ) &gt; 8.50 ( d, 1Η, J = 6.2Hz ) , 7.84 - 7.7 8 ( m, 1 H ) - 7.4 5 -7.3 9 ( m, 2H ), 7.38-7.32 ( m, 2H) &gt; 7.16 ( t, 2H, J = 8.8Hz) &gt; 6.85 ( d, IH, J = 6.2Hz ) , 4.26 ( s, 2H) - 3.75 ( s, 2H ) , 3.34 ( -148- (145) 1324926 br s, 4H ) , 2.49 ( br s, 4H ) ; MS ( ESI+ ) : m/z 5 06.2 3 (M + H) + . Example 3 9

1 - ( 4 - ( 3 - ( 3 - ( 4 -aminohexahydropyridin-1-yl)propan-1 -ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-( 2-(4-Fluorophenyl)ethenyl)urea, trihydrochloride 1H NMR (DMSO-^6) δ 11.07 ( s, 1 Η ) &gt; 1 0.62 ( s,

1 Η ) - 8.8 1 ( s, 1 Η ) &gt; 8.48 ( d, 1 H, J = 6. 1 Hz ) &gt; 8.3 1 ( s, 2H ) &gt; 7.80 ( dd,1 H, J = 2.2, 1 2.7 Hz ) , 7.44 - 7.33 ( m, 4H ) , 7.19 - 7.13 (m, 2H) &gt; 6.78 (d, 1H, J = 5.7 Hz) &gt; 4.40 ( s, 2H ) · 3.74 ( s, 2H ) &gt; 3.64-3.60 ( m, 2H ), 3.34-3.22 ( m, 1H) - 3.19-3.13 ( m, 2H) &gt; 2.16-2.13 ( m, 2H ) , 1.99-1.8 8 ( m, 2H) ; MS ( ESI+) : m/z 5 06.23 ( M + H) +. Example 40 -149- 8 (146) 1324926

(± ) -1 · ( 4 - ( 3 - ( 3 - ( 3 • Aminopyrrolidin-1-yl)propan-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)- 3-(2-(4-Fluorophenyl)ethyl fluorenyl) urea, trihydrochloride]H NMR ( DMSO-^6 ) δ 11.08 ( s, 1 Η ) &gt; 10.65 ( s, 1 Η ) &gt; 8.96 ( s, 1Η ) &gt; 8.54 ( d, 1Η, J = 6.1Hz ) , 7.83 ( d, 1H, J = 12.7Hz ) , 7.43 ( s, 2H) , 7.3 7-7.3 3 ( m, 2H &gt; 7. 1 6-7. 14 ( m, 2H ) &gt; 6.90 ( d, 1H, J = 5.6Hz ) &gt; 4.62 ( s, 2H) &gt; 4.06-3.8 7 ( m, 1H ) , 3.75 (s, 2H), 3.70-3.55 (m, 3H) &gt; 3.49-3.44 ( m, 2H ) &gt; 2.25-2.08 ( m, 1H ); MS ( ESI+ ) : m/z 506.22 ( M + H ) + .

1-(3-Fluoro-4-(3-(3-((3R,4R)-3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)prop-1-yl) Pyridin-4-yloxy)phenyl)-3--150-(147) 1324926 (2-(4-fluorophenyl)ethenyl)urea, trihydrochloride

A) (3Λ,4Λ)-1-(3-(4-(2-fluoro)4-nitrophenoxy)pyridine-3-yl)prop-2-ynyl)-4-(pyrrolidine- 1-) Pyrrolidine-3-ol 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)propan-2-yn-1-ol (compound of Example 36) A' 43 mg, 0.15 mmol) and a solution of DIPEA (45 μL &gt; 0.26 mmol) in dry THF (1.5 mL) was cooled to 〇 ° C, and methanesulfonium chloride (15 mg, 0.11 mmol) was added portion by portion. ). After stirring at 〇 ° C for 1 hour, the mixture was concentrated under reduced pressure. DMF (1.OmL) ' DIPEA ( 45 ^ L « 0.26 mmol ) and (3 and 47? ) -4-(pyrrolidin-1-yl)pyrrolidin-3-ol (

The residue obtained was treated with Lexicon Pharmaceutical Corp., 94 mg, 0.6 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc EtOAc (EtOAc)EtOAc. Purification by flash chromatography on EtOAc (EtOAc: EtOAc:EtOAc 59%). h NMR (DMSO-heart) &lt;5 8.72 ( s, 1 Η ) , 8.54 ( d, 1H, J = 5.6 Hz ) , 8.40 ( dd, 1H, J = 10.7, 2.5 Hz), 8.14 (d, 1 H, -151 - (148) 1324926 J = 9.2Hz ) &gt; 7.43 ( t, 1 H, J = 8.6Hz ) &gt; 7. 1 5 ( d, 1H, J = 5.6Hz ) &gt; 4.99-4.8 1 ( m , 1 H ) ' 4.11-4.10 ( m, 0.5H ),

3.92-3.84 (m, 1H) &gt; 3.54( s, 2H ) , 3.59-3.50 (m, 0.5H ), 3.16-3.15 (m, 1H) , 2.79-2.75 (m, 1H) &gt; 2.60-2.32 ( m, 4H), 1.70-1.59 (m, 4H); MS (ESI+): m/z 427.24 ( M + H ) + .

B) (3Λ, 4/〇-1-(3-(4-(4-Amino-2-fluorophenoxy)pyridine-3-yl)prop-2-ynyl)-4-(pyrrolidine) -1-yl)pyrrolidin-3-ol

Iron powder (67 mg, 1.2 mmol '2.4 mmol) was added to (3Λ,4Λ)-1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)propane a mixture of 2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (35 mg, 0.082 mmol), DMF (1 mL), ethanol (1 mL) and water (1 mL) Stir at 100 ° C for 45 minutes. The mixture was filtered through Celite®, which was made basic with sodium bicarbonate and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was dried with EtOAc (EtOAc m.) MS (ESI+): m/z 3 97.2 8 ( M + H ) + » -152- (149) 1324926 c) 1-( 3-fluoro-4-(3-(3-( (3/?,4Λ) -3-hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)propanyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluoro) Phenyl)ethinyl)urea, trihydrochloride, in a similar manner to step D of Example 33, from (3/?,4/?)-1.(3-(4-(4-amino) -2·oxyphenoxy)pyridinium-3-yl)propan-2-ynyl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol (16 mg, 0.04 Φ mmol) The title compound was prepared from a 0.3M solution of EtOAc (EtOAc m. The product was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) 3%) 〇JHNMR(DMSO-A) (5 11.06 (s, 1 Η ), 10.62 ( s, 1 Η ) , 8.86 ( s, 1 Η ) , 8.45 ( d, 1 H, J = 6.1 Hz ), 7.8 1 ( d, 1H, J = 12.2Hz) , 7.45-7.40 ( m, 4H ) &gt; Φ 7.3 3 -7.2 8 ( m,4H) , 7.16 ( dd, 2H, J = 9.2,8,6Hz), 6.80 ( d, 1H, J = 6.1Hz) · 4.64 ( s, 1 H ) &gt; 4.34 ( s, 2H )

, 3.84-3.70 (m, 4H) &gt; 2.70-3.55 (m, 2H) &gt; 3.55-2.98 ( m, 3 H ) &gt; 2.08- 1.92 ( m, 2H ) , 1.92-1.75 (m, 2H); MS (ESI+): m/z 5 76.25 (M + H) +. Example 42 (150) 1324926

F

1-(3-Fluoro-4-(3-(3-(2-pyrrolidin-1-yl)acetamido)propanyl)pyridin-4-yloxy)phenyl)-3 - (2-(4-Fluorophenyl)ethenyl)urea, dihydrochlorate A) #-B〇C-propargylamine dissolves diacetate diacetate (21.8 mg, 100.0 mmol) In THF (25 mL) and the resulting solution was cooled to 〇 ° C, then a solution of propargylamine was added dropwise (Aldrich, 5.0 g) while maintaining the temperature below 15 °C. , 90.0 mmol). The mixture was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue obtained was dissolved in hexanes and filtered through a silica gel column and washed with Ο-ΐ 00 % methylene chloride / hexanes. The product-containing eluate was concentrated in vacuo to give a colorless oil which was dissolved in hexanes (1 50 mL) and cooled to 〇 ° C to give white crystals. . The crystals were collected by filtration and dried in vacuo to give the title compound (l.sup.5g, 75%) «iNlVIRCCDCh) 64·75 (s, 1Η), 3.95 (s, 2H) &gt; 2.25-2.24 ( m, 1H ) · 1.48 ( s, 9H). -154- (151) 1324926

B) 3-butyl 4-(4-(2-fluoro)-4-nitrophenoxy)pyridin-3-yl)propan-2-ynylamine

According to step C of Example 35, Pd(Ph3P) 4 (9 mg, 0.008 mmol) and Cul (1.5 mg 1 0.008 mmol) in 1:1 triethylamine/THF (3 m L) were used. Nagasica cross-linking reaction ( Sonagashira crosscoup 1 ingreacti ο η ) from TV-B oc -propargylamine (98 mg, 0.63 mmol) and 4-(2-fluoro-4-nitrophenoxy) -3 -iodohydrazinium J.D. (Compound A of Example 33, 150 mg, 0.42 mmol). The title compound (124 mg, 7 6%) was obtained as a red oil. [H NMR (DMSO-i/e) δ 8.66 ( s, 1 Η ) , 8.50 (d3 1H, J = 5.6 Hz ) , 8.40 ( dd, 1 Η, J = 2.5, 10.7 Hz) , 8.15 ( d, 1H, J = 9, 2 Hz ) , 7.52 ( dd, 1H, J = 8.1, 8.6 Hz) &gt; 7.3 3 -7.3 0 ( m, 1H ) , 7.0 7 ( d,1H,J = 5,6Hz ) , 3.95 ( d,2H, J = 5.6Hz ) , 1.35 ( s, 9H ) ; MS (ESI+ ) : m/z 3 8 8.1 2 ( M + H ) +.

C) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yne--155_ ® (152) 1324926 1-amine treated with TFA (2 mL) 3 - ( 4 -( 2 -Fluoro-4 -nitrophenoxy)pyridin-3-yl)prop-2-ynylaminecarboxylic acid tert-butyl ester (300 mg, 0.78 mmol) in dichloromethane ( 10 mL) of the resulting solution was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was separated and washed with EtOAc (EtOAc m.) 4 NMR (DMSO-i^) δ 8.65 ( s, 1 Η ) &gt; 8.47 ( d, \Η, J = 5.6 Hz ) - 8.43 ( dd, 1 Η, J = 10.7, 2 - 5 H z ) ' 8.17 ( d, 1H, J = 8.6Hz) - 7.54 (t, 1H, J =

8.6Hz ) &gt; 7.04 ( d, 1H, J = 5.6Hz ) &gt; 3.49( s, 2H ) : MS (ESI+ ) : m/z 2 8 8.1 7 ( M + H ) +»

D) #-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1·yl)acetamidine Amine 3-(4-(2-Fluoro-4,nitrophenyloxy)pyridin-3-yl)prop-2-yn-1-amine (80 mg, 0.26 mmol) in anhydrous dichloromethane 2.5 mL) The resulting solution was cooled to 〇 ° C, and chloroethyl chlorobenzene (40 mg, 0.37 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to remove the solvent and excess reagents, and -156- (153) 1324926 was dissolved in CH.sub.3CN (1.5 mL). 55 mg, 0.78 mmol) and stirred at room temperature for 4 hours. The mixture was dissolved in ethyl acetate and aq. EtOAc (aq.). The title compound was obtained as a brown oil (4 mg, m. • ). NMR (DMSO-heart) 5 8.66 ( s,1H ), 8.50 ( d,1H, J = 6«lHz) ' 8_41 ( dd,1H, J = 2.8, 10.4 Hz ) , 8.18-8.15 (m,2H) &gt ; 7.5 1 ( dd, 1H, J = 8.3, 8.8Hz ) , 7.06( d, 1H, J = 5.5Hz ) ' 4.10 ( d, 2H, J = 5.5 Hz ) &gt; 3.01 ( s, 2H ) &gt; 2.47 - 2.43 (m, 4H) &gt; 1.67- 1.63 (m, 4H); MS (ESI+): m/z 3 99.2 7 ( M + H ) + .

E) (3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)propan-2-yl-yl)-2-(pyrrolidin-1-yl)acetamide In a similar manner to the procedure of Example 3-5, (3-(4-(2-fluoro)-4) was obtained by using iron powder (67 mg, 1.21 mmol) and ammonium chloride (128 mg, 2.42 mmol). Reduction of -nitrophenoxy)pyridin-3-yl)propan-2-yl)-2-(pyrrolidin-1-yl)acetamide (35 mg, 0.088 mmol) afforded the title compound. This product was used directly in the next step of -157-(154) 1324926 without any purification. Yellow oil (30 mg ' 9 3%) °MS (ESI+): m/z 319.24 (M + H) + ° F) 1-( 3-fluoro-4-(3- (3- (2- Pyrrrolidine·fluorenyl)ethylamino)propanylpyridin-4-yloxy)phenyl)-3(2-(4.fluorophenyl)ethenyl)urea, dihydrogen Chlorate was used in a similar manner to Step D of Example 3, using 'THF (0^0.5 mL), from #-(3-(4-(4-amino-2-difluorophenoxy)pyridine) 3-yl)prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (32 mg '0.088 mmol) and 2-(4-fluorophenyl)ethenyl isocyanate formed in toluene A 0.3 M solution (Compound D of Example 11, 0.40 mL, 0.12 mmol) The product was purified using preparative HPLC (Layer B). The title compound (30 mg, 63%) was obtained as a pale yellow solid. 4 NMR (DMS〇-& suspicion) &lt;5 11.07(s,1H), l〇.62(s,1H), l〇.G9(s,1H) ' 9.17-9.14 ( m, 1Η ) - 8.65 ( s, 1 Η ) &gt; 8.43 ( d, 1H, J &quot; 5.6Hz) &gt; 7.81 ( dd, 1 H, J = 2.5, 12.7Hz ) &gt; 7.44-7.3 3 ( m,4H) ' 7.19- 7.12 (m,2H) · 4.3 1 ( d, 2H, J = 5.6Hz ) ' 4.05 ( d, 2H, J = 5.6Hz ) &gt; 3.74( s, 2H ) , 3.56-3.51 ( m,2H ) ,3.05 -2.99 ( m,2H ) ,1 · 9 6 - 1.9 0 ( m,2 H ) ' 1 .8 8- 1 .79 ( m, 2H ) ; MS ( ESI+ ) : m/z 54 8.26 ( M + H ) -158- 8 (155) 1324926 Example 4 3

1-(3-Fluoro-4-(3-(3-(2-(4-hydroxyhexahydropyridin-1-yl)acetamidine-amino)propan-1-ynyl)pyridin-4-yloxy Phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride

A) #-(3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxyhexahydropyridine-1- Acetamine

3 - (4-( 2 ·fluoro-4-n-nitrophenoxy)pyridin-3-yl)propan-2-yne-1-amine according to the procedure of Step D of Example 42 (Example The title compound was prepared from the compound of EtOAc, EtOAc (EtOAc) The title compound (40 mg, 36%) was obtained eluted eluted elut elut elut elut elut elut . 1H NMR ( OMSO-d6 ) δ 8.65 ( s, 1 Η ) , 8.49 ( d, 1H, J = 5.5Hz) , 8.4 1 (dd, 1 H, J = 10.4, 2.7 Hz) , 8.18-8.12 ( -159 - (156) 1324926 m, 2H ) &gt; 7.55-7.50 ( m, 1H) &gt; 7.05 ( d, 1H, J = 6.0Hz) &gt; 4.54 ( d, 1H, J - 3.8Hz ) , 4.11 (d, 2H, J = 6.0Hz), 3.43 -3.36 ( m, 1H ) - 2.86 ( s, 2H ) &gt; 2.64-2.58 ( m, 2H) &gt; 2.12-2.05 ( m, 2H ) , 1.67-1.61 (m, 2H) , 1.44-1.36 (

m, 2H); MS (ESI+): m/z 429.18 (M + H)+.

B) #-(3- (4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxyhexahydropyridine-1- Acetamine

iV-(3-(4-(2-fluorine) was used in a similar manner to Step E of Example 35, using iron powder (67 mg, 1.21 mmol), chlorinated (128 mg, 2.42 mmol) Reduction of benzyl 4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxyhexahydropyridin-1-yl)acetamide (33 mg, 0.077 mmol), To prepare the title compound. The product obtained was a yellow oil (30 mg, 100%) which was used directly in the next step. MS ( ESI+): m/z 3 99.27 (M + H)+. C) 1-(3-Fluoro-4-(3-(3-(2-(4-hydroxyhexahydropyridin-1-yl)acetamido)propan-1-ynyl)pyridin-4-yl Oxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride according to the procedure similar to step D of Example 3, from #-( 3 -( 4-(4-Amino-2- per basic oxy)indole 卩疋-3-yl)propan-2-indyl)-2-(-160-(157) 1324926 4-hydroxyhexahydropyridine-1 a base solution of acetamide (25 mg, 0.063 mmol) and 2-(4-fluorophenyl)ethenyl isocyanate in toluene (Compound D, 0.40 mL '0.12 mmol), The title compound was prepared using THF (0.5 mL). The product was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) . 4 NMR (DMSO-heart) • (5 1 1.08 ( s, 1H ) · 1 0.64 ( s, 1 Η ) &gt; 9.83-9.72 ( m, 1 Η ) .9.25-9.20 ( m, 1 Η ) &gt; 8.66 ( s, 1 Η ) , 8 · 4 5 ( d,1 Η, J = 6.1Hz) , 7.83 ( dd, 1 H, J = 2.0, 13.2Hz ) , 7.46-7.35 ( m, 3 H ) &gt; 7.21 -7.11 ( m, 2H ) ^ 6.77 ( d, 1H, J = 6.1Hz) -4.33-4.3 1 ( m, 2H ) , 3 · 9 9 - 3 · 9 4 ( m,2 H ) &gt; 3.92-3.89 ( m, 1 H ) - 3.76 ( s, 2H ) &gt; 3.46-3.40 ( m, 2H ) , 3.29-3.21 (m, 2H ) &gt; 3 . 1 0-3.00 ( m, 1 H ) , 1.9 8 - 1 · 8 7 ( m, 2 H ), 1.72- 1.62 ( m, 2H ) ; MS ( ESI+ ) : m/z 528.25 ( M + H ) + s. Example 4 4

(51)-1-(3-Fluoro-4-(3-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamido)propynyl)pyridine·4 -yloxy)phenyl)-3-(158) 1324926 (2-(4-fluorophenyl)ethenyl)urea, dihydrochloride

A) (S) (3-(4-(2-Fluoro-4)nitrophenoxy)pyridin-3-yl

-propan-2-mercapto)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide 3-(4-(2-fluoro-4-nitrophenoxy)pyridine -3-yl)propan-2·yne-p-amine (Compound A '55 mg of Example 36, 0.19 mmol) was dissolved in dichloromethane (5 mL), and 4-nitrophenyl chloroformate (0.38 mg, 0.19 mmol) and shame D (15//L, 0.19 mmol). The mixture was stirred at room temperature. After 1 hour, treated with triethylamine (30 mL, 0,20 mmol) and (S) - ( + ) -1 - (2-pyrrolidinylmethyl)pyrrolidone (Aldrich, 32 mg' 0.21 mmol) The mixture was stirred at room temperature for 15 hours. Then, the mixture was diluted with methylene chloride (50 mL), washed with 1M sodium sulfate and brine, dried over magnesium sulfate and concentrated in vacuo to give crude product. The title compound (53 mg, 60%) was obtained as a yellow oil (yield: EtOAc: EtOAc: EtOAc) ), 8.49 ( d, 1H, J = 6.1Hz) , 8.41 ( dd, 1H, J = 2.8Hz, l〇.5Hz) , 8.16 ( d, 1H, J = 7.7Hz ) &gt; 7.52 ( dd, 1H, J = 8.3, 8.8Hz ) &gt; 7.05 ( d, 1 H, 7 = 6. 1 Hz ) , 4.11-4.06 (m, (159) 1324926 2H ) - 3.99-3.9 5 ( m, 2H ) , 3.76 ( s , 2H) &gt; 3.16-3.11 ( m, 2H ) , 2.5 7-2.4 8 ( m, 2H ) , 2.43-2.4 1 ( m, 2H ), 3.36-2.34 ( m, 2H) &gt; 1.90-1.86 ( m , 2H) - 1.76-1.62 (m, 3H); MS (ESI+): m/z 468.27 (M + H)+.

B) (S)-iV-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1- Methyl)pyrrolidine-1-carboxamide in a similar manner to Step E of Example 35, by using iron powder (67 mg &gt; 1.21 mmol), chlorinated saddle (128 mg, 2.42 mmol), S) -iV-( 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl) Reduction of pyrrolidine-1-carboxamide (50 mg, 0.1 1 mmol) gave the title compound. The product obtained (36 mg, 75%) was obtained as a yellow oil which was used directly in the next step. MS ( ESI+): m/z 438.30 (M + H) +. C) (5)-1-(3-fluoro-4-(3-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamido)prop-1-yne a pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, a dihydrochloride salt, in a similar manner to step D of Example 3, From (5)-#-(3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl-163-(160) 1324926 )·2· (Ladly steep methyl) ralliidine-oxime-carbamidine (36 mg, 0·05 7 mmo丨) and 2-(4-phenylphenyl)ethyl fluorenyl-cyanate in toluene The title compound was prepared from a 0.3M solution (Comp. The title compound (10 mg, EtOAc) was obtained from EtOAc EtOAc 2 5 % ) » 1 Η NMR ( DMS Ο - heart) 5 1 1 _ 0 6 ( s, 1 H )

' 10.60 ( s, 1Η), 9.56 ( s, 1Η), 8.58 ( s' 1Η) ' 8.38 (d,1 H, "/ = 5 _ 6 H z ), 7.8 0 ( dd,1 H,J = 2 ·6,1 2 · 7 HZ ) ' 7.42 ( dm, 1 H, J = 1 0.6Hz ), 7.3 8 - 7.3 1 ( m,2 H ) 7,3°&quot; 7.25 ( m, 1 H ) · 7.20 -7.1 0 ( m, 2H ) ' ό. 6 9 ( d,1 H, / = 6.1Hz) &gt; 4.26-4.12 ( m, 2H ) » 3 79.3.69 ( m, 3H) 3.56 (s, 2H) ,3.31-3.18 (m,2H),3·17-2.93 (m,2H) 2.14-2.02 ( m, 4H) &gt; 2.03-1.76 ( m 5H ) 71-1.61 ( m, 1 H ) ; MS ( ESI+ ) : m/z 617.20 ( M + H ^

Example 4 5

(5)-1-(4-(3-(3-(4-Amino)-hexahydropyrrolidine-1-yl)ketopropan-1-enyl)pyridin-4-yloxy)-3- Fluorophenyl)(2-(4-nitrophenyl)-indenyl)urea, bis(trifluoroacetate)-164- (161) 1324926

5)-T-butyl ester

4·(2-Fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33, 150 mg, 0.42 mmol), chloroformic acid, by vacuum/argon rinsing A mixture of tributyl vinegar (Aldrich, 1 07 mg, 0.84 mmol), tri-n-butylamine (〇 21 mL, 0.92 mmol) and DMF (2 mL) was degassed, then Pd (OAc) 2 (17 mg, 0.078 mmol). The mixture was heated at '100-130 ° C for 45 minutes in an argon atmosphere, and then the mixture was cooled to room temperature and dissolved in ethyl acetate and aqueous sodium hydrogencarbonate. The phases were separated and EtOAc (EtOAc m. The title compound (1) was obtained as a pale yellow oil (yield). 1 8 mg, 78%) which will solidify at room temperature. 1H NMR (DMSO - core) (5 9.02 ( s, 1H ) » 8.49 ( d, 1H, J = 5.5 Hz ) , 8.46 ( dd, 1H, J = 2.5, 1 1.7 Hz ) , 8.21 ( dm, 1 H, J = 9.2Hz ) &gt; 7.74 ( d, 1 H, J = 1 6.3Hz ) &gt; 7.65 ( dd, 1H, J = 8.1, 8.6Hz ) · 6.95 (d,1H, J - 6.1Hz) &gt; 6.77 ( d, 1H, J = 1 6.3Hz ) &gt; 1.47 (s,9H) ; MS ( ESI+ ) :m/z 361.15 (M + H)+ (162) 1324926

B) ( £ ) -3- (4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)acrylic acid Add 1:1 TFA / dichloromethane (6 mL) to 3-( 4-(2-#2-fluorophenyl-4-nitrophenoxy)pyridin-3-yl)acrylic acid (£)-t-butyl ester (115 mg, 0.32 mmol), and stirred at room temperature 1.5 hour. The mixture was concentrated in EtOAc (EtOAc)EtOAc. Treatment with methanol (5 mL) and EtOAc (EtOAc) (EtOAc) NMR ( DMSO-i/e ) δ 9.17 ( s, 1H) &gt; 8.62 ( d, IH, J = 6.6 Hz ) , 8.50 ( dd, 1 H, J = 2.6, 10.1 Hz) ' 8.25 ( d, 1 H , Φ J = 9.1Hz) &gt; 7.78 ( d, 1 H, J = 1 6.3Hz ) &gt; 7.74 ( dd, 1H, J =8.1, 8.6Hz ) &gt; 7. 1 7 ( d, 1H, 7 = 6.1 Hz), 6.87 (d, 1H, J = 1 6.3 Hz); MS (ESI+): m/z 305.11 (M + H)+.

C) 1-( 3- (4-(2-carboyl-4·nitrophenoxy) 妣-3-yl) propyl sulfhydryl) hexahydropyridin-4-ylaminecarboxylic acid (£)- Tributyl ester-166- (163) 1324926 Add DIPEA (160 L, 0.92 mmol), and TBTU (160 mg, 0.50 mmol) to (£) -3-(4-(2-fluoroyl-4-nitro) Phenoxy)pyridinium-3-methyl)propanoid acid (143 mg, 0.42 mmol), 4-A^-Boc-amino hexahydropyramid (Aldrich, 84 mg, 0.42 mmol) in DMF ( 1.5 mL) of the resulting solution, and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate, washed with aq. sodium hydrogen sulfate and brine and dried over magnesium sulfate. The obtained crude product was purified by flash chromatography on a silica gel eluting with 30-100% ethyl acetate/hexanes and 5% methanol/dichloromethane. The title compound (110 mg, 54%). 4 NMR (DMSO-i/&lt;!) δ 9.15 ( s, 1 Η ) &gt; 8.48 ( d, IU, J = 5.6 Hz ) , 8.44 ( dd, 1H, · / = 2.5,

1 0.5Hz ) &gt; 8.18 ( d, 1H, J = 9.2Hz ) - 7.69 ( d, 1H, J = 15.3Hz) · 7.58 ( dd, 1H, J = 8-6 &gt; 8.6Hz) &gt; 7.50 ( d , 1H, ·/ = 15.7Hz), 6.97 (d,1H, J = 5.6Hz) . 6.89 ( d, 1H, J Lu = 7.6Hz), 4.31-4.16 ( m,2H) ' 3.5 5 -3.46 ( m ,1H) ' 3.20-3.14 ( m,1H),2.83-2.81 (m,1H) ,1.82-1.71 (m, 2H) &gt; 1.34-1.18 (m5 2H) ' 1-37 (s, 9H) ; MS (ESI+) : m/z 43 1.04 (1 00 ) [(M-C4H9) +H]+ : m/z 487.1 0 ( 90 ) ( M + H ) + . NHBoc

-167- (164) 1324926 D) 1-( 3-(4-(4-amino-2-hexylphenoxy)anthracene-stirty-yl)propanol.oxy)hexahydropyridine·4*yl The carbamic acid-second butyl ester was prepared in the same manner as in the step 实施 of Example 35 by using iron powder (55 mg, 2.7 mmol), ammonium chloride (2 80 mg, 5 · 3 mmol), 3-(4-(2-Fluoro-4-nitrophenoxy)indole ratio of tert--3-yl)propenyloxy)hexahydropyridin-4-ylaminecarboxylic acid (5)-third butyl vinegar (100 The title compound was prepared by reduction with mg '0.2 1 mmol. The product obtained was a light brown solid (90 mg '95%) which was used directly in the next step. MS ( ESI+) : m/z 457.18 ( M + H) + °

E) 1-(3-(4-(2-Fluoro- 4-(3-(2-(4-fluorophenyl)ethyl) ureido)phenoxy)pyridin-3-yl)propenyloxy (6)-Hexahydropyridin-4-ylaminocarboxylic acid (5)-tert-butyl ester. 1-(3-(4-(4-Amino-2-)yl), in a similar manner to Step D of Example 33 Phenoxy)pyridin-3-yl)propenyloxy)hexahydropyridin-4-ylaminecarboxylic acid (£)-T-butyl ester (42 mg, 0.092 mmol)

The title compound was prepared from a solution of EtOAc (EtOAc m.). The obtained crude product was adsorbed to silica gel and purified by flash chromatography (eluent eluting with 0-5% methanol/ethyl acetate) to give the title compound (20 mg, 33%) as white solid. -168 - (165) 1324926 NMR ( DMSO-c/6 ) 6 11.05 ( s, 1H ) , 10.59 ( s, 1 H ), 9.03 ( s, 1 H ) &gt; 8.37 ( d, 1 H, J = 5 ,6Hz ) ' 7.82 -7.74 ( m, 2H ) &gt; 7.47 ( d, 1 H, y = 1 5 , 8Hz ) &gt; 7.42- 7.3 3 ( m, 4H ) &gt; 7.20-7.13 (m5 2H) - 6.89 (d, 1H, 7 = 8.1Hz) &gt; 6.63 (d, 1 H, J = 5.6Hz ) - 4.3 1 ( d, 1 H &gt; J = 1 3.7Hz ) - 4.19 ( d, 1 H, J = 12.7Hz ) &gt; 3.74 ( s5 2H ) &gt; 3.5 6-3.47 ( m, 1 H )- 3.22-3.13 (m, 1H) &gt; 2.84-2.76 (m, 1H) &gt; 1.76 (s, 2H)

, 1.37 ( s, 9H ) , 1.32 - 1.20 (m, 2H); MS (ESI+): m/z 636.23 ( M + H ) + . F) (5)-1-(4-(3-(3-(4-Aminohexahydropyridin-1-yl)-3- ketopropenyl)pyridin-4-yloxy)-3-fluoro Phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, bis(trifluoroacetic acid) 1-(3-(4-(2-fluoro)- 4-(3-(2) -(4-fluorophenyl)ethenyl)ureido)phenoxy)pyridin-3-yl)propenyloxy)hexahydropyridin-4-yl carbamic acid (penta)-t-butyl ester (15 mg , 0.024 mmol) was dissolved in anhydrous methanol (0.5 mL), 4M HCI /1,4-dioxane (1_5 mL) was added and stirred for 1 hour. The mixture was concentrated in vacuo to give a crude material which was purified using preparative HPLC (layer A). The product-containing fractions were treated with an excess of 1M EtOAc. EtOAc (EtOAc) ),1〇·61( s,lH),9.10(s,lH) · 8.44 ( s, 1Η ) &gt; 7.9 1 ( m, 3H ) &gt; 7.86-7.69 ( m, 2H ) , 7 · 5 5 - 7.2 8 ( m,5 H ) , 7.23 -7.08 ( (166) 1324926 m, 2H ) , 6.8 0-6.72 ( m, 1 Η ) &gt; 5.61-5.33 ( m, 1H) &gt; 4.45 -4.20 ( m, 2H) , 3.74 ( s, 2H) , 3.3 9-3.07 ( m, 2H) , 2.82 - 2.68 (m, 1H) &gt; 1.91-1.51 ( m, 2H ) 1.50-1.15 ( m,lH) ; MS ( ESI+ ) : m/z 536.16 (M + H)+. Example 4 6

1 - (3 -Fluoro-4 -( 3 - ( 2 -(pyridin-2-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl) Acetyl) urea, dihydrochloride

A) 2-(2-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine 4-(2-fluoro group) by vacuum/argon rinsing 4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33, 50 mg, 0.1 mmol) and 2-ethynyl D are D (Aldrich, 57 mg, 0-54 mmol), A mixture of THF (1 mL) and triethylamine (1 mL) was degassed and successively added Cul (3 mg, 0.016 mmol) and (Ph3P) 4Pd (10 -170-8 (167) 1324926 mg' 0.009 mmol ). The mixture was heated at 60 ° C for 45 minutes, cooled, EtOAc (EtOAc m.) A crude product is obtained. The title compound was obtained as a brown oil (yield: EtOAc (EtOAc) 42 mg ' 89% ). 4 NMR ( DMSO-c/d ) δ 8.91 ( s, 1 Η ) 5 8.60 ( d, 1H, J = • 4.5 Hz ) , 8.45 ( dd, 1H, J = 2.6, 1 0.7 Hz ), 8.19 ( d, 1H , J = 9.1Hz) , 7.86-7.83 ( m, 1H) &gt; 7.66 ( dd, 1H, J = 8.7, 8.7Hz) - 7.57 ( d, 1H, J = 7.6Hz ) &gt; 7.45 -7.42 ( m, 2H) ' 7.14 ( d, 1H, J = 4.5 Hz); MS (ESI+): m/z 33 6.20 (M + H) +.

B) 3-fluoro- 4-(3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)aniline in a similar manner to Step E of Example 35, from 2- 2-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)ethylidene)pyridine (30 mg &gt; 0.090 mmol). ) 〇 MS (ESI+): m/z 306.20 (M + H) +. C) 1-(3-Fluoro-4-(3.(2-(pyridin-2-yl)ethynyl)pyridine-4- 8 -171 - (168) 1324926 oxy)phenyl)-3- (2-(4-fluorophenyl)ethenyl)urea, dihydrochloride

In a similar manner to Step D of Example 3, from 3-fluoro-p-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)aniline (19 mg, 0.062 mmol) The title compound was prepared from a 0.3 Μ solution of 2-(4-fluorophenyl)ethylidene isocyanate in toluene (Compound D of Example 1 1 , 0.50 mL &gt; 0.15 mmol). Purification of the reaction mixture by flash chromatography on EtOAc (m. The title compound (19 mg, 60%) was obtained as a white solid. 4 NMR (DMSO-heart) 5 11.07 ( s, 1 H ) , 10.6] (s, 1 Η ) , 8.79 ( s, 1 Η ) , 8.63 ( d, 1H, J = 5.6 Hz ) , 8.47 ( d, 1 H , J = 5_6Hz) &gt; 7.8 9-7.86 ( m, 1 H ) , 7.83 ( dd, 1H, J = 1.5,

12.7 Hz), 7.67 (d, 1H, J = 7.6 Hz), 7.47-7.43 (m, 2H • ), 7.3 9-7.3 5 ( m,1H ) » 7.3 0-7.27 ( m, 1 H ) &gt; 7.20 -7.16 (m, 2H ) , 7.14-7.10 (m, 1H) &gt; 6.77 ( d, 1H, J = 5.6Hz ), 3.75 ( s, 2H ) ; MS ( ESI+ ) : m/z 4 8 5.1 7 ( M + H ) + Example 4 7 -172 8 (169) 1324926

1-( 3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl) Acetyl) urea, dihydrochloride

A) 3-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine 4-(2-fluoro-based) by vacuum/argon rinsing 4-Nitrophenoxy%) ·3· iodopyridine (Compound a of Example 33, 50 mg, 0.14 mmol) and 3-ethynylpyridine (57 mg, 0.54 mnl), THF (1 mL And a mixture of triethylamine (1 mL) was degassed and sequentially added Cul (3 mg '0.016 mmol) and (Ph3P) 4Pd (10 mg, 0.009 mmol). The mixture was heated at <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The title compound (33 mg, obtained as a brown solid) was purified by flash chromatography eluting with EtOAc. '77%). NMR (DMSO-heart) 5 '-173- (170) 1324926 8.86 (s,lH) , 8.65 (s,lH) &gt; 8.6 1 -8.57 ( m, 2H ),

8.45 ( dd, 1 H, J = 2.6,1 0.7 Hz ) , 8.18 ( d, 1 H, J = 9.2 Hz ), 7.90 ( d, 1 H, J = 9.2 Hz ) , 7.62 ( dd, 1 H, J = 8.7, 8.7 Hz), 7.46 (dd, 1 H, J = 4.6, 8.1 Hz) &gt; 7.17 ( d, 1H, J = 5.6 Hz) ; MS ( ESI+ ) : m/z 336.19 (M + H)+ .

# B ) 3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)aniline

In a similar manner to Step E of Example 35, from 3-(2-(4-(2-fluorophenyl-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridine (30 mg &gt; The title compound was obtained from EtOAc (mjqqqqq C) 1-(3-Fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorobenzene) The ethylamino)urea, dihydrochloride salt, in a similar manner to step D of Example 33, from 3-fluoro-4-(3-(2-(pyridin-3-yl)ethynyl)pyridine a 0.3 M solution of -4-yloxy)aniline (22 mg, 0.072 mmol) and 2-(4-fluorophenyl)ethenyl isocyanate in toluene (1 D of compound D, 0.50 mL &gt; 0.15 Methyl) to prepare the title compound. Purification of the reaction mixture by flash column chromatography (eluent eluting with EtOAc - EtOAc/EtOAc) The title compound (1 5 mg, 38%) was obtained as a white solid. 1H MMR ( DMSO-i/6 ) 5 1 1 .04 ( s5 1H ) , 10.59 (s, 1H) , 8.76 ( s, 1 H ) , 8.74 ( d, 1 H, J = 1. 1 Hz ) , 8.60 ( dd, 1H, J = 5.6, 1 . 1 Hz ) , 8.45 ( d, 1H, J = 6.1Hz) , 7.98 ( d,1 H, J = 7.7Hz ) , 7.80 ( d, 1H, J = 1 2 1 Hz ) , 7.47- 7.45 ( m, 1 H ) &gt; 7.4 1 ( s, 2H ) &gt; 7.3 6- 7.3 4 ( m, 2H ), 7.16 ( dd, 2H, J = 8.8, 8.9Hz ) , 6 · 7 8 ( d,] H, J = 5.5 H z )&gt; 3.74 ( s, 2H ) ; MS ( ESI+ ) : 485.13 m/z. Example 4 8

TV-(4-(2-Amino D|t-s--4-yloxy)-3-phenyl)-2-indolylisoxylamine, trifluoroacetate

A) 2-Bromo-isonicotinium chloride-175 8 (172) 1324926 2-Bromo-isonicotinic acid (Lancaster, 70 mg, 0.34 mmol) in sulfinium chloride at reflux temperature ( 1.2 mL) The resulting solution was heated for 1.5 hours. The mixture was concentrated and the crude product of 2-bromoisonicotinium chloride was used directly in the next step without further purification. B) iV-(4-(2-aminopurine-Jinding-4-yloxy)-3-gas-based)-2-indiylisonicotinamide

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 70 mg, 0.32 mmol) m. The solution was added to the above residue, and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and purified to purified crystal crystal crystal crystal crystal crystal crystal crystal 4 NMR (DMSO-heart) δ 11.03 ( s, 1 Η ) &gt; 8.62 ( d, 1H, J = 5.0 Hz ) &gt; 8.17 ( s, 1H ) , 7.89-8.04 ( m, 4H ) , 7.7 1 ( d, 1H, J = 8.8 Hz), 7.5 1 (t, 1H, J = 9.3 Hz), 6.72 (dd, 1H, J = 7.1, 2.2 Hz), 6.18 (d, 1H, J = 2.2 Hz); MS (ESI+ ) m/z 403,405 ( M + H ) +. Example 49 -176- 8 (173) 1324926

(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylanilino)isonicotinamide, bis(trifluoroacetate) 4-fluoro

A) 2-(4-Fluoroanilino) isonicotinic acid

Sodium hydride (500 mg, 60% (in-oil)) was added to 2-fluoro-isoxyl base acid (Aldrich, 423 mg, 3.0 mmol) and 4-fluoroaniline (555 mg' 5.0 at room temperature Methyl) in a mixture of DMF (18 mL), and at 751, the mixture was heated for 75 min. Acetic acid (0.7 mL) was added to the reaction mixture and concentrated in vacuo. Ethyl acetate (100 mL) and water (20 mL) were added to the obtained residue, and the mixture was stirred for 20 min, and the solid was filtered, washed with ethyl acetate and dried to give a brown solid. Product (600 mg, 50%). NMR ( OMSO-d6 ) δ 8.98 ( s, 1 Η ) &gt; 8.43 ( s, 1 Η ) , 8.0 4 ( d, 1 Η,·· = 4 · 9 Η z ) , 7.69 (dd, 2H, J = 8.8, 4.9 Hz) &gt; 7.24 ( s, 1H ) , 7.05 ( dd, 2H, y = 8.2, 6.0 Hz); MS ( ESI+ ) m/z 2 3 3.3 ( M + H ) + . (174) 1324926

CIOC

FB) 2-(4-Fluoroanilino) isonicotinium chloride at reflux temperature, face, (A ^ V Μ 2- ( 4 - fluoroanilino) isonicotinic acid ( 464 mg, 2 · 0 Ment) and sulfinium chloride (1 〇 mixture heating 2

hour. The reaction mixture was concentrated in vacuo and the obtained crude product was used directly in the next step. &lt;:)#-(4_(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluoroanilino)isonicotinamine decylamine at ice bath temperature '4 -( 4 -Amino-2-indole basic oxy)pyridine-2-amine (compound β of compound μ, 45 0 mg '2·1 mmo) at 1, while stirring The solution of 2-dichloroethane (1〇^^) was slowly added to the solution of the hydrazino chloride obtained in the previous step in a solution of 2 二 dichloroethane φ (10 mL). The reaction mixture was allowed to stand at room temperature overnight. Ethyl acetate (150 mL) and saturated aqueous sodium hydrogen carbonate (50 mL) was then added to the reaction mixture. The table was dried and concentrated in vacuo. EtOAc EtOAc (EtOAc) )(5 10.90 ( s, 1Η ) &gt; 9.32 ( s, 1 Η ) * 8.27 ( d,

1H, J = 5.5Hz), 7.92-7.07 (m, 11H) &gt; 6.68 ( dd, 1H, J = 7.1, 2.2Hz ) , 6.10 ( d, 1 H, J = 2.2Hz ) ; MS ( ESI+ ) m /z 217.9 ( M + H) +o -178- (175) 1324926 Example 5

iV-(4-(2-amino-2-pyrene-4-yloxy)-3-carbyl)-6-mercapto-1,6-dihydropyridine-2-carboxamide, trifluoro Acetate at room temperature, EDCI·HC1 (50 mg '0.26 mmol) and 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 42 mg, 0.19 mmol) was added to 6-carbyl-based residual acid (Aldrich, 28 mg, 0·20 mmol) and Η Ο B t (28 mg, 0.21 mmol) in DMF (2 mL) The reaction mixture was stirred overnight at room temperature and at room temperature. Purification of the reaction mixture by preparative HPLC gave the desired product (24 mg, 25%) (trifluoroacetate) &quot;HNMR CCDs OD δ 8.03 ( dd, 1H, J = 12.6, 2.2 Hz) &gt; 7.79-7.36 ( m, 5H) , 6.85 ( d, \R, J = 8.8Hz ) , 6.67 ( dd , 1 H, J = 7 · 2, 4.4 H z ) , 6.22 ( d, 1 H , J = 2.2 Hz); MS (ESI+): m/z 341.3 (M + H)+. Example 5 1 179- (176) 1324926

iV-(4-(2-Amino DJtD-1,4-yloxy)-3-phenyl)-2-indolyl-1,2-dihydropyridine-3-carboxamide, trifluoroacetate

At room temperature, EDCI·HC1 (80 mg, 0.30 mmol) and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 65 mg, 0.30 mmol) was added to a solution of 6-based hydrazide ratio D residual acid (Aldrich, 42 mg, 0.30 mmol) and HOBt (18 mg) in DMF (2 mL), and at room temperature The reaction mixture was stirred for 20 hours. Purification of the reaction mixture by preparative HPLC gave the desired product (j. NMR (CD3OD) &lt;5 8.5 9 ( dd, 1H, J = 7.1, 2.2 Hz) - 8.03 ( dd, 1H, J = 12.6, 2.2 Hz ) , 7.83 ( d, 1 H, J = 7.7 Hz ) , 7.75 ( dd, 1 H, J = 6.6, 2.2 Hz), 7.44 (d, 1H, 7 = 8.8 Hz), 7.32 (t, 1H, 7 = 8.8 Hz), 6.67 (m, 2H)&gt;6.21 (d, 1H, J = 2.2 Hz); MS (ESI+) m/z 341.2 (M + H) +. Example 5 2 8 -180- (177) 1324926

TV-(4-(2-amino-2-pyrene-4-yloxy)-3-phenyl)-6-methyl-2-indolyl-1,2-dihydropyridine-3-methyl Indoleamine, trifluoroacetate, EDCI·HC1 (130 mg, 0.68 mmol) and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Example 24) at room temperature Compound B, 110 mg, 0.50 mmol) was added to 2-keto-6-methylzolic acid (Lancaster, 7 2 mg, 0.47 mm ο 1 ) and Η Ο B t (50 mg) in DMF (5 The reaction mixture was stirred for 72 hours at room temperature and at room temperature. Purification of the reaction mixture by preparative HPLC gave the desired product (1 25 mg, 55%) (trifluoroacetate) as a beige solid. 1H NMR (CD3OD) 5 8.46 ( d, 1 H, J = 7·9Ηζ), 8.03 ( dd, 1 Η, J = 12.7, 2.8 Hz), 7.83 (d, 1 Η, J = 7.1 Hz), 7.44 ( Dd, 1 H, J = 7.9Hz ) , 7.33 (t, 1 H, J = 8.8Hz ) &gt; 6.67 ( dd, 1 H, J = 7.7, 2.7Hz ) &gt; 6.45 ( d, 1H, J = 7.7 Hz ) &gt; 6.21 ( d, 1H, J = 2.8 Hz ) &gt; 2.40 ( s, 3H ) ; MS ( ESI+) m/z 3 5 5.2 ( M + H ) + . Example 5 3 8 -181 - (178) 1324926

H2n JV- (4-(2-amino-2-indol-4-yloxy)-3-phenyl)-5-yl-2-enyl-1,2-dihydropyridine-3 -Procarbamide, trifluoroacetate, EDCI·HC1 (130 mg &gt; 0.68 mmol) and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine ( Compound B of Example 24, 110 mg, 0.50 mmol) was added to 2-hydroxy-5-chloronicotinic acid (Avocado, 87 mg, 0.50 mm ο 1 ) and Η Ο B t (40 mg) in DMF ( 4 mL) of the resulting solution, and the reaction mixture was stirred at room temperature for 72 hours. Purification of the reaction mixture by preparative HPLC gave the desired product (1 1 5 mg,

4 5%) (trifluoroacetate). 4 NMR ( CD 3OD ) δ 8.50 ( d, 1 H, J = 3 , 3 Hz ) , 8.03 ( dd, 1H, J = 12.6, 2.1 Hz) &gt; 7.84 (m, 2H ) -7.46 ( d, 1H , J = 8.8 Hz ), 7.34 ( t, 1 H, J = 8.8 Hz), 6.67 ( dd, 1 H, · / = 7.2, 2.2 Hz ) &gt; 6.2 1 ( d, 1H, J = 2.2 Hz); MS ( ESI+ ) m/z 375.1, 3 7 7.1 (M + H) +.

Example 54 -182- (179) 1324926

Br

H2N TV-(4-(2-Aminopyridin-4-yloxy)-3.fluorophenyl)-5-bromo-2-one®-l,2-dihydropyridine-3-carboxamidine Amine, trifluoroacetate salt, EDCI·HC1 (160 mg, 0.83 mmol) and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Example 24, respectively) at room temperature Compound B, 147 mg, 0.67 mmol) was added to 2-hydroxy-5-bromonicotinic acid (147 mg, 0.67 mmol, Syn. Comm., 1 9 8 9, 1 9, 5 5 3 -

559) and HOBt (30 mg) in a solution of DMF (4 mL), and the mixture was stirred overnight at room temperature. Purification of the reaction mixture by preparative EtOAc (EtOAc) eluted , 1 2.23 ( s, 1 Η ) , 8.40 ( d, 1 H, J = 2.8 Hz) , 8.14 ( d, 1 H, J = 2.8 Hz ) , 8.12 - 7.46 (

m, 5H ) &gt; 6.68 ( dd, 1 H, J = 7.2, 2.2 Hz ) &gt; 6.14 ( d, 1H, J = 2, 2 Hz ) ; MS ( ESI+ ) m/z 4 1 9 / 42 1 ( M + H ) +. Example 5 5 -183- (180) 1324926

N -( 4 -( 2 -Amino(1:1!-1,4-yloxy)-3-indolyl)-6-methyl-4-indolyl-1,4-dihydropyridine-3 -Metformamide, trifluoroacetate, EDCI·HC1 (130 mg - 0.68 mmol) and 4-(4-amino-2-fluorophenoxy)pyridine-2-amine at room temperature Compound B of Example 24, 110 mg, 0.50 mmol) was added to 4-amino--6-methyl-Schiffic acid (Wako, 7 7 mg, 0.50 mm ο 1 ) and HOBt (50 mg) in DMF (5 mL) In the resulting solution, and at room temperature, the reaction mixture was stirred overnight, then heated at 75 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, using preparative HPLC The title compound (70 mg, 29%) (trifluoroacetic acid salt) &quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;5 13.22 (brs, lH), 12.53 (s, 1 Η ) , 8.47 (d, 1 Η, J = 5.5Hz), 8.04 ( d, 1 Η, J = 2.2Hz), 7.95 ( d, 1 Η, J = 8.2Hz ) &gt; 7.82 ( s, 2Η ), 7.46-7.42 ( m, 2Η ) , 6.70 ( dd,1 Η, J = 7.7,2·7Ηζ ) , 6.39 (s,lH) , 6.14 (d,lH,*7=2.2Hz) ; MS ( ESI+ ) m/z 3 5 5.3 ( M + H ) +. Example 5 6 - 184 8 (181) 1324926

#* (4-(2-Amino-D-1,4-yloxy)-3-phenyl)-5-indolyl-4-indole-yl-l-dihydropyridine-3-carboxamide Trifluoroacetate

OH OH

A) 3-Bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol phenylmagnesium bromide (1M in THF, 11 mL, 11 mmol) at -78 ° C under argon a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10 mmol, prepared according to the procedure of 2001, 2175-2179) in anhydrous THF (20 mL) in. After stirring for 15 minutes, a n-butyllithium solution (2M solution of cyclohexane, 5.5 mL) was added, and the mixture was stirred at -78 ° C under argon atmosphere for 15 minutes. Benzoaldehyde (2.15 mL) was added to the mixture, and the reaction mixture was stirred at -78 °C under argon for 2 hours. Add benzaldehyde (2.15 mL) to the mixture and stir the mixture for 2 hours at -78 ° (:). The reaction mixture was quenched by the addition of acetic acid (3 mL) and TFA (3 mL). Concentrate in vacuo and use flash column chromatography on tannin (hexane-185-(182) 1324926 / ethyl acetate / methanol / / 750: 250: 50, and hexane / Ethyl acetate / methanol / triethylamine / / 460: 460: 50: 10 elution), the obtained residue was purified to give the desired product as a white solid (2.8 5 g &gt; 9 1%) oiHNMR CCDsOD ) ¢58.13 (s,lH) · 8.04 ( s, 1 Η ) * 7.41-7.20 (m, 5H) &gt; 5.94 ( s, 1H ) ; MS ( ESI+ ) m/z 280,282 ( M + H ) + .

B) 3-Benzyl-5-bromopyridin-4-ol 3-Bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol (2.55 g, 91 mmol) at room temperature The mixture of TFA (16 mL) and triethyl sand in dichloromethane (30 mL) was stirred for 1 hour. The reaction mixture was concentrated in vacuo and purified by flash column chromatography eluting with hexane/ethyl acetate/methanol//600:3 00^:50, and hexane/ethyl acetate Ester / methanol / triethylamine / / 4 〇〇: 4 〇 0: 5 〇: 1 〇 elution), the residue obtained is purified to obtain an impure product; tanning with a small amount of methanol and ether, The desired product was obtained as a white solid (25 5 mg, 10%). NMR (DMSO-heart) 5 1 1 .75 ( br s, 1 Η ) &gt; 8.13 ( s, 1 Η ) &gt; 7.54 ( s, 1H ) . 7.26- 7.14 ( m, 5H) - 2.49( s, 2H ) . 8

-186- (183) 1324926 C) 5. Benzyl-4-hydroxynicotinic acid was added to a solution of methyllithium (1.5 THF in THF, 0.61 mL '0.92 mmol) at -78 °C under argon. A solution of 3-benzyl-5-bromopyridin-4-ol (220 mg, 0.83 mmol) in dry THF (8 mL). After stirring for 5 minutes, n-butyllithium (2M cycloheximide solution '0.5 mL' 1.0 mmol) was added, and the mixture was stirred at -78 °C under an argon atmosphere for 15 minutes. Carbon dioxide was bubbled through the # reaction mixture at -78 °C for 20 minutes. Then, the reaction mixture was quenched by the addition of acetic acid (2 mL), EtOAc (EtOAc) 35%) (trifluoroacetate). NMR ( DMF-J/) δ 12.99 ( br s, 1H) » 8.69 ( s, 1H) * 8.28 ( s, 1H ) &gt; 7.35-7.19 (m, 5H) , 3.90 (s, 2H) ; MS ( ESI+ m/z 23 0. 1 ( M + H ) +. ® D) //-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-5-benzyl-4·keto-1,4-dihydropyridine-3- Methionine, trifluoroacetate, EDCI·HC1 (80 mg, 0.42 mmol) and 4-(4-amino-2-fluorophenoxy)pyridine-2-amine were sequentially obtained at room temperature (Examples Compound B of 24, 35 mg, 0.16 mmol) was added to a solution of 4-hydroxy-5-benzylnicotinic acid (35 mg, 0.15 mmol) and HOBt (30 mg) in DMF (2.5 mL), and The reaction mixture was stirred for 40 hours at room temperature. Purification of the reaction mixture by preparative HPLC gave the desired product (35 mg, 43%) as white solid. 4 8 -187- (184) 1324926 NMR (DMSO·heart) δ 13.25 ( br s,1H) , 12.44 ( s,1H ), 8.59 ( d, 1 H, / = 4.9 Hz ) , 8.08 ( dd, 1H, J = 13.2, 2.2Hz) - 7.97 ( d, 1H, J = 7.1Hz) &gt; 7.8 1 ( d, 1 H, J = 9.4Hz )

&gt; 7.52-7.19 ( m, 7H) &gt; 6.72 ( dd, 1H, J = 7.2, 2.2Hz) &gt; 6.15 (d, lH, y = 2.5Hz) &gt; 3.81 ( s, 2H ) · 3.51 ( br s, 2H); MS (ESI+) m/z 431.2 (M + H)+.

(4-(2-aminopurine to D-1,4-ethyloxy)-3-phenylphenyl-1,2-dihydropyridine-3-carboxamide, trifluoroacetate-2-fluorenyl benzene

H3co2c co2ch3 A) 2-(3-(anilino)alenylene)malonic acid (penta)·dimethyl ester An aniline (300 mg, 3.2 mmol) was added to 2-(3-A) at room temperature a solution of oxyallyl) malonyl malonate (Acros Organics, 200 mg, 1.0 mmol) in THF (2 mL), and at -188- (185) 1324926 6 〇 ° C, The reaction mixture was heated for 8.5 hours. Purification of the reaction mixture by preparative HPLC gave the desired product (150 mg, 7%) as a yellow solid. 'H NMR (DMSO 〇 5 1 0. 16 ( d, 1 H, J =12.7 Hz) - 8.06 ( t, 1H, J = 12.7 Hz ) &gt; 7.74 ( d, 1H, J = 12.7 Hz ) &gt; 7.30 ( t, 2H, J = 8_7Hz), 7.16 ( d, 2H, J = 7.7Hz ) , 6.98 ( t,1 H, / = 7.7Hz ) - 6.35 ( t, 1H, J = 12.1Hz) , 3.69 ( s, 3H), 3.65 (s, 3H).

H3CO2C B) methyl 2-keto-1-phenyl-1,2-dihydropyridine-3-carboxylate

Sodium hydride (50 mg of 60% sodium hydride in oil, 1.2 mmol) was added to the previously obtained aniline adduct (130 mg, 0.50 mmol) in methanol (8 mL). The solution was stirred at room temperature for 3 hours. Acetic acid (0.3 mL) was added to the mixture, which was concentrated to a volume of ~4 mL, and purified to give the desired product (105 mg, 92%) as a yellow solid. NMR ( CD3 〇 D ) δ 8.30 ( dd, 1H, J = 7.2, 2.2 Hz ) , 7.87 ( dd, 1H, J = 6.6, 1, 7 Hz ) &gt; 7.57-7.38 (m, 5H ) * 6.53 ( t, 1H, J = 7.0 Hz) &gt; 3.84 ( s, 3H ); MS ( ESI+ ) m/z 23 0.3 ( M + H ) + . Ho2c

-189- 0 (186) 1324926 C) 2-keto-1-phenyl-1,2-dihydropyridine-3-carboxylic acid 2-keto-1-phenyl-1 at room temperature A solution of dihydropyridine-3-carboxylic acid methyl ketone (70 mg, 0.31 mmol) and lithium hydroxide (40 mg) in methanol (6 mL) and water (1 mL) was stirred overnight. Ethyl acetate (50 mL) and 1N aqueous HCl (15 mL) were added to the mixture. The ethyl acetate layer was separated, dried <RTI ID=0.0>

. NMR (DMF-heart) &lt;5 11.77 ( br s, 1 Η ) , 8.57 ( dd, 1 Η, J = 7.4, 2.0 Hz ) , 8.26 ( dd, 1H, J = 6.6, 1,6 Hz ), 7.64-7.55 ( m, 5H) &gt; 6.88 ( t, 1H, J = 7.0 Hz); MS ( ESI+ ) m/z 2 1 6.2 ( M + H ) + . D) W-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-one-1-phenyl-1,2-dihydropyridine-3-carboxamidine Amine at room temperature, EDCI·HC1 (45 mg &gt; 0.23 mmol) # and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 36 mg, 0·17 mmol) added to 2-keto-1-yl-1,2-dihydrobendre-3-residic acid (36 mg, 0.17 mmol) and HOBt (18 mg) in DMF (3) The reaction mixture was stirred overnight at room temperature and at room temperature. The title compound (35 mg, 43%) (trifluoroacetic acid salt) was obtained as a beige solid. 4 NMR (DMSO-i^) 5 13.35 (br s, 1H) ' 12.11 (s, 1H) 8.52 (dd, 1H, J = 7.3, 2.1 Hz) &gt; 8.08 (dd, 1H, J = 6.6, 2.1 Hz 8.03 ( d, 1H, J = 2.3Hz ), -190- 8 (187) 1324926 7.89 ( d, 1H, «7 = 7.2Hz) , 7.81 ( s, 1 H ) , 7.54 - 7.3 6 ( m 6H ) , 6.69-6.63 (m, 2H), 6.08 (d, 1H, · / = 2.4 Hz), 3.55 ( br s, 1 H ) ; MS ( ES1+) m/z 417.2 ( M + H) + . Example 5 8

#-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-6-(4-fluorophenyl)pyridine oxidized-decylamine, trifluoroacetate

A) 6-(4-Fluorophenyl)pyridinecarboxylic acid was rinsed with a gas-gas mixture of 2-bromo-pyrrolic acid (Aldrich, 2.02 g, 10 mmol) in DME containing 4 mL of 10% aqueous sodium carbonate. The solution formed. It will be 1£1(??113)4,2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborane (A丨drich, 2_40 g' 11.5 mmol) and ethanol (20 mL) were added to the mixture, and the mixture was rinsed with argon. The reaction mixture was heated at 1 ° C for 2.5 hours in a sealed tube. Add additional 2-bromo-BJt D residual acid (900 mg) and Pd(PPh3) 4' and after rinsing with argon, at -10 - (188) 1324926 at 4 °C, heat 4 _ 5 hours. Trifluoroacetic acid (20 m L) was added to the reaction mixture &lt; and the mixture was concentrated in vacuo. Methanol (150 m L) was added to the residue obtained and the insoluble material was filtered and concentrated in vacuo. The obtained layer was obtained by flash column chromatography on silica gel ( successively ethyl acetate / methanol / / 900: 100, and ethyl acetate / methanol / acetic acid / / 700 : 1 500 : 50 elution) Purification of the residue gave the desired product as a white solid (1·0 g, 40% (based on φ starting borane compound) &quot;jNMR CCDsOD) (58.01 ( d, 1 H, y = 7.7 Hz ) ' 7.94-7.87 ( m,3H ) , 7.73 ( d,1H, J = 7.7 Hz ) , 7.13 ( t, 2H, J = 8.8 Hz); MS ( ESI+ ) m/z 23 4 ( M + H ) + .

B) 6 - (4-fluorophenyl)pyridinecarboxylic acid oxide

The mixture of the pyridinecarboxylic acid derivative (1.0 g, 4.6 mmol), Na2HP04 (1.2 g), and m-CPBA (ll g, ~70%, Aldrich) in CH2C1CH2C1 (30 mL) was stirred at room temperature. 2 hours. Additional Na2HP04 (0.8 g) and m-CPBA (1.0 g) were added to the reaction mixture and stirred at room temperature for 3 hours. Additional Na2HPO4 (0.5 g) and w-CPBA (0.5 g) were added to the reaction mixture and stirred overnight at room temperature. CHC13 (160 mL) and 2N EtOAc (50 mL) EtOAc (EtOAc) Purification of the residue obtained by flash column chromatography (eluent eluting with ethyl acetate / methanol / acetic acid / / / : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : · Pollution of CPBA. Purification of the impure product by preparative HPLC gave the desired product ( 175 mg, 16%) as white solid. 4 NMR (DMF-heart) 5 8.45 (dd, 1H, J = 8.3, 2.2 Hz), 8.15 (d, 1H, J = 2.2 Hz) &gt; 8. 1 3-8.00 ( m, 4H ) &gt; 7.45 ( t, 2H, J = 8.7 Hz) C) #-( 4-(2-aminopyridin-4-yloxy)-3-phenyl)-6-(4-phenylphenyl)pyridine Oxidation of decylamine, trifluoroacetate at room temperature, followed by EDC1·HC1 (30 mg, 0.16 mmol) and 4-(4-amino-2-fluorophenoxy)pyridin-2-amine ( Compound B of Example 24, 22 mg, 0.1 mmol) was added to 6-(4-fluorophenyl)pyridinic acid-//-oxide (23 mg, 0.1 mmol) and HOBt (10 mg) in # DMF (2 mL) of the resulting solution and the reaction mixture was stirred overnight at room temperature. The title compound (25 mg, 46%) (trifluoroacetic acid salt) &quot;&quot;HNMRCDMSO-t&quot; (5 14.00 (s, 1 H), 8.43 ( dd, 1H, J = 8.0, 2.2 Hz), 8.15 (dd, 1 Η, J = 12.8, 2.4 Hz), 8.08 (d, 1 Η, J = 7.1 Hz), 7 _ 9 9 - 7.3 7 ( m, 9 H ) , 6.72 ( dd, 1H, J = 7.0, 2.4Hz ) , 6.32 ( d, 1H, J =

2.3 Hz ) , 3.7 ( br s, 2H ) ; MS ( ESI+) m/z 417.2 ( M + H , + (190) 1324926 Example 59

1-(4-(3-(4-(2-amino-2-mercaptoethyl)phenyl)lide-4-yloxy) phenyl)-3-fluorophenyl)-3-(2- (4-fluorophenyl)ethinyl)urea, hydrochloride

N〇2 NA) 2-(4-(4-(2-carbo-4-nitrophenoxy)indole Jt-threo-3-yl)phenyl)acetic acid 4-(2-carbyl-4) Nitrophenoxy)-3 -pyranyl D (Compound A '120 mg' 0.33 mmol of Example 33) '2-(4,4,5,5-tetramethyl-1,3 , 2 -dioxaborolan-2-yl)phenyl)acetic acid (Frontier Scientific, 131 mg, 0.50 mmol), hydrazine (triphenylphosphine) pin (〇) (Strem Chemicals, 38 mg &gt; 0.03 3 mmol), and sodium carbonate (245 mg, 2.3 mmol) were placed in a 25 mL round bottom flask. The flask was flushed with nitrogen, and then dioxane and water (1 mL each) were charged. After stirring at 80 ° C for 1 hour, the mixture was allowed to cool to room temperature and then concentrated in vacuo. The title compound (120 mg, EtOAc (EtOAc) 99%) ° 'H NMR ( CD3OD ) (5 8.61 ( s, 1Η ) &gt; 8.48 ( d, 1H, J = 5.6Hz ) , 8.22 ( dd, 1 H, J = 10.4, 2.8Hz) · 8.14-8.11 ( m, 1 H ) , 7.54 ( d, 2H, J = 8.1Hz) , 7.41 ( d, 2H, J = 8.0Hz) , 7.40 ( m,1H ) &gt; 7.05 ( d, 1 H, J = 5.7Hz ), 3.56 ( s, 2H ) ; MS ( ESI+) m/z 369.1 6 ( M + H ) + .

N02 B) 2-(4·(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamidamine 2-(4-(4·(2-fluoro) 4-Benza-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (50 mg, 0.136 mmol), HOBT (46 mg, 0.34 mmol), and EDCI (65 mg, 0.34 mmol) in 25 mL In the round bottom bottle. The flask was flushed with nitrogen and then DMF (1 mL) was added. After stirring at room temperature for 1 hour, the solution was cooled to and added with ammonium hydroxide (0.5 mL). The reaction was stirred at 0&lt;0&gt;C for 1 h then diluted with brine (5 mL) andEtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The title compound (33 mg, 6 6%) was obtained as a colorless oil. - (192) 1324926 〇'Η NMR ( CD3OD ) &lt;58.49 (s,1Η) &gt; 8.38 ( d, 1H, J = 5 6Hz) , 8.10 ( dd,1H, J = 10.4, 2.4Hz ) * 7.99 ( m, 1H )' 7.45 ( d, 2H, J = 8.2Hz ) &gt; 7.30 ( d, 2H, J = 8.2Hz ) « 7.28 ( m, 1H ) , 6 · 9 3 ( d,1 H,·/ = 5 · 6 H z ) , 3.44 ( s, 2H) ; MS ( ESI+) m/z 3 68.1 8 ( M + H ) + . C) 1-(4-(3-(4-(2-Amino-2-ketoethyl)phenyl)pyridine-4-% oxy)-3-fluorophenyl)-3-(2) -(4-Fluorophenyl)ethinyl)urea was treated with zinc powder (59 mg, 0.9 mmol) and ammonium chloride (48 mg, 0.9 mmol) to give 2-(4-(4-(2-fluoro) A solution of -4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide (33 mg, 0.09 mmol) in THF (0.8 mL) and methanol (1.2 mL). The mixture was stirred for 4 hours at room temperature and then filtered through a Celite® thin filter pad (with methanol). The filtrate was concentrated and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was dried over anhydrous sodium sulphate and concentrated in vacuo to give a crude product (25 mg, 82%) Further purification. h NMR ( CD3OD ) δ 8.33 ( s, 1H) * 8.19 ( d, 1H, J = 5.6Hz ) &gt; 7.49 ( d, 2H, 7 = 8.1Hz) &gt; 7.32 ( d, 2H, J = 8.2Hz) * 6.82 ( t, 1H, J = 8.8Hz) &gt; 6.61 ( d, 1H, J = 5.6Hz ) , 6.44 ( qd , 1H , J =1 2.8 , 2.8Hz ) , 3.48 ( s, 2H ) ; MS ( ESI+) m/z 3 3 8.2 5 (M + H) +. The above amine was dissolved in THF (1 mL), then 2-(4-fluoro-196-(193) I324926 phenyl)ethyl decyl isocyanate (Compound D of Example 1 1 , 250 L '10 74 〇 ^) 〇1, a 0.3^1 solution in toluene). After stirring 1 &amp; at room temperature, the title compound was obtained as a white solid. This solid was dissolved in dioxane (2 inL) and cooled to 0 °C. Anhydrous HCl (2 mL in 1N in diethyl ether) was added. After stirring at 0 ° C for 5 minutes, the solution was concentrated. The resulting hydrochloride salt was lyophilized from acetonitrile/water to give the title compound as a white solid (2 3 mg &gt; 5 7%) «'HNMRC DMSO-heart) 5 1 1 .02 ( s, 1 Η ), 10.59 ( s, 1 η ) . 8.83 ( s, 1 Η ) - 8.58 ( d, 1Η, J = 6.4Hz )' 7.79 ( dd,1H,= 12.8,2.4Hz) &gt; 7.60 ( d, 2H, J = 8.4Hz) ' 7.46-7.34 ( m, 4H ) - 7.3 1-7.28 ( m, 2H ), 7.11 ( t,2H, j = 8.7Hz ), 6.88 ( d, 1H, J = 5.6Hz), 3.70 ( s, 2H ) - 3.40( s, 2H ) ; MS ( ESI+) m/z 517.19 ( *· M + H ) +.

1-( 4_ ( 3- ( 4-aminomethyl)phenyl)pyridin-4-yloxy)-3·fluorophenyl)·3_(2·(4-fluorophenyl)ethenyl)urea ,Trifluoroacetate 197- (194) 1324926

A) 4-(4-(2-Fluoro-4-nitrophenoxy)pyridyl)benzaldehyde was prepared as the title compound as a colorless oil. (86%) °lHNMR(CD3〇D) (5 • 9.92(s,1H), 8.56(s,lH),8.4l (d,lH'"/=6Hz), ' 8.12 ( dd, 1H, J = 10.3, 2.6Hz) - 8.05-8.01 ( m, ih ) ' 7.90 ( d, 2H, J = 8.3Hz ) , 7.73 ( d, 2H, J = 8.2Hz ) &gt; 7.35 ( t, 1H, J = 8.4Hz &gt; 6.95 (d, 1H, J = 6Hz); MS ( ESI+) m/z 339.19 ( M + H) + .

B) 4-(4-(2-Fluoro-4-nitrophenoxy)pyridine·3·yl)benzylaminecarboxylic acid tert-butyl ester followed by ammonium acetate (185 mg '2.4 mmol) and cyanide Sodium hydride (16 mg, 0.24 mmol) was added to 4-(4-(2-fluoro-4-phenylphenoxy)pyridin-3-yl)benzaldehyde (81 mg < 0.24 mmol) in methanol ( 2 mL) of the resulting solution. The reaction was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue obtained was dissolved in water (5 mL) andEtOAcEtOAc The combined organic extracts were washed with aq. EtOAc EtOAc EtOAc. The obtained crude product was dissolved in dichloromethane (2 mL). Then, triethylamine (50 vl, 0·36 mmol), DMAP (the amount of the tip of the spatula), and didicarbonate were sequentially added. Dibutyl vinegar (Aldrich ' 57 mg ' 0.26 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then the title compound was obtained as a colorless oil. 3 mg, 12%) 〇'H NMR(CD3OD ^ ) 5 8.50 ( s, 1H) &gt; 8.37 ( d, 1H, J = 5.6 Hz) · 8.09 ( dd, 1H, J = 6.1, 2.6 Hz) &gt; 8.01 -7.99 ( m, 1 H ) , 7.45 ( d, 2H, «7 = 8Hz) &gt; 7.26 ( d, 2H, J = 8.2Hz) * 7.25 ( m, 1H ), 6.95 ( d, 1H, J = 5.6 Hz) , 4.16 ( s, 2H) , 1.35 ( s, 9H) ; MS ( ESI+) m/z 440.19 (M + H) +» C) 1-(4-(3-(4-(amino) Phenyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The preparation was carried out in the same manner as in the step C of Example 59. After the formation of guanyl urea, 4N HCl (5 mL in dioxane) was added. After stirring at room temperature for 5 minutes, the reaction mixture was concentrated in vacuo. The residue was suspended in EtOAc (EtOAc m.) The obtained crude material was purified by preparative HPLC. The appropriate fractions were concentrated in vacuo to remove methanol. Toluene was added and then concentrated (2 X 5 mL). The resulting solid was lyophilized from acetonitrile / water to give the title compound (6 mg -199 - 8 (196) 1324926 &gt; 2 5%) as a white solid in the form of trifluoroacetic acid o'HNMRC DMSO-heart) δ 11.00 ( s, 1 Η ) , 10.53 (s, 1 Η ) &gt; 8.55 ( s, 1 Η ) &gt; 8.40 ( d, 1 Η, J = 4Hz ) &gt; 7.73 (dd, 1 Η, J = 12 , 4Hz ) , 7.67 ( d, 2Η, J = 8Hz ) &gt; 7.5 1 (d, 2H, J = 8Hz ) &gt; 7.3 4- 7.27 ( m, 4H ) &gt; 7.13-7.09 ( m, 2H ) , 6.73 (d, 1 H, J = 4 Hz), 4.03 (s, 2H), 3.68 (s, 2H); MS ( ESI+ ) ni/z 489.18 ( M + H).

1-(3-Fluoro-4-(3-(6-(hexahydropyrazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl-3-(2-(4) -fluorophenyl)ethinyl)urea, hydrochloride

A) 4-(4-(4.(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)pyridine-2-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester according to The title compound (87%) was obtained as crystals eluted eluted elute 4 NMR ( CD3OD ) 〇 8.62 ( s, 1 Η ) , 8.46 ( d, 1 H, J = 6 Hz ) , 8.36 -200- (197) 1324926 (d, lH, J = 2.4 Hz) &gt; 8.24 ( dd5 1 H, 7 = 1 0.4, 2.8Hz ) ' 8. 1 5-8. 1 1 ( m, 1H ) &gt; 7.84 ( dd, 1 H, J = 8.8, 2.4Hz ) &gt; 7.4 1 ( t, 1H, J = 8.4Hz ) 7.04 ( d, 1H, J = 5.6Hz ) &gt; 6.92 ( d, 1 H, J = 8.8Hz ) , 3.6 卜 3 · 5 9 ( m, 4 H ) &gt; 3.56-3.54 ( m , 4H ) , 1.50 ( s, 9H ) ; MS ( ESI+ ) m/z 496.23 ( M + H ) + .

B) 4-(4-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)pyridin-2-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester according to The title compound (96%) was obtained as a colourless oil. 4 NMR (

CD3〇D) (5 8.34 (s, lH) &gt; 8.29 ( d, 1H, J = 2Hz) &gt; 8.18 (d, 1H, J = 6Hz ) , 7.78 ( dd, 1H, J = 9.2, 2.8Hz ) , 6 · 8 7 - 6.8 3 ( m, 2 H ) , 6 · 6 1 ( d, 1 H, · / = 5.6 H z ) , 6.4 8 ( dd, 1 H, J = 12.8, 2.8 Hz) &gt; 6.44-6.41 ( m, 1H) &gt; 3.50-3.46 ( m, 8H ) &gt; 1.3 8 ( s, 9H ) ; MS ( ESI+ ) m/z 466.25 ( M + H) + C) 1-( 3- Fluoro-4-(3-(6-(hexahydropyrazin-1-yl)pyridin-3-yl)pyridine-4-yloxy)phenyl)-3-(2-(4-fluorophenyl) The title compound (28%) was obtained in the form of the hydrochloride salt. 'H NMR (DMSO-heart) δ 1 1 .33 ( s, 1 Η ) , 1 0.76 ( s, 1 Η ) , 9.09 ( s, 1 Η ) &gt; 8.74 ( d, 1 H, J = 6.8 Hz ) &gt ; 8.57 ( d, 1H, J = 2.4Hz ), 8.16 ( dd, 1H, J = 8.8, 2Hz ) , 7.91 ( dd, 1H, J = 12.8, 2Hz ) - 7.61 ( t, 1H, J = 8. 8Hz ) - 7.5 5 -7.5 0 ( m, 1 H ) &gt; 7.42 -7.3 8 ( m, 2H ) &gt; 7.28 ( d, 1H, J = 6.5Hz ) - 7.27-7. 1 8 ( m, 3H ) , 3.98 ( m,4H) , 3'82 ( s, 2H), • 3.23 (m, 4H) ; MS (ESI+) m/z 545.19 (M + H)+. Example 62

φ #-( 3-fluoro-4-(3-(6-(hexahydropyrazin-1-yl)pyridin-3-yl)pyridin-4-yloxy)phenyl)-2-one- Phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloride salt followed by 2-keto-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (Example 57 Compound C, 15 mg '0.069 mmol), DIPEA (60 L' 0.35 mmol), and TBTU (Fluka, 33 mg, 0.10 mmol), added to 4-(5-(4-(4-amino-2) -Fluorophenoxy)pyridin-3-yl)pyridin-2-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Compound B of Example 61, 32 mg, 0.069 mmol) in D-HF/ A solution of DMF (1 mL each). After stirring at room temperature for 18 hours, the reaction solution was diluted with ethyl acetate (5-202-(199) 1324926 mL), followed by 10% aqueous lithium chloride (2 x 5 mL) and saturated hydrogen carbonate. Aqueous sodium (1 x 5 mL) was washed <RTI ID=0.0>, </ RTI> dried over anhydrous sodium sulfate and concentrated in vacuo. The residue obtained was suspended in diethyl ether, cooled to EtOAc &lt;RTI ID=0.0&gt;&gt; The solution was allowed to warm to room temperature and then stirred at room temperature for 2 hours. The solution was concentrated under vacuum&apos; and the crude product obtained was purified using preparative HPLC. The appropriate fraction of φ is concentrated to remove methanol and then made basic with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous solution was extracted with ethyl acetate (2×10 mL) and the organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue obtained was dissolved in THF (2 mL). After stirring at 0 ° C for 5 minutes, the mixture was concentrated. The title compound (26 mg, 56%) was obtained from EtOAc (EtOAc) 4 NMR (DMSO-Luxin) accounted for 12.16 (s, 1H), 8.92 (s, lH), 8.59 ((1,1Η,·/ = 6·4Ηζ) * 8.53 ( dd, 1 Η, J = 7.2, 2Hz &gt; 8.47 ( d, 1Η, J = 2 4Hz ) » 8. 1 0 ( dd, 1 H, 7 = 6.4, 2Hz ) &gt; 8.04 ( d, 1H, J = 12Hz) , 7 99 ( dd, 1H , J = 8.8, 2.4Hz ) &gt; 7.54-7.46 ( m, 7H) ' 7.20 ( d, 1 H, J = 6.4Hz ) &gt; 7.97 ( d, 1 H, 7 = 9.2Hz ) * 6-6B ( m, 4H) &gt; 3.12 (m, 4H) - (200) 1324926

(( /?) -2·Amino-2-keto-1-phenylethyl)-#- (3-fluoro-based 4-(3-(6-(hexahydropyrazin-1-yl)pyridine) -3-yl)pyridin-4-yloxy)phenyl)propanediamine, hydrochloride • DIPEA (60/zL, 0.35 mmol) and 3-chloro-3-ketopropionic acid Ester (Aldrich, 10 μL, 0.076 mmol) 'added to 4-(5-(4-(4-amino-4-phenoxyphenoxy)pyridin-3-yl)pyridine in THF C 1 mL) 2-Based hexahydropyrazine-1-carboxylic acid tert-butyl ester (Compound B of Example 61, 32 mg, 0.069 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (5 mL) and then rinsed with saturated aqueous sodium hydrogen carbonate (1×5 mL), dried over anhydrous sodium sulfate and dried Concentrate in vacuo. The obtained yellow oil (^ 65 mg) was dissolved in THF (2 mL), and then aqueous sodium hydroxide (2 mL) was added. The solution was stirred at room temperature for 6 hours. The solution was concentrated to remove THF and then acidified to pH 4-5 with aqueous <RTIgt; The solid was collected by vacuum filtration and washed with water to give the corresponding acid (30 mg, 78% (yield)). MS ( ESI+) m/z 552.2 1 (M + H) +. The above acid was coupled with /) (-)-phenylglycinamide (Bachem) as described above to give the title compound as a white solid as a white solid (32%) ojNMRC DMSO-i ^) 6l〇,64(s, -204- (201) (201)1324926

1H ) - 8.89 ( s, 1 H ) &gt; 8.74 ( d, 1H, J - 8Hz ) &gt; 8.56 ( d, 1H, J = 5.6Hz ) , 8.46 ( d, 1 H, J = 2.4Hz ) , 7.96 ( d, 1 H, J = 8.8 Hz ) , 7.84 ( d, 1H, J = 1 2 Hz ) , 7.74 ( s, 1H ), 7.46-7.3 7 ( m, 4H ) - 7.3 1 -7.22 ( m, 5H ) , 7.06 ( d, 1H, J = 9.2Hz ) , 5.34 ( d,1 H, "7 = 8Hz ) , 3.81-3.78 ( m, 4H ) , 3.40 ( s, 2H ) , 3.12 ( m, 4H) ; MS ( ESI+ ) m/z 5 84.2 5 ( M + H ) +.

1-(3-carboyl-4-(3-(usus D--3-yl)pyridinium-decyl-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethyl Urea, urea, hydrochloride

A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)pyridine was prepared in a similar manner to Step A of Example 59 to give a colorless oil. The title compound. 1H NMR ( CD3OD ) 6 8.83 ( d, 1H, J = 1 , 6 Hz ) &gt; 8.69 ( s5 1H ) &gt; 8.61 ( d, 1H, J = 5Hz ) &gt; 8.56 ( d, 1H, J = 5.8Hz) , 8.27 ( dd, 1 H, -205- (202) 1324926 J = 10.4, 2.8Hz ) &gt; 8.20-8.1 4 ( m, 2H ) &gt; 7.72-7.55 ( m, 1 H ) , 7.53 (t, lH , J=8.6Hz) - 7.08 ( d, 1 H, J = 6Hz ) ; MS (ESI+) m/z 312.15 (M + H),

φ B ) 3-fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)aniline was prepared in a similar manner to Step C of Example 59 to give a colorless oil. The title compound of the substance. MS ( ESI+ ) m/z 282.1 2 (M + H) +. C) 1-(3-Fluoro-4-(3-(pyridin-3-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea was prepared in a similar manner to Step C of Example 59 to give the title compound as the title compound as a yellow solid (yield 47% of Steps B and C) &lt;1&gt;HNMR (DMSO-i/ 6) &lt;5 11.14(s, 1H )&gt; 10.73 ( s, 1 Η ) &gt; 9.16 ( d, 1 Η, J = 1 , 6 Hz ) , 9.08 (s, 1 Η ) , 8.90 ( dd, 1 Η, J = 5.2, 1·2Ηζ), 8.78 ( d, 1 Η, J - 6.4Hz ) , 8.56 (d,1 Η, J = 8Hz ) , 7.95 -7.90 ( m, 2Η ) &gt; 7.60 ( t, 1H, J = 8.8 Hz) · 7.5 5 -7.5 2 ( m, 1H ) &gt; 7.44- 7.4 1 ( m, 2H ) · 7.26-7.2 1 ( m, 3H ) ; MS ( ESI+ ) m/z 461.16 ( M + H ) +. -206- (203) 1324926 Example 6 5

1-( 3 -xiao(yl-4-(3-(4-(hexafluoropyrene-extended-1-yl)) fluorenyl)-pyridyl-4-yloxy)phenyl)-3-(2- (4-fluorophenyl)ethinyl)urea, trihydrochloride

A) 4-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)hexahydropyrazine-1-carboxylic acid tert-butyl ester according to Example 59 The title compound was obtained as a colorless oil. 1H NMR ( CD3OD ) 5 8.48 ( s, 1 Η ) , 8.32 ( d,1 Η, J = 5.6 Hz ) , 8.08 ( dd, 1 Η, J = 12.4 Hz ) &gt; 7.97 (d, lH, J=8 Hz ) &gt; 7.38 ( d, 2H, J = 8.8Hz ) « 7.21-7.18 (m, 1H) &gt; 6.95 -6.92 ( m, 3H ) &gt;

3.46 (m, 4H), 3.09-3.06 (m, 4H), 1.10 (s, 9H); MS (ESI+) m/z 495.23 ( M + H ) + . -207- (204) 1324926

B) 4-(4-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)phenyl)hexahydropyrazine-1-carboxylic acid tert-butyl ester according to the examples The title compound was obtained as a colorless oil (yield: 94% yield of steps A and B). 'H NMR(CD3OD) (5 8.3 0 ( s, 1 Η ) - 8.14 ( d, 1 H, J = 5.6 Hz ) , 7.45 ( d, 2H, J = 8.8 Hz ) , 6.98 ( d, 2H, J = 8.8Hz ) &gt; 6.83 ( t, 1 H, J = 8.8Hz ) &gt; 6.58 ( d, 1 H, J = 5.6Hz ) &gt; 6.48 ( dd, 1H, &lt;/ = 12.8, 2.4Hz ) , 6.43 -6.41 (m, 1H ) , 3.49 (m, 4H) &gt; 3.11-3.09 ( m, 4H ) &gt; 1.16( s,9H) ; MS ( ESI+ ) m/z 465.24 ( M + H ) + % C 1-(3-Fluoro-4-(3-(4-(hexahydropyrazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-3-(2-(4-) The fluorophenyl)ethinyl)urea was prepared in a similar manner to step C of Example 59 to give the title compound (3 7%) as a pale yellow solid. 1 H NMR (DMSO-heart) &lt;5 1 1 .0 1 ( s,1 Η ) &gt; 1 0.60 ( s, 1 Η )

, 8.77 ( s, 1Η ) , 8.5 1 ( d, 1H, J = 6·4Ηζ) , 7.78 ( d, 1 H, J = 12Hz ) , 7.59 ( d, 2H, J = 8.4Hz ) , 7.44 - 7.40 ( m, 2H ) , 7.3 1-7.28 ( m, 2H ) &gt; 7. 1 3-7.08 ( m, 4H ), 7.03 ( d, 1H, J = 6.4Hz ) , 3.70 ( s, 2H ) , 3.42 ( m , 4H-208-(205) 1324926), 3.15 (m, 4H); MS (ESI+) m/z 544.26 (M + H) +. Example 66

(3-Fluoro-4-(3-(4-hydrohexazin-1-yl)phenyl)pyridin-4-yloxy)phenyl)-2-one-1-phenyl-1 2-Dihydropyridine-3-carboxamide, trihydrochloride, was prepared in a similar manner as Example 62 to give the title compound as the title compound as a pale yellow solid (43%). NMR (DMSO-heart) δ 1 2.1 5 ( s, 1 Η ) , 8.83 ( s, 1 Η ) &gt; 8.56-8.52 (m, 2H ) , 8.10 ( dd, 1H, J = 6.8, 2.4 Hz ) , 8.04 ( dd, 1H, J = 11.6, 2Hz) , 7.61 ( d, 2H, J = 8.8Hz) &gt; 7.55-7.45 ( m, 7H ) &gt; 7.15 ( d, 1H, J = 6.8Hz ) , 7.09 ( d , 2H, J = 8.8Hz) &gt; 6.61 ( t, 1 H, J = 6.8Hz ) , 3.44(m,4H), 3.15 ( m,4H) ; MS ( ESI+ ) m/z 562.36 ( M + H) +. Example 6 7 -209- 8 (206) 1324926

(3-Fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-one-1-phenyl-1,2- Dihydropyridine-3-carboxamide

'NA) 3-(4-(2-butyl dimethyl decyloxy)ethyl)phenyl)-4-(2-fluoro-4-nitrophenoxy)pyridine according to and practice The title compound (77%) was obtained as a colourless oil. h NMR ( CD3 〇 D ) δ 8.67 ( s, 1 Η ) , 8.56 ( d, 1 H, J = 8 Hz ) , 8.27

(dd, 1 H, J = 12, 4 Hz), 8.16 (d, 1 H, J = 8 Hz), 7.58 (d, 2H, J = 8 Hz) &gt; 7.39 ( d, 2H, J = 8 Hz ) &gt; 7.36 ( m, 1H ) , 7.15 (d, lH, J=4Hz) - 3.9 1 ( t, 2H, J = 8Hz ), 2.90 ( t, 2H, J = 8Hz ) , 0.90 ( s, 9H ) , 0.00 ( s , 6H); MS ( ESI+ ) m/z 469.1 5 (M + H) +.

8 (207) 1324926 6) 3-(4-(2-(Terhanyl dimethyl decyloxy)ethyl)phenyl)-4-(2-fluoro-4-nitrophenoxy) The title compound was obtained as a pale yellow oil. 1 Η NMR ( CD 3 Ο D ) &lt; 5 8.44 ( s, 1 Η ) , 8.32 ( d, 1 Η, J = 4 Hz ) , 7.57 ( d, 2H, J = 8 Hz) , 7.36 ( d, 2H, J = 8.4Hz ) - 6.59 ( t, 1H, J =8Hz ) , 6.75 ( d,1H, y = 4Hz ) , 6.61 ( d, 1H, J = 8Hz

), 6.55 ( d, 1 H, J = 4Hz ) , 3.90 ( t, 2H, J = 6.8Hz ) - 2.89 ( t, 2H, J = 6.4Hz ) &gt; 0.87 ( s, 9H ) , 0.00 ( s, 6H) ;MS ( ESI+ ) m/z 43 9.26 ( M + H ) + . C) #-( 3-Fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl-2-keto-1-yl-1 , 2-Dihydropyridine-3-carboxamide was prepared in a similar manner to Step C of Example 62. After the decylamine was formed, the obtained yellow oil was dissolved in THF (2 mL), then Treated with TBAF (Aldrich, 180/L, 1M in THF) for 1 hour at room temperature. Dilute the reaction with ethyl acetate (1 mL), with water and brine (5 m each) L) was rinsed, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (10% methanol / ethyl acetate) on silica gel. The title compound (72%) was obtained as a yellow solid. 4 NMR (CD3OD) (5 8.5 9 ( dd, 1H, J = 7.6, 2.0 Hz ) , 8.41 ( s, 1H) &gt; 8.26 ( d, 1H, J = 5.6 Hz » 7.91-7.85 ( m, 2H ) , 7.55-7.46 ( m, 5H) « 7.41 ( d, 2H, J = 6.7Hz) &gt; 7.29 ( -211 - (208) 1324926 d, 2H, J = 8.1Hz ) « 7.26 ( m, 1 H ) - 7. 1 3 ( t, 1 H, J = 8.7Hz ) » 6.69 ( d, 1 H, J = 6Hz ) · 6.64 ( t, 1 H , 7 = 7.2 Hz ) - 3.73 ( t, 2H, J = 7.2 Hz ) &gt; 2.82 ( t, 2H, J = 6.8 Hz ) ; MS ( ESI + ) m / z 522.27 ( M + H ) + . 8

#- (4-(3-(4-(2-Aminoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-2-one-1-phenyl-1, 2-Dihydropyridine-3-carboxamide, dihydrochloride, followed by DIPEA (27/zL' 0.154 mmol) and methotrexate

Chlorine (Aldrich, 7p: L, 0.092 mmol) added to #-(3-fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridine-4-) in THF (1 mL) Benzyl)phenyl)-2-keto-1-phenyl-1,2·dihydroxypyridine-3-formamide (Compound C of Example 67, 40 mg, 0.077 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 3 mL of ethanol and transferred to a pressure tube.

. Ammonium hydroxide (7 mL) was added and the tube was sealed and heated at 50 °C for 8 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with ethyl acetate (10 mL) and then washed with water (2×10 ml) and brine (1×10 mL) Dry and concentrate in the air at True-212- (209) (209) 1324926. The obtained crude product was purified by the preparation of HPL C. The appropriate fractions were concentrated to remove methanol and basified with saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc (2×20 mL) and EtOAc (EtOAc) The residue obtained was dissolved in EtOAc (2 mL). The title compound (24 mg, 53 〇/〇) was obtained as a white solid. NMR ( DMSO-A) δ 12.13 ( s, 1H) , 8 74 ( s, 1 Η ) ' 8.5 5 - 8.5 1 ( m,2 Η ) ' 8 · 0 9 ( dd,i H,J = 6 4 H z ), 8.03 (m, 1H) » 7.64 (d, 2H, J = 6Hz) &gt; 7.63 (m, 1H) , 7.54 - 7.41 ( m, 6H) . 7.38 ( d, 2H, 8.4H2), 7.04 ( d,1H,= 6HZ) ' 6.68 ( t,1H,= 6.8Hz) ,3 〇2 ( m, 2H) ' 2.89 ( m,2H) ; MS ( ESI+) m/z 521 ” ( M + H) +

V-(4-( 3-(4-((2)(methylamino)ethyl)amine))yl)phenyl)H is more than D--4-yloxy)-3-fluorophenyl)·! _ ( 4_fluorophenyl)·2 keto group _ -213- (210) 1324926

A) 4-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl ester was obtained in a similar manner to The title compound (77%). CD3〇D ) δ 8.66 ( s, 1 Η ) , 8.52 ( d, 1 H, J = 6Hz ) (dd, 1 H, J = 10.4, 2.8Hz) &gt; 8.16-8.13 (m, 1H) (d, 2H, J = 8.4Hz ) &gt; 7.97 ( d, 2H, J = 8Hz ) &gt; ' 1H, J = 8.5Hz ) &gt; 7.06 (d, lH, y = 6Hz ) &gt; 3.93 ( ;MS ( ESI+ ) m/z 3 69.22 ( M + H ) +. Preparation of formic acid, NMR ( -8.22 &gt; 8.10 ^•44 ( t, s, 3H )

B) 4-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)phenyl ester was obtained in a similar manner to Step C of Example 59. The title compound (99%). 'Η CD3〇D ) δ 8.38 ( s, 1 Η ) , 8.24 ( d, 1 H, J = 6Hz ) (d, 2H, J = 8.4Hz ) - 7.66 ( d, 2H, J = 8.4Hz ) &gt; Preparation of formic acid methyl, NMR ( &gt; 8.01 6.85 ( (211) 1324926

t,1 Η , J = 9.2 H z ), 6.65 ( d, 1H, J = 6Hz ) , 6.48 ( dd, 1Η, J = 12.8, 2.4Hz ) &gt; 6.43 ( d, 1 H, J = :2.8Hz ), 3.82 ( s, 3H ) ; MS ( ESI+ ) m/z 3 3 9.2 8 ( M + H ) + O

C) 4-(2-(2-fluoroiyl-4-(1-(4-(phenyl))-2-indolyl-1,2-hydrogen]pyridin-3-carboxamido)phenoxy The title compound (8 1 %) was obtained as a yellow oil. 1H NMR ( CD3 〇 D ) δ 8.66 ( dd, 1H, J = 7.2, 2Hz) , 8.56 ( s, 1H ) , 8.40 ( d, 1 H, J = 6Hz ) , 8.13 ( d, 2H, J = 8.4Hz ), 7.97-7.95 (m, 2H), 7.78 (d, 2H, J = 8.4Hz), 7.55-

7.52 ( m, 2H ) , 7.38-7.31 ( m, 3H) - 7.26 ( t, 1H, J = 7.2Hz ) , 6.82 ( d,1 H, J = 5.6Hz ) , 6.72 ( t, 1H, J = 6.7 Hz ) , 3.94 ( s, 3H ) ; MS ( ESI+) m/z 5 5 4.2 1 ( M + HD) #-(4-(3-(4-(methylamino)ethyl)) Mercapto)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-bu(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxamide

1N aqueous sodium hydroxide (5 mL) was added to EtOAc (5 mL 215 (212) 1324926). The reaction solution was stirred at room temperature for 20 hours and then concentrated to remove THF. The aqueous solution was acidified with 1 N aqueous HCl. The acid was collected by filtration and washed with water to give the desired product (144 mg &lt; MS (ESI+) m/z 5 4 0.2 1 ( M + Η ) + s s s s s s s s s s s s s s %). NMR (DMSO-heart) δ 12.21 ( s, 1 Η ) &gt; 8.93-8.90 ( m, 2H ) ’ 8.68-8.64 ( m, 2H) &gt; 8.21 ( dd, 1H, J = 6.4, 2Hz) »

8. 1 6 ( m, 1 H ) &gt; 8.11 ( d, 2H, J = 8Hz ) * 7.90 ( d, 2H, J =8.4Hz ) , 7.69-7.65 ( m,2H ) , 7.60-7.47 ( m, 4H ), 7.16 ( d, 1H, J = 5.6Hz ) , 6.80 ( t, 1H, J = 7Hz) , 3.64 (t5 2H, J = 5.2Hz ) &gt; 3.17 ( t, 2H, J = 5.2Hz) . 2.65 ( s, 3H ) ; MS ( ESI+) m/z 596.37 ( M + H ) +.

#-(4-(3-(4-(2-Aminoethyl)aminemethanyl)phenyl)pyridine, 4·yloxy)-3-fluorophenyl)-1-(4-fluorobenzene Benzyl-2-keto-1,2-dihydropyridine-3-carboxamide, dihydrochloride-216- (213) 1324926 Prepared in a similar manner to Example 69 to give an off-white The title compound is in the form of a solid hydrochloride. NMR ( DMSO-c/6) (5 1 2.1 7 ( s, 1 Η ) , 8.8 7-8.8 5 ( m, 2H ) , 8.64 (d, 1H, J = 6.4 Hz ) , 8.59 ( dd, 1H, J = 7.6, 2.4 Hz ), 8.16 ( dd, 1H, J = 6.8, 2.4 Hz ) &gt; 8.10 ( m, 1 H ) &gt; 8.06 ( d, 2H, J = 8.4 Hz) &gt; 8.00 ( br s, 2H &gt; 7.85 ( d, 2H, J = 8.4Hz ) , 7.64-7.60 ( m, 2H ) , 7.5 5 -7.42 ( m, 4H ),

7.13 ( d, 1 H, J = 6Hz ) &gt; 6.75 ( t, 1H, J = 7.2Hz ) &gt; 3.56- 3.53 ( m, 2H ) , 3.0 4 - 2 · 9 9 ( m, 2 H ) ; MS (ESI+) m/z 5 8 2.3 2 (M + H) +.

^-(4-(3-(4-(2.dimethylamino)ethyl)amine)methyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1-( 4-Fluorophenyl)-2-keto-1,2,dihydropyridine-3-carboxamide, dihydrochloride salt was prepared in a similar manner to Example 69 to give hydrogen as an off-white solid. The title compound (56%) in the chlorate salt.咜NMR ( DMSO-A) 6 1 2.08 ( s, 1 Η ) &gt; 8.87 ( br s, 1 Η ), 8.75 ( s, 1 Η ) , 8.54 - 8.51 ( m, 2 Η ) 8.08 ( dd, 1H, J = -217 (214) 1324926 6.8, 2.4Hz) , 8.02 ( m, 1 H ) , 7.99 (d, 2H, J = 8.4Hz), 7.77 ( d, 2H, J = 8.4Hz ) , 7.5 6 -7.5 3 ( m, 2H ) &gt; 7.47- 7.34 (m,4H) &gt; 6.99 ( d, 1H, J = 5.6Hz ) , 6.67 ( t, 1H, J = 6.8Hz ) - 3.61 -3.57 ( m, 2H ) , 3.23 -3.21 (m, 2H) &gt; 2.77 ( s, 3H ) , 2.76 ( s, 3H ) ; MS ( ESI+ ) m/z 610.30 ( M + H) + . φ Example 7 2

H2n 1-(4-(3-Amino-B-butyl-4-yloxy)-3-phenyl)-3-(2-(4-(phenylphenyl)ethenyl)urea

A) 3-Fluoro-4-(3-nitropyridin-4-yloxy)aniline Sodium hydride (80 mg, 2 mmol, 60%) was added to DMF at room temperature under nitrogen. 4-Amino-2-fluorophenol in 5 mL) (Ref. Step A of Example 19, 127 mg, 1.0 mmol). After stirring at room temperature for 10 minutes, 4-chloro-3-pyridinium hydrochloride was added (

Lancaster, 195 mg, 1.0 mmol). The mixture was stirred at room temperature for -218-(215) 1324926 for 1 hour, then diluted with ethyl acetate (50 mL) and then water, 10% aqueous lithium chloride and brine (each) X 30 mL ) wash. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The title compound (150 mg, 60%) was obtained as a yellow orange solid. NMR (DMS0-i/&lt;5) (5 9.13(

s, 1 Η ) &gt; 8.63 ( d, 1 Η, J = 6Hz ) &gt; 7.09 ( t, 1Η, J = 9.2Hz ), 6.92 ( d,1 H, J = 6Hz ) , 6.55 ( dd, 1H, J = 13.2, 2.4 Hz) » 6.45 ( dd, 1 H, J = 9.2, 2.4 H z ) , 5.61 ( s, 2H) ; MS (ESI+) m/z 250_18 (M + H)+.

B) Bu (3-fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea 2-(4 a solution of -fluorophenyl)ethenyl isocyanate in toluene (Compound D of Example 11, 1.3 mmol) was added to 3-fluoro-4-(3-nitropyridin-4-yloxy)aniline ( 158 mg, 0.63 mmol) was added to a solution of THF (3 mL), then stirred at room temperature for 2 hr and then at 50 ° C for 5 min. The mixture was concentrated and the residue obtained was treated with DMF (15 mL) and EtOAc (150 mg), and the mixture was concentrated to dryness in vacuo and applied to a column of cerium oxide layer. The layer was eluted with 20-60% ethyl acetate/hexanes to give the desired product - 219- (216) 1324926 to afford the desired product which was further purified by tanning with isopropyl ether. A pale yellow solid (1 2 0 mg, 2 5 %) was obtained. 'Η NMR ( OMSO-d6) 6 11.07 ( s, 1H) &gt; 1 0.63 ( s, 1H ) , 9.19 ( s, 1H) - 8.67 ( d, 1 H, J = 5.6Hz ) , 7.85 ( d, 1H , J = 11.7Hz), 7.46-7.45 (m, 2H) &gt; 7.3 9-7.3 5 ( m, 2H ) &gt; 7. 1 8 ( dd, 2H, J = 8.6, 8.6Hz ) &gt; 7.01 ( d , 1H, J = 6.1Hz) &gt; 3.76 ( s, 2H ).

C) 1-(4-(3-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea from latex balloons Hydrogen, 1-(3-fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (125 The suspension of mg, 0.29 mmol) in 3:1 methanol / THF (20 mL) was hydrogenated on Pt20 (50 mg) for 6h. The title compound (85 mg, 74%) was obtained as a white solid. 4 NMR (DMSO-heart) (5 11.03 ( s, 1 Η ) , 10.55 (s, 1 Η) , 8.03 (s, 1 Η), 7.75 (dd, 1 H, J = 2.5, 1 3.2 Hz) &gt; 7.65 (d , 1 H, J = 5 .1 H z ) &gt; 7.38-7.35 (m, 3H) , 7.23-7.16 (m, 3H) , 6.42 (d, 1H, J = 5.1Hz), 5.26 ( s, 2H ) , 3.75 ( s, 2H ) ; MS ( ESI + ): m/z 3 99.3 5 ( M + H ) +. Example 7 3 -220- (217) 1324926

1-(4-(3-(15,45) ·4-Aminocyclohexanecarbamimidyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4) -fluorophenyl)ethinyl)urea, trifluoroacetate

A ) ( 1 heart 45 ) -4- ( ( 4- ( 2-fluoro-4-(3-(2-(4-fluorophenyl)ethenyl)))) phenoxy)pyridine-3- Tert-butyl methionyl)cyclohexylaminecarboxylic acid, W-Boc-cis-1,4-diaminocyclohexanyl residue (Chem-Imprex)

The solution of International, 24 mg, 0.10 mmol) in THF (1 mL) was cooled to 0 &lt After 5 minutes, 1-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-3·(2-(4-fluorophenyl)ethenyl)urea was used. The solution of the compound C of Example 72, 27 mg, 0.06 8 mmol) in THF (0.5 mL) was applied to the mixture, and the mixture was stirred at 〇t, stirred for 1 Torr, and then stirred at room temperature for 2 hours. . The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. Purification of the crude product by flash column chromatography eluting with EtOAc (EtOAc) ' twenty one % ) . M S ( ESI+ ) : m/z 624.25 ( M + H ) +. B) 1-(4-( 3-((1&lt;S,4&lt;S)-4-Aminocyclohexanecarboxamido)pyridin-4-yloxy)-3-phenyl)-3 - (2-(4-Phenylphenyl)Ethyl) Pulse 'φ Trifluoroacetate will be (15,45)-4-( (4-(2·Fluoro- 4-(3-(2-) 4-fluorophenyl)ethinyl)ureido)phenoxy)pyridin-3-yl)aminecarboxylidene butylcyclohexylamine carboxylic acid tert-butyl ester (10 mg '0.016 mmol) in anhydrous methanol (0.5 mL) The resulting solution was cooled to 0 ° C and treated with 4M EtOAc / EtOAc (2 mL). The mixture was stirred at 0 ° C for 1.5 hours, then at room temperature for 20 minutes, and finally concentrated in vacuo to give a crude material. The title compound (4 mg, 3 3%) was obtained as a yellow solid (yield: </ RTI> NMR ( DMSO-^) 5 1 1 . 1Η )· 10.64 ( s, 1Η ) » 9.28 ( s, 1Η ) , 8.40-8.37 (m,1Η) .7.94 ( s, 1H ) « 7.83 ( dd, 1H, J = 2.1, 12.7Hz) &gt; 7.47- 7.33 ( m, 5H ) &gt; 7.19-7.14 ( m, 3H ) &gt; 7.07-7.02 ( m, 1H ), 3.75 ( s, 2H) , 3.25-3.15 ( m, 1H ) 1 2.8 5 -2.7 6 ( m , 1 H ) , 1.97-1.84 (m, 2H), 1.85-1.61 (m, 5H); MS (ESI+): m/z 524.26 ( M + H ) + . -222- 1324926

1-(4-(3-()-4-aminocyclohexanecarbamamino)pyridin-4-yl

Oxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, bis(trifluoroacetate)

FA ) ( \R,4R ) -4-( ( 4-(2-Fluoro-4-(3-(2-(4-fluorophenyl)ethenyl))) phenoxy)pyridine-3 -Alkylmercapto)cyclohexylaminecarboxylic acid tert-butyl ester in a similar manner to that described in Step A of Example 73, from 1-(4-(3-aminopyridin-4-yloxy) 3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (Compound C of Example 72, 57 mg, 0.14 mmol) and W-Boc-trans-4-amine The title compound (32 mg, 66%) was obtained. MS (ESI+): m/z 624.4 1 (M + H) +. B) 4-(3-((H4/?)-4-Aminocyclohexanecarbamoyl)pyridyl-223-(220) 1324926 pyridine-4-yloxy)-3-fluorophenyl )-3-(2-(4-fluorophenyl)ethenyl)urea, bis(trifluoroacetate)

In a similar manner to that described in Example 73, from (1&amp;4S)-4-((4-(2-fluoro)-4-(3-(2-(4-fluorophenyl)ethenyl)) The title compound was prepared from the ureido)phenoxy)pyridin-3-yl)amine carbhydryl) butylhexylamine carboxylic acid tert-butyl ester (25 mg). The title compound (7 mg &gt; 2 3%) was obtained as a white solid. 'H NMR (DMSO-heart) δ 11.06 ( s, 1 Η ), 10.61 ( s, 1H) , 9_94 ( s, 1H) , 9.19 ( s, 1H) , 8.28 ( d, 1 H, J = 5.6 Hz ) , 7.82 ( dd, 1 H, J = 2.0, 1 3.2 Hz ), 7.79-7.76 ( m, 3H ) , 7.43 ( dd, 1H, J = 2.0, 8.6 Hz ), 7.3 8 -7.3 3 ( m, 2H) , 7.17 ( dd, 2H, J = 9.2, 6.6 Hz), 6.86 ( d, 1 H, J = 5, 6 Hz ) &gt; 3.74 ( s, 2H ) &gt; 3.0 8-2.9 5 ( m, 1 H ) &gt; 2.67-2.43 ( m, 1H) - 2.0 1 -1 . 8 8 ( m, 4H ) &gt; 1.53- 1.43 ( m, 2H ) &gt; 1.3 7- 1.2 7 ( m, 2H ) ; MS ( ESI+) : m /z 524.3 5 ( M + H ) +. Example 7 5

1-(4-(3-((1Λ,4/?)-4-(Aminomethyl)cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3- (2-(4-fluorophenyl)ethenyl-224- (221) 1324926

A) ( ( \R,4R ) -4- ( (4-(2-Fluoro-4-(3-(2-(4)fluorophenyl)

Ethyl benzyl) ureido)phenoxy)pyridin-3-yl)amine carbazyl)cyclohexyl)methylamine benzyl ester benzyl ester according to Step A of Example 73, from 1-(4-(3-amine) Pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (Compound C of Example 72, 50 mg, 0.13 mmol) 4-((Benzyloxycarbonyl)methyl)cyclohexanecarboxylic acid (40 mg, 0-14 mmol, according to Schaus, JM et al. J. Med. Chem. 1 998, 41, 1 943- 1 95 5 The title compound was prepared to give the title compound (30 mg, 34%). MS (ESI + ): m/z 672.34 (M + H) +. B) 1-(4-(3-((17?, 47?)-4-(Aminomethyl)cyclohexanecarboxamido)pyridin-4-yloxy)-3-fluorophenyl)- 3-(2-(4-Fluorophenyl)ethenyl)urea uses hydrogen from a rubber balloon to give (-4-(4-(2-fluoro)-4-(3-(2-(4) -fluorophenyl)ethinyl)ureido)phenoxy)pyridin-3-yl)aminecarboxylidene benzyl cyclohexyl)methylaminecarboxylate (25 mg, 0.037 mmol) in methanol (1.5 mL) The resulting solution was hydrogenated over 10% -225-(222) 1324926 palladium-carbon (15 mg) for 4 hours. The catalyst was filtered off and the filtrate was evaporated to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H ) , 9'64(s, 1 H ) , 9.01(s,lH) &gt; 8.17 ( d, 1H, J = 5.6Hz) - 7.79 ( dd,1 H, J = 2.5, 1. 7Hz ) ' 7.42 -7.35 ( m,4H) , 7.30 ( dd, H, J -- =8.6, 9.2 Hz ) , 7.1 8 ( m, 2H ) , 6.66 ( d,1H5 J = • 6Hz ) -3.75 ( s, 2H ), 2.39 (d, 2H, J = 6.6Hz), .87-1. 8 1 ( m, 4H ) &gt; 1.46- 1.35( m,1H ) , 1.33-1 · 1 0 ( m, Η ), 0.95 -0.77 ( m , 4H ) ; MS (ESI+) : m/z 5 3 8.28 (

M + H) +. Example 7 6

• 1-(4-(3-(cyclohexanecarbamimidino)pyridine·4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea treated with triethylamine (l〇&quot; L, 0.074 mmol) and cyclohexanecarbonyl chloride (Aldrich &gt; 11 mg &gt; 0.074 mmol) to treat 1-(4-(3-aminopyridin-4-yl) Oxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (Compound C of Example 72, 25 mg, 0.062 mmol) in dichloromethane (2 mL) The resulting solution was stirred at room temperature for 2 hours. An additional portion of cycloheximide hydrazinyl chloride (11 mg, 0.074 mmol) -226-(223) 1324926 was added to the mixture and the reaction was allowed to continue for 18 hours. The mixture was diluted with EtOAc (EtOAc) EtOAc. The title compound (19) was obtained as a white solid (yield: Mg, 61%). W NMR (DMSO-heart) &lt;5 1 1 ·〇3 ( s, 1Η )&gt; 1 0.57 ( m, 1 Η ) - 9.60 ( m, 1 Η ) &gt; 8.99 ( s, 1 Η ) ' • 8 . 1 5 ( d, 1 H, J = 5.6 Hz ) &gt; 7.76 ( dd, 1 Η, J = 2.0, 13.2 Hz ), 7.39-7.33 (m, 3H) , 7.28 (dd, lH, J = 8.6, 9.2 Hz) , 7.18-7.14 (m, 2H) « 6.65 ( d, 1H, J = 5.1Hz) · 3.73 ( s, 2H ) , 1.81-1.71 ( m,5H ) » 1.64-1.61 ( m, 1 H ) ' 1.43- 1.34 Cm, 2H),].29-1.14 (m,3H); MS (ESI+): m/z 509.27 ( M + H ) + . Example 77

1_( 4-(4-Aminohexahydropyridin-1-carboxamido)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl) Acetyl)urea, bis(trifluoroacetate) -227 8 (224) 1324926 α

(2-(4-fluorophenyl)ethenyl)urea

The solution of phosgene (50 mg, 0 · 1 7 mm ο 1 ) in dichloromethane (〇. 4 m L ) was cooled to _ 10 ° C, and 1 - ( 4 - ( 3 -amine) Pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (Compound C of Example 72, 67 mg, 0.17 mmol) A solution of DIPEA (65 &quot; L, 0.37 mmol) in dichloromethane (0.4 mL) was worked up. The mixture was stirred at -10 °C for 1 Torr, then 4-((benzyloxycarbonyl) decylamino) hexahydropyridine (4 〇 mg, 〇 17 mmol ' with Schaus, JM et al. * /. Merf. CAem. 1998, 4/, prepared by the procedure described in 1943-1955) and a solution of DIPEA (65/zL, 0.37 mmol) in dichloromethane (〇·4 mL) was treated. After the mixture was stirred for 2 minutes, it was allowed to warm to room temperature and then heated to 40 ° C for 10 minutes. The mixture was diluted with aq. EtOAc (EtOAc) EtOAc. The title compound was obtained as a yellow solid (5 mg &lt;&gt;;&lt;&gt;&gt; 4 5%) »MS(ESI+) : m/z 659.29 (M + H)+. -228- (225) 1324926 B ) 1·( 4-( 3-( 4_Aminohexahydropyridine-indole-carboxamido)pyridin-4-yloxy)phenyl)-3-(2 -(4-Fluorophenyl)ethinyl)urea, bis(trifluoroacetate) using hydrogen from a rubber balloon, [-]-(3-fluoro- 4-(3-(4-(2-benzene) Oxyacetamido) hexahydropyridine-y-carbamamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (45 mg , φ 0.06 8 mmo1) A solution of anhydrous methanol (2.5 mL) was hydrogenated on 1% palladium on carbon (15 mg) for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H NMR (DMSO-i/6) &lt;5 1 0.57 ( s, 1 Η ) &gt; 8.5 5 ( s, 1 Η ) » 8.27 ( m, 1 Η ) &gt; 8.14 (d, 1Η, J = 5.6Hz) « 7.75 ( dd, 1H, J = 2.0, 12.7Hz), 7.3 7-7.3 3 ( m, 3H) ' 7.23-7.14 ( m,3h) , 6.65 ( d,1H, J = 5.1Hz) ' 4.05-3.98 (m, 2H) , 3_73(s, 2H) - 3.05-

• 2.9 1 ( m, 1 H ) &gt; 2.8 8-2.8 3 ( m, 2H ) &gt; 1 .83- 1.74 ( m, 2H )&gt; 1.34-1.20 ( m, 2H ) ; MS ( ESI+) : m /z 525.3 5 ( M + H) +. Example 78

(226) 1324926 1-(4-(2-Amino-3-(4-(2-amino-2-ketoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl )-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate

Φ A ) 2-(4-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine-3-yl)phenyl)acetic acid rinsing with vacuum/argon (2-Fluoro-4-nitrophenoxy)-3-bowl-based phosphonium-2-amine (Compound C of Example 34, 88 mg, 0.23 mmol), 4-(dihydroxyborane)benzene Tetramethyl glycol acetate

Frontier Scientific Inc., 92 mg, 0.35 mmol), a mixture of sodium carbonate (170 mg '1.61 mmol), 14-dioxane (2 mL) and water (2 mL) was degassed and used with hydrazine (triphenyl) Palladium (27 mg, 0.023 mmol) was treated. At 100. (:, after stirring the mixture for 3 hours, the pH was adjusted to pH 6 with 1 N hydrochloric acid. The mixture was concentrated under vacuum, and the residue obtained was dissolved in ethyl acetate and pH 7 phosphoric acid. In the ester buffer, the aqueous phase was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to give crude product. This product gave the desired product (70 mg, 80%) as an orange-brown solid. H NMR ( DMSO-s) δ 12.34 ( s5 1 Η ) - 8.23 ( dd, 1 Η, J = 3.1, 10.5 Hz ) ' 8.05 (d,1H,J= 10.2Hz) * 7.94 ( d, 1 H, -230- (227) 1324926 J = 6.1Hz) &gt; 7.3 2 - 7.2 5 ( m, 5H ) &gt; 6.26 ( d , 1H, J = 6.1 Hz) - 5.62 ( s, 2H ) &gt; 3.57 ( s, 2H ) ; MS ( ESI+ ): m/z 3 84.1 6 ( M + H ) + .

B) 2-(2-(2-Amino-4-(2-carboyl-4-nitrophenoxy)-deep-3_)phenyl)acetamide followed by PyBOP (125 mg' 0.24 mmol) Treatment of 2-(4-(2-amino-) with HOBt (32 mg* 0.24 mmol), and DIPEA (60 &quot; L, 〇. 3 5 mmol) with chlorinated money (19 mg, 0.35 mmol) A solution of 4-(2-oxo-4-nitrophenoxy)indene-stamp-3-yl)phenyl)acetic acid (65 mg, 0.17 mmol) in anhydrous DMF (1. After the mixture was stirred for 20 minutes at room temperature, the mixture was concentrated in vacuo and the obtained residue was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The title compound was obtained as an amber oil (40 mg) using flash column chromatography eluting with EtOAc (EtOAc) ' 6 2%). NMR (DMSO-heart) 6 8.23 ( dd, 1H, J =

10.7,2·5Ηζ) ' 8.05 ( d, 1H, J = 9.2Hz) · 7.93 ( d, 1H, J =6.1Hz) , 7.42 - 7.32 ( m,2H ) &gt; 7.33 -7.25 ( ms 4H ), 6.92 ( s, 1 H ) &gt; 6.25 ( d, 1H, J = 5.6 Hz) , 5.64 ( s, 2H) 8 231 - (228) 1324926 , 3.36 ( s, 2H ) ; MS ( ESI+ ) : m/z 3 83.1 7 ( M + H )

C) 2-(4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridine)phenyl)acetamide with iron powder (67 mg, 1.2 mmol) and chlorinated Ammonium (128 mg mmol) for the treatment of 2-(4-(2-amino-4-(2-fluoro-4-yl)pyridin-3-yl)phenyl)acetamidamine (32 mg, Mixture of 0.086 mmo] DMF (1 m L), ethanol (1 m L) and water (1 m L) and heat the mixture for 20 minutes at 100 ° C. Bring the mixture through Celite® with phosphate The buffer was adjusted to the pH of the filtrate, and then the mixture was extracted with ethyl acetate. The organic extract was dried over magnesium and concentrated to give a yellow-brown solid (20 mg &gt; 6 7% MS ( ESI+) : m/z 3 5 3.3 2 ( M + H ) D) 1-(4-(2-Amino-3-(4-(2-amino-2-ketoethyl)) Phenyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethyl)urea, trifluoroacetate, similar to that described in Step D of Example 3 The way 2-(4-(2-Amino-4-(4-amino-2-fluorophenyl)pyridin-3-yl))acetamidamine (19 mg, 0.054 mmol) and 2-(4- Fluorophenyl) isocyanate dissolved in 0.3M of toluene Liquid (Example -3-yl-2.4 phenoxy 1) ', and filtered pH 7 sulfuric acid product f fluorenyl) fluorenyl group, phenyl acetamide-232- 8 (229) 1324926 D, 0.27 mL , 0.081 mmol) to prepare the title compound. The title compound (911^, 26%) was obtained as a white solid. 111\1^11(01^0-heart): ό 1 1 .03 ( s, 1 Η ) , 10.57 (s, lH) , 7.93 (d, lH, J = 7.1 Hz), 7.76 ( dd, 1 H , J = 2.0, 1 3.2Hz ) &gt; 7.44-7.42 ( m, 3H ) &gt; 7.3 7-7.29 ( m, 6H ) &gt; 7.16 ( dd, 2H, J = 8.6,

8.8 Hz ) &gt; 6.94 ( s, 1 H ) &gt; 6.31 ( d, 1H, J = 7.1Hz) &gt; 3.72 (s, 2H ) &gt; 3.43 ( s, 2H ) ; MS ( ESI+ ) : m/z 5 3 2.24 ( M + H) +. Example 7 9

1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluoro) Phenyl)ethylidene)urea, dihydrochloride

N〇2 A) 4-(2-Fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine 8-233- (230) 1324926 4-(2-Fluoro-4-nitrophenoxy)-3-bowl-based hydrazide-2-amine (Compound C of Example 34, 100 mg, 0.27) by vacuum/argon rinsing Mixture of mmol) and 2-ethynyl-based (Aldrich, 57 mg, 0.54 mmol), THF (2 mL) and triethylamine (2 mL), and using C u I ( 6 mg ' 0 · 0 3 2 mm ο 1 ) and (P h 3 P ) 4 P d (20 mg, 0.01 17 mmol) 'treated. The mixture was heated at 60 ° C for 45 minutes, cooled and allowed to dissolve in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a crude material. The title compound (55 mg, 58%) was obtained eluted elut elut elut elut elut elut elut »

NMR (DMSO-heart) (5 8.53 (d, 1 H, J = 5.1 Hz), 8.39 (dd, 1H, J = 2.5, 10.7 Hz) &gt; 8.15 (dm, 1H, J = 8.1 Hz), 7- 97 ( d, 1H, J = 5.6Hz) * 7.8 1 ( d, 1H, J = 8.1Hz), 7-71 ( d, 1H, J = 7.6Hz ) , 7.52 ( dd,1H, J = 8.6, 8.6 Hz φ ) * 7.38-7.34 (m, 1H) &gt; 6.71 (s, 2H) &gt; 6.21 (d, 1H, J = 5.6 Hz); MS ( ESI+ ) : m/z 351.25 (M + H)+.

B) Dry powder (65 mg' 1 · 0 mmol) 4-(4-Amino-2.fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridine-2-amine And gasification (53 mg, 1.0 -234- (231) 1324926 mmol) to treat 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl) a mixture of ethynyl)pyridin-2-amine (35 mg, 0.1 mmol), THF (1.5 mL) and methanol (1.5 mL), and heated at 60 ° C for 45 minutes. The mixture was cooled, filtered and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was separated, EtOAc (EtOAc m. MS (ESI+): m/z 32 1.2 (M + H) +. C) 1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-( 4-fluorophenyl)ethinyl)urea, dihydrochloride salt 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl) The solution of pyridin-2-amine (25 mg, 0.078 mmol) in THF (2 mL #) was cooled to 〇 ° C, and formed with 2-(4-fluorophenyl)ethyl decyl isocyanate in toluene. M solution (Compound D of Example 11 1 , 0.26 mL, 0.078 mmol) was worked up. After 1 hour, the mixture was warmed to room temperature and stirred for 15 minutes. The mixture was concentrated in vacuo and the residue obtained was purified using EtOAc EtOAc EtOAc EtOAc The trifluoroacetate salt was dissolved in dry methanol and treated with 1M EtOAc / diethyl ether and stirred for 5 min. The title compound (18-235-(232) 1324926 was obtained as a brown solid.

Mg &gt; 4 1%) o'HNMRCDMSO-heart) &lt;5 11.06 ( s, 1 H ), 10.63 ( s, 1H) , 8.62 ( d, 1H, J = 4.5 Hz) , 8.22 ( s5 2H ), 7.99 ( d, 1 H, J = 7.1 Hz), 7.94-7.8 1 ( m, 3H ), 7.4 8-7.44 ( m, 3H ) , 7.3 7-7.3 3 ( m, 2H) &gt; 7.16 ( dd, 2H, J-6.2, 9.2Hz) &gt; 6.30 ( d, 1H, J = 7.1Hz) - 3.74 ( s, 2H) ; MS (ESI+) : m/z 5 00.2 1 ( M + H ) +. φ Example 8 0

1-(4-(2-Ethylaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride

A) 4-(2-Aminomethylpyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester 4-(4-Amino-2-fluorophenyloxy) at 65t Pyridylcarbamide (Compound B' of Example 24, 190 mg, 0.76 mmol), third butanol (2 mL), 1,4-dioxane (1 mL), DMF (1 mL) and 8 A mixture of -236- (233) 1324926 B0C2O (167 mg, 0.76 mmol) was heated for 16 h. An additional two portions of Boc2(R) (85 mg and 60 mg) were added after 16 hours and 32 hours, respectively, and the mixture was heated for a total of 40 hours. The mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo to give crude material. The title compound (180 mg' 68) was obtained as a brown solid. %). NMR (DMSO-i^) 5 9.74 (s,lH) &gt; 8.52 ( d, 1H, J = 5.6 Hz ) &gt; 8.13 ( s, 1H ) , 7.72 (s, 1H ) &gt; 7.62 ( d, 1 H , J = 13.7Hz), 7.35-7.31

(m, 3H) - 7. 1 8 ( dd, 1 H, J = 5.6, 2.5 Hz ) , 1.39 ( s, 9H ); MS ( ESI+ ) : m/z 348.22 (M + H)+.

B) 4-(2-Aminopyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester A solution of potassium hydroxide (280 mg, 5.0 mmol) in water (2 mL) Cool to 0-5 ° C and add bromine (162 mg, 1.0 mmol) dropwise and stir the mixture for 5 min. Adding tert-butyl 4-(2-aminoformamidin-4-yloxy)-3-fluorophenylaminecarboxylate (347 mg, 1.0 mmol) as a solid to the mixture, then 1,4-Dioxane was added to dissolve the solid. The reaction mixture was stirred at room temperature for 8 minutes at 8 - 237 - (234) 1324926 and then stirred at 55 ° C for 45 minutes. Next, the mixture was cooled to room temperature, treated with acetic acid (0.5 mL), and stirred until the foaming was subsided. The mixture was heated to 55 ° C for a further 20 min then cooled to rt. EtOAc (EtOAc) The organic extract was dried over magnesium sulfate and concentrated in vacuo. The title compound ( 265 mg, 8) was obtained by flash column chromatography eluting with EtOAc (EtOAc) 3%). 'HNMRC DMSO-heart> &lt;5 9.67 ( s, 1Η ) &gt; 7.77 (d, 1 H, J = 6.1 Hz), 7.56 (d, 1H, J = 11.7 Hz) ' 7.26-7.18 ( m, 2H) , 6.12 ( dd, 1H, J = 2.0, 6.1Hz), 5.93 ( s, 2H ) , 5.74 (d, 1H, J = 2.5Hz) , 1.47 ( s, 9H) ; MS ( ESI+ ) : m/z 3 20.23 ( M + H ) +.

C) 4-(2-Acetylaminopyridin-4-yloxy)-3·fluorophenylaminecarboxylic acid tert-butyl ester 4-(2-aminopyridin-4-yloxy)-3- The third butyl fluorophenylaminecarboxylate (150 mg, 0.47 mmol) (in 0.5 mL of anhydrous pyridine) was cooled to 1.00 and treated with ethyl chlorobenzene (33 # L ' 0.47 mmol) and the mixture was stirred 45 minute. Another portion of acetamidine chloride (16/iL' 0.24 mmol) was added to the reaction mixture and stirring was continued for 25 minutes. The mixture was diluted with EtOAc-EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) • iHNMRCDMSO-c/d) &lt;5 1 0.55 ( s, 1Η ) -9.7 1 ( s, 1Η ) &gt; 8. 1 6 ( d, 1 Η, 7 = 5.5Hz ) &gt; 7.63 -7.55 ( m , 2Η ) ' 7.29-7.23 ( m,2Η ) &gt; 6.6 8 -6.63 ( m, 1H ), 2.02 ( s, 3 H ) &gt; 1.48 ( s, 9H ) ; MS ( ESI+ ) : m/z 362.22 ( M + H) +.

D) #- (4-(4-Amino-2-fluorophenoxy)pyridin-2-yl)acetamide

4-(2-Ethylaminopyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester (110 mg, 0.30 mmol) in 4M HC 1 / 1, 4 The solution of dioxane (1.5 mL) was stirred for 20 minutes and then stirred at room temperature for 25 minutes. The mixture was diluted with ethyl acetate (25 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) and stirred vigorously for 5 min. The ethyl acetate phase was washed with EtOAc (EtOAc EtOAc (EtOAc) ) ' 8. 1 3 ( d, 1 H, y = 5.6Hz ) · 7.60 ( m, 1 H ) &gt; 6.95 ( dd, 1 H, ·/ = 8.6,9.2Hz ) , 6.60 ( dd,1H,· / = 2,5,5.6Hz ) ' 6.48 (dd, 1H, J = 2.5, 13.2Hz) , 6.40 ( dd, 1H, J = 2.0, 8.6Hz) , 5.44 ( s, 2H) , 2.02 ( s, 3H ). -239- 8 (236) 1324926 E) 1-(4-(2-Ethylaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl) a solution of 2-(4-fluorophenyl)ethenyl isocyanurate in toluene in 0.3 M solution (Compound D of Example 11, 0.26 mL, 0.77 mmol), To treat the solution of 4-(4-amino-2-hexyloxyphenoxy)pyridin-2-yl)acetamide (20 mg, 0.77 mmol) in THF (1 mL), and The mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo to give crystals crystals crystals crystals The trifluoroacetate salt was dissolved in dry methanol and treated with 1M EtOAc / diethyl ether and stirred for 5 min. The title compound (1 2 mg &gt; 33%) &quot;WNMRC DMSO-A): δ 11.04 ( s, 1 Η ), 10.65 (s, 1H), 10.58 (s, 1H) , 8.18 (d, 1H, J = 6·1Ηζ • ), 7.77 (dd, lH, J = 2.0, 12.7 Hz) &gt; 7.56 ( m, 1H ), 7.40-7.30 ( m, 5H &gt; 7.18-7.14 ( m, 2H) &gt; 6.71 ( dd, 1H, J = 2.5, 6.1Hz) &gt; 3.74 ( s, 2H ) &gt; 2.03 ( s, 3H ) ; MS ( ESI+ ) : m/ z 441.18 ( M + H ) +. Example 8 1 -240- 8 (237) 1324926

//-(4-(2-Ethylaminopyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide, hydrochloride

Treatment of #-(4-(4-amino-2-fluoro) with 01? ugly eight (15 private [, 0.086 111111〇1) and 2,6-difluorobenzylbenzyl chloride (10 mg, 0.057 mmol) a solution of the phenoxy)pyridin-2-yl)acetamide (Compound B of Example 24, 15 mg, 0.057 mmol) in THF (0.5 mL) and stirred at room temperature 1.5 hours. The mixture was concentrated in vacuo and the title compound was purified eluted elut elut elut elut The trifluoroacetate salt was dissolved in anhydrous methanol and treated with 1M EtOAc/EtOAc at EtOAc and stirred for 5 min. The title compound (15 mg · 60%) was obtained as an off-white solid in vacuo <1H NMR, </ RTI> </ RTI> 1 1 · 1 7 ( s, 1 Η ), 10.79 ( s, 1 Η) &gt; 8.21 ( d, 1H, J = 6.1Hz) &gt; 7.89 ( dd, 1H, J = 2.0, 12.7Hz ) &gt; 7.66-7.5 9 ( m, 1H ) , 7.53-7.50 ( m, 2H ) , 7.42 ( dd, 1H, J = 8.6, 9.2Hz), 7.28 ( dd, 2H, J = 8.1, 8.1Hz) » 6.80 ( dd, 1H, J = 2.0, 6. 1Hz) &gt; 2.06 (s, 3H ) ; MS (ESI+): m/z 4021. (M + H) +. -241 - (238) 1324926 Example 8 2

1-( 3-fluoro-4-(2-(2-morpholineethylamino)pyridin-4-yloxy)

A) #-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)acetamide

(3-Fluoro-4-hydroxyphenyl)acetamide (Compound A of Example 13, 1.33 g, 7.87 mmol), 2-chloro-4-nitropyridine (Aldrich, at 100 °C) A mixture of 1.24 g, 7.87 mmol), K2C03 (1.6 g, 11.8 mmol) and DMF (25 mL) was heated for 9 h. The mixture was concentrated in the air and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The title compound (1_6 g) was obtained as a pale yellow solid (yield: EtOAc) , 73%). NMR (DMSO-i/6) 6

10.25 ( s, 1Η ) &gt; 8.35 ( d, 1 H, J = 7Hz ) · 7.80 ( d, 1H, J -242- (239) 1324926 =1 4 Η z ) , 7.50 ( d, 1 Η, J = 3 Η ζ ) , 7.33 ( m, 2 Η) , 7.02 (m, 1 Η ) , 2_06(s, 3H) ; MS ( ESI+ ) : m/z 281.16 ( M + H) + .

B) (4-(1-Oxo 2-chloropyridin-4-yloxy)-3-fluorophenyl)ethyl decylamine

#-(4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)acetamide (〇·98 g, 3.5 mmol), &gt;90% at room temperature A mixture of chloroperoxybenzoic acid (1.3 g, 7.6 mmol) and CHC13 (50 mL) was stirred for 60 hours. The title compound (0.89 g, 86%) eluted elute 4 NMR (DMSO - heart) (5 10.25 ( s, 1 Η ) &gt; 8.35 ( d, 1H, J = 7.3 Hz ) - 7.80 ( d, 1H, J = 13 Hz ) &gt; 7.3 3 -7.3 2 ( m, 3H &gt; 7.02 ( dd, 1H, J = 3.5, 7.5Hz ) , 2.06 ( s, 3H ) ; MS ( ESI+) : m/z 295.04 (M + H) + 8 (240) 1324926

C) #-( 3-fluoro-4-(1-oxo-2-(2-morpholineethylamino)pyridinyloxy)phenyl)acetamide

V-(4-(1-Oxo-2-chloropyridin-4-yloxy)-3-fluorophenyl)acetamidine hydrochloride (205 mg, 0.62 mmol), 4-(2- A mixture of aminoethyl)morpholine (Aldrich, 169 mg, 1.30 mmol) and absolute ethanol was heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue obtained was taken with water (3 mL) and applied to a 10 g Varian C-18 filter cartridge. The filter cartridge was washed with water and 30% methanol/water. The eluate containing the desired product was combined and concentrated to a volume of 5 mL and extracted three times with ethyl acetate. The title compound (1 〇〇 mg, 40%) was obtained eluted eluted eluted eluted 1H NMR (DMSO-heart) 5 1 0-22 ( s,1Η ) , 7.84 ( d,1H, J = 6Hz ) , 7.77 ( dd, 1Η&gt; J = Ί, 12Hz ) « 7.31 ( dd, 1Η, J = 2, 9Hz ) , 7.24 ( dd, 1H, J = 9, 9Hz) , 6.4 1 ( m, 1H ) · 6.13 ( dd, 1H, J = 2,6Hz) &gt; 5.81 ( d, 1H, J = 2.5Hz ) « 3.56-3.48 ( m, 2H ) '3.31-3.19 ( m, 4H ) &gt; 2.38 ( t, 2H, J = 7Hz ) - 2.40-2.28 ( m, 4H ), 2.06 ( s, 3H) ; MS ( ESI+) : m/z 405.2 2 (M + H) +. -244- (241) 1324926

ο

Y ch3

D) (3-Fluoro-4-(2-(2-morpholineethylamino)pyridin-4-yloxy)phenyl)acetamide, trifluoroacetate

#-( 3-Fluoro-4-(1-oxo-2-(2-morpholineethylamino)pyridin-4-yloxy)phenyl)acetamide (100) at 135 °C Mg, 0.26 mmol), and a mixture of triphenylphosphine polymer (1.4-2.0 mmol/g) and DMF (2 mL) on polystyrene (500 mg) were stirred for 15 hours. The mixture was filtered to remove the resin and the resin was rinsed with DMF and ethyl acetate. The filtrate and washings were combined and concentrated. The title compound (45 mg, 24%) was obtained. iH NMR (DMSO-heart) δ 10.33 ( s, 1 Η ) , 8.02 ( d, 1 Η, J = 7 Hz), 7.84 ( dd, 1 Η, J = 2,1 3 Hz ) , 7.3 9 - 7.3 1 ( m , 2 Η ) &gt;6.52 (s, 1Η ) &gt; 6. 1 0 ( s, 1Η ) , 3.83 ( s, 4Η ) &gt; 3.60-3.48 ( m, 2Η ) , 3.32-3.18 (m,6Η), 2.08( s, 3Η) ; MS ( ESI+ ) : m/z 3 75.1 2 ( M + H ) +.

NH2 E ) 4-(4-Amino-2.fluorophenoxy)^-(2-morpholinoethyl)pyrrole I 8 (242) 1324926 pyridine-2-amine, hydrochloride

V-( 3-fluoro-4-(2·(2-morpholineethylamino)pyridin-4-yloxy)acetamide trifluoroacetate (40 mg), methanol (1 mL And a mixture of 6M EtOAc (0.2 mL) EtOAc. 1H NMR (DMSO-i/fi) (5 1 1 . 1 2 ( s, 1 Η ) , 8.85 (s, lH) * 7.95 ( d, 1H, J = 7Hz ) , 7.08 ( dd, 1H, J = 9 , 9Hz ) , 6.65-6.63 ( m,2H) &gt; 6.54 ( d, 1H, J = 8Hz) , 6.31 ( s,1H) &gt; 3.90- 3.75 ( m,6H) &gt; 3.3 7-3.2 1 ( m , 6H) ; MS ( ESI+) : m/z 373.1 4 ( M + H ) +. F) 1-( 3 -Galyl-4-(2-(2-propofolinylethylamine)-steep- 4-(Alkyloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride salt treated with triethylamine (2 mL) 4-(4-amine a solution of 2-fluorophenylphenoxy φ)-#-(2-morpholinoethyl)pyridine-2-amine hydrochloride (15 mg, 0.045 mmol) in methanol (5 mL), And the mixture was stirred for 5 minutes at room temperature. The mixture was concentrated to remove methanol, and the obtained residue was suspended in THF (1 mL) and a 0.3 M solution of 2-(4-fluorophenyl)ethyl decyl isocyanate in toluene (Example) The compound D was treated with a solution of EtOAc (EtOAc m.). The ethyl ester phase was washed with brine, dried over magnesium sulfate and concentrated with EtOAc EtOAc EtOAc EtOAc EtOAc The residue is purified to give the title compound as a trifluoroacetic acid salt. The trifluoroacetic acid salt is dissolved in anhydrous methanol and treated with &lt;RTI ID=0.0&gt; The title compound (10 mg, 43°/) was obtained as a white solid. mp NMR (DMSO-d6) &lt;5 11.05 ( s, 1H ) , 10.61 (s, 1H) ), 7.98 (d, 1 Η, · / =

7.1Hz ) , 7.86- 7.73 ( m, 1H ) » 7.48-7.3 8 ( m, 1 H ) ' 7.37-7.30 ( m,3H) , 7.24 - 7.04 ( m,2H) , 6.60 ( s, 1H) &gt; 6.26 ( s, 1H ) , 3.98-3.60 ( m, 8H ) , 3.74 ( s, 2H), 3.39-3.19 ( m, 4H) ; MS (ESI+): m/z 512.2 (M + H) Example 83 - 8 5 was prepared in a similar manner to that described in Example 82.

1-(3-Fluoro-4_(2-(3·norfosylpropylamino)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea, hydrochloride 'H NMR ( OMSO-d6 ) δ 11.06 ( s, 1Η ) , 1〇62 ( s, -247- 8 (244) 1324926 1 Η ) , 7.93 ( d,1Η, J = 7.1Hz ), 7.83 ( d, 1 H, J = 12.7 Hz), 7.45 -7.3 3 ( m, 4H) &gt; 7.16 ( dd, 2H, J = 8.6, 9.2 Hz ) , 6.64 ( s, 1H) &gt; 6.23 ( s, 1 H ) &gt; 3.95 -3.76 ( m, 4H ) &gt; 3.74 ( s, 2H ) &gt; 3.70-3.4 8 ( m, 4H ) &gt; 3.4 8-3.3 5 ( m, 2H) , 3.20-3.04 (m, 2H), 2.02-1.93 (m, 2H). Example 8 4

1-(4-(2-(3-Dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl Urea, hydrochloride 1H NMR ( DMSO-i/tf ) δ 11.06 ( s, 1Η ) &gt; 10.62 ( s,

1 Η ) &gt; 1 0.3 7 ( s, 1 Η ) - 7.93 ( d, 1 Η, 7 = 7. 1 Hz ) , 7.82 (dd, 1H, J = 2.0, 12.7 Hz ) &gt; 7.45 ( dd, 1 H, J = 2.6, 8.6 Hz) &gt; 7.40 ( d, 1H, J = 8.6 Hz ) &gt; 7.3 7-7.3 3 ( m, 2H ) &gt; 7. 1 6 ( dd, 2H, J = 8.7, 9.1 Hz) - 6.65 ( s, 1H ) &gt; 6.24 (s, 1 H ) &gt; 3.75 ( s, 2H ) &gt; 3.4 5 -3.3 6 ( m, 2H ) &gt; 3.13- 3.03 ( m, 2H ) , 2.73 ( s, 3H) , 2.72 ( s, 3H) &gt; 1.94 - 1.90 ( m, 2H ). Example 8 5 -248- 8 (245) (245) 1324926

1-(4-(2-(4-(Dimethylamino)butylamino)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethyl Sulfhydryl urea, hydrochloride MS (ESI+): m/z 498.2 (M + H) +.

Example 8 6

1-(4-(2,6-diaminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloric acid salt

A) 4-Chloropyridine-2,6-dimethylguanamine A mixture of 4-hydroxypyridine-2,6-dicarboxylic acid (3.19 g&gt; 17.0 mmol), PC15 (2.1 g) and CC14 (30 mL) After refluxing for 6 hours, it was cooled to 65 ° C and methanol (5 m L) was added under gentle reflux. The mixture was refluxed for 5 hours and then concentrated in vacuo - 8 - 249 - (246) The obtained residue was treated with ice water (50 m L) and the solid precipitated from the mash was collected by filtration method and air-dried on a funnel to obtain a 2,6-double as a needle. (methoxycarbonyl)-4-chloropyridine (2.4 g). The product was treated with ~7M NH3 / methanol and stirred at room temperature for one hour. The mixture was filtered to give the title compound (l······· 1H NMR (DMSO-heart) (58·91 (s, 2H), 8 · 1 5 (s, 2H), 7.87 (s, 2H).

B) 4-(2,6-Diaminopyridinyl-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester treated with potassium tert-butoxide (124 mg, 1.1 mmol) Boc-4-amine

A solution of benzyl-2-fluorophenyl (228 mg, 1.0 mmol) in DMF (2 mL), and the mixture was stirred at room temperature for 2 hr. The mixture was treated with 4-chloropyridine-2,6-dimethylamine (200 mg' 1.0 mmol) and potassium carbonate (35 mg, 0.5 mmol). The mixture was concentrated in vacuo and treated with ethyl acetate (10 mL) and water (10 mL) and filtered to remove insoluble material. The ethyl acetate phase was washed with brine and dried over magnesium sulfate and concentrated in vacuo. Purification of the residue obtained by flash column chromatography eluting with EtOAc (EtOAc (EtOAc) (1 70 mg, 4 4 % 8 -250-(247) (247) 1324926) containing 10% starting chloropyridine. |11\1^11(〇?43〇-心) &lt;5 9.7 7 ( s, 1H ) , 8.86 ( s, 2H) , 7.87 ( s, 1H) , 7.63 ( d, 1H, J = 12.1 Hz) &gt; 7.55 ( s, 2H ) , 7.38-7.31 (m, 2H) &gt; 1 .48 ( s, 9H ).

C) 4-(2,6-Diaminopyridin-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester using a procedure similar to that described in Step B of Example 80, from 4 - (2,6-Diaminopyridinyl-4-yloxy)-3-fluorophenylaminecarboxylic acid tert-butyl ester (110 mg, 0.28 mmol). Flash chromatography on EtOAc (EtOAc:EtOAc) 4 NMR ( DMSO-i/6 ) δ 9.60 ( s, 1 Η ) , 7.50 ( dd, 1H, J = 1.8, 1.3 Hz) &gt; 7.2 1 ( dd, 1 H, J = 2.2, 8.7 Hz ) &gt; 7.13 ( dd, 1 H, J = 8.7, 9.2 Hz ) , 5.40 ( s, 4H) , 5.13 ( s, 2H), 1.47 (s, 9H) ; MS ( ESI+ ) : m/z 335.23 (M + H)+ .

D) 4-(4-Amino-2-fluorophenoxy)pyridine-2,6-diamine -251 - 8 (248) V4926

Prepared in a similar manner to that described in Step D of Example 80, from tert-butyl 4-(2,6-diaminopyridin-4-yloxy)-3.fluorophenylaminecarboxylate. The title compound (2 〇 mg '100%) of the oil. MS (ESI+): m/z 23 5.22 (M + H) +. Ε) 1· (4-( 2,6-diaminopyridin-4-yloxy)·3-fluorophenyl-3-( 2·(4-fluorophenyl)ethenyl)urea, hydrochlorochloride Acid salt

In a similar manner to Step D of Example 33, 4-(4-Amino-2-fluorophenoxy)pyridine-2,6-diamine (19 mg, 0.081 mmol) and 2- (4- The title compound was prepared as a solution of fluorophenyl)ethyl sulphate in the toluene (3·········· The title compound was obtained as a trifluoroacetic acid salt by preparative HPLC (layer column A). The trifluoroacetate salt was dissolved in dry methanol and treated with 1M EtOAc/EtOAc at EtOAc and stirred for 5 min. The title compound (8 mg, 2 4%) cjNMRC DMSO-A) &lt;5 11.01 (s, 1H), 10.51 (s, 1 Η ), 7.68 ( dd, lH, "/= 2.6,12·7Ηζ), 7.36-7.30 (m, 3H), 7.22-7. 4 (m,3H), 5.52 (s,4H), 5.15 (s,2H),3.73 ( s, 2H) ; MS ( ESI+ ) : m/z 4 14.09 ( M + H ) + Example 87 - 252 - (249 > 1324926

1-(4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)methyl)-3-fluorobenzyl)-3-(2.(4.fluorophenyl) Urea, urea, dihydrochloride

NHBoc A) tert-butyl 4-bromo-3-fluorophenylaminecarboxylate (Boc) 2〇 (8.10 g, 37.1 mmol) and triethylamine (5.17 mL '37.1 mmol) were added at room temperature to 4-Bromo-3-fluoroaniline (Lancaster '7.05 g, 37.1 mmol) in a solution of anhydrous tetrahydrofuran (40 ml). The reaction mixture was heated to reflux overnight. After the reaction mixture was cooled, it was concentrated under reduced pressure. Purification of the residue obtained by flash column chromatography on silica gel eluting with 20% dichloromethane/hexanes and 20% ethyl acetate/hexanes gave 4- Tert-butyl bromide-3-fluorophenylaminecarboxylate (5.30 g, yield 4.9). MS ( ESI+) : m/z 290.2 ( M + H ) + 〇

8 (250) 1324926 B ) 4-((2-Chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester at -7 8 °C 'via syringe, Add M e M g B r (3.0 ', '3.1 mL' 9.3 mmol in diethyl ether) to tert-butyl 4-bromo-3-fluorophenylaminecarboxylate (2.60 g 9.0 mmol) in dry THF ( 30 mL) in the solution formed. At this temperature, the solution was stirred for 10 minutes and then allowed to warm to 〇 ° C for 0.5 hours. After the solution was cooled back to -78 °C φ, during the 4 min period, butyllithium (1.7M in hexanes, 10.6 mL &lt; The resulting solution was stirred for 5 minutes and then, during 3 minutes, 2-chloroisonicotinaldehyde (1.41 g, 10 mmol) was added (for preparation, see: Frey, L. F. et al.

Ze&quot;. 2001, 6815) A solution formed in anhydrous THF (25 mL). The reaction mixture was stirred at -8 8 ° C for 20 min and 2.0 mL methanol was added. Then, the solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (200 mL). The mixture was washed successively with water (2 φ X 50 mL) and brine (2 X 50 mL) and dried (MgSO4). After filtration and concentration, the obtained residue is purified by flash chromatography (extracted with 0%-50% ethyl acetate / hexane) on cerium (2) (2) -Chloropyridine-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (1.30 g' yield 41 ° / 〇). MS ( ESI+): m/z 3 5 3.2 8 / 3 5 5.24 (M + H) +. -254- (251) 1324926

NHBoc O' C ) 4- ( ( f 2-Chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester w-CPBA (70%, 2.34 g &gt ; 9.48 mmol) added to 4-(

(2-Chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (1.20 g, 3.40 mmol) in dichloromethane (100 mL)EtOAc. A mixture of mL) is formed in the solution. The reaction mixture was stirred at room temperature for 2 hours and then heated to reflux for 5 hours. The solvent was removed under reduced pressure and flash chromatography was carried out on cerium oxide (50% ethyl acetate/hexane, 100% ethyl acetate and 10% methanol/ethyl acetate) The residue obtained is purified to obtain 4-((W-oxy-2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester ( 840 mg, yield 67%): m/z 3 69.1 3 / 3 7 1.1 3 (M + H) +.

D) 4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester-255- 8 (252 1324926 Add W,AM · dimethylpropane-ls3.diamine (225 mg, 2.2 mmol) to 4-((... oxidized 2-chloropyridine-4-yl)(hydroxy)methyl)· 3_ A solution of butyl fluorophenylaminecarboxylate (80 mg, 0.22 mmol) in ethanol (2.0 mL). The reaction mixture was heated at 80 ° C for 12 hours, and the solvent was removed to give the crude 4-((#-(2-(3-dimethylamino)propylamino) pyridine) 4-yl group. ) (Hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester, which can be used directly in the next step. MS ( ESI+): m/z 435.37 (M + H) +. Zinc (114 mg, 1.75 mmol) and NH4C〇2H (139 mg, 2-20 mmol) were added to 4·((#-oxidized 2-(3-(dimethylamino)propylamino)pyridin-4-yl) ( Hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (~0.22 mmol) in a solution of methanol (2.0 mL). The suspension was refluxed overnight. Add more zinc (1 1 4 m g ) and

NH4C02H (139 mg)' and the suspension was refluxed for 2 h. After cooling, the solution was filtered&apos; and the filtrate was concentrated under reduced pressure. Then, the obtained residue is purified by flash chromatography (extracted with 10-30% methanol/DC) on cerium oxide to obtain 4-((2-(3-(2)) Methylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (80 mg, yield 87%). MS (ESI+): m/z 4 19.34 (M + H) +.

-256 (253) 1324926 E) 4-(4-Amino-2-fluorobenzyl)·;^(3-(dimethylamino)propyl)pyridin-2-amine 2 mL of concentrated hydrochloric acid and a pin on carbon (1%, 2〇〇mg) is added to 4-((2-(3-(dimethylamino)propylamino)pyridine)-4-yl)(yl)methyl)-3- A solution of butyl fluorophenylaminecarboxylate (8 mg, 〇19 mmol) in methanol (5 mL) was obtained. At 75. The suspension was heated under a nitrogen atmosphere for 24 hours. The mixture was cooled, Φ was concentrated and concentrated in vacuo. The residue obtained was dissolved in 1 mL of concentrated NH4OH and extracted with DCM (5 X 5 mL). The combined organic layer was dried over sodium sulfate. After filtration, concentration in vacuo gave 4-(4-amino-2-fluorobenzyl)-w-(3-(dimethylamino)propyl)pyridine-2-amine (31 mg, yield Rate 40%) &quot;MS(ESI+): m/z 303.3 1 (M + H) +. F) 1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl) Φ methyl)_3_fluorophenyl)-3-(2-(4-fluorobenzene) Ethyl carbazide, dihydrochloride salt solution of 2-(4-fluorophenyl)ethenyl isocyanate (Compound D of Example n, 0.347 M in toluene, 0.25 mL) was added to 4- A solution of (4-amino-2-fluorobenzyl)-#-(3-(dimethylamino)propyl)pyridin-2-amine (30 mg, 0.1 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 0.5 hours, then quenched with methanol. The solution was concentrated in vacuo and the residue obtained was purified using preparative HPLC. The desired fractions were collected and vacuum Concentration was carried out in -257-8 (254) 1324926. The residue obtained was dissolved in methanol, and di-ethyltriamine (50 mg) bound to the polymer was added to remove trifluoroacetic acid. After concentration, the obtained residue was converted to a hydrochloride by hydration by adding IN HC1 (0.5 mL), and lyophilized to obtain 1-(4-((2-(3-(dimethylamino))) ) propylamino)pyridin-4-yl)methyl)-3-fluorophenyl)- 3-(2-(4-Fluorophenyl)acetamyl urea hydrochloride (8.0 mg, yield 14%). MS (ESI+): m/z 482.24 (M + H)

1-(4-((2.(3.(dimethylamino)propylamino)pyridin-4-yl)yl)methyl)phenyl)-3-(2-(4-fluorophenyl)acetonitrile Urea

NHBoc A ) 4_((2-Chloropyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester was prepared in a similar manner as described in Step 87 of Example 87. -Chloro-isonicotinaldehyde (141 mg '1_〇mmol) was converted to 4-((2-chloro-pyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl-258- (255) 1324926 Ester (190 mg, yield 57 ° /.) ° MS (ESI+): m/z 3 3 5.2 7 / 3 3 7.2 7 ( M + H ) + .

〇- NHBoc

B) 4-((iV-Oxo-2-chloropyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester was carried out in a similar manner as described in Step C of Example 78 preparation. Conversion of 4-((2-chloropyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid terpene vinegar (78 mg, 0.23 mmol) to 4-((7V-oxidized 2-chloropyridine) -4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester (36 mg, yield 44%) °MS (ESI+): m/z 3 5 1.2 8 / 3 53.27 ( M + H ) + .

C) 4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester according to step D of Example 87 The preparation was carried out in a similar manner. Conversion of 4-((7V-oxy-2-chloropyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester (36 mg, 0.1 mmol) to 4-259- 8 (256) 1324926 ((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylaminecarboxylic acid tert-butyl ester (16 mg, yield 40%). 1^( ESI+ ) : m/z 40 1.3 8 ( M + H ) +.

Methanol) Et3SiH (0.1 mL) / TFA (10%, 2 mL) in DCM was added to 4-((2-(3-dimethylamino)propylamino)pyridine-4-

Base ()hydroxy)methyl) phenylaminecarboxylic acid tert-butyl ester (16 mg, 0.04 mmol) in 1 mL of DCM. The mixture was stirred for 0.5 hours and was found to be unreacted by LC-MS. An additional 0.1 mL of Et3SiH and 0_8 mL of TFA (10% in DCM) was added and the mixture was stirred for 2 hours. The solvent is removed and purified by solid state extraction (Waters Oasis® MCX extraction cartridge) to give (4-aminophenyl)(2-(3-(dimethylamino)propylamino)pyridine-4 Methanol (6.0 mg, yield 50%) mp (ESI+): m. E) 1-(4-((2-(3-(Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl) Ethyl)urea was prepared in a similar manner to that described in Step F of Example 87, -260-(257) 1324926. Conversion of 4-aminophenyl-(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol (6.0 mg '0.02 mmol) to b (4-( (2-( 3-) Dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, bis-trifluoroacetate (6.1 Mg, yield 43%). 1H NMR (CD3OD) &lt;57.82(d, \W, J =

6.4 Hz ) , 7.50 ( m, 2H ) , 7.36 ( m, 4H ) , 7.07 ( m, 3H ) &gt; 6.75 ( m, 1H ) &gt; 5.68 ( s, 1 H ) , 3.71 ( s, 2H),

3.21-3.49 (m,4H) &gt; 2.90 ( s, 6H ) - 2.08 ( m, 2H ) ; MS (ESI+): m/z 480.3 1 ( M + H ) + . Example 8 9

1-(4-((2-Aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate

NHBoc A ) 4-((ΛΓ-Oxidation of 2-(allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester 8 -261 - (258) 1324926 Allylamine (1.0 rnL, 13.6 mmol) was added to 4- ((Λ,- oxidized 2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid, second awake (Example) Step C of 87, 500 mg, 1.36 mmol) in a solution of ethanol (14 mL). The mixture was heated overnight under sot. After cooling, the solvent is removed and the residue obtained is purified by flash chromatography (extracted with 〇%-1 5% methanol / DCM) on cerium oxide to give 4 - (#_Oxidation of 2-((Allylamine φ)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid, tert-butyl ester (440 mg, yield 83%). MS (ESI+): m/z 390.19 (M + H) +.

NHBoc

B) 4-((2-(Allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester is similar to that described in Step D of Example 87 The way to prepare. Convert 4-((#·2-(Allylamino)pyridin-4-yl)(yl)methyl)-3-oxyphenylaminecarboxylic acid tert-butyl ester (440 mg, 1.13 mmol) to 4 - (2-(Allylamino)pyridin-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (40 mg, yield 95%). MS ( ESI+): m/z 3 74.33 (M + H) +. -262- (259) 1324926

NHBoc C) (2-(allylamino)pyridinyl)-(4-(t-butoxycarbonyl)-2-fluorophenyl)methyl acetate

Add diisopropylethylamine (DIEA) (0.2 mL, 1.1 mmol), 4-dimethylaminopyridine (DMAP) (360 mg, 3.0 mmol) and Ac20 (〇·29 mL. 3.0 mmol) to 4-((2-(allylamino)nJ±D-4-yl)(hydroxy)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester (400 mg, mm〇i) in THF (10 mL) in the solution formed. The mixture was stirred overnight and then heated to reflux for 1 hour. After the mixture is cooled, the solvent is removed under reduced pressure and the residue obtained is purified by flash chromatography ( eluting with 0%-100% ethyl acetate) on cerium. Obtained (2-(allyl)pyridin-4-yl)(4-(t-butoxycarbonyl)-2-fluorophenyl)methyl acetate (390 mg, yield 85%) &quot;MS(EST) :m/z416.33(M + H)+.

NHBoc D) Acetic acid (2-aminopyridin-4-yl)(4-(t-butoxycarbonyl)-2-fluorophenyl)methyl ester-263- (260) 1324926 by passing nitrogen into acetic acid (2 -(Allylamino)pyridin-4-yl)(4-(t-butoxycarbonyl)-2-fluorophenyl)methyl ester in a solution of ethanol/water mixture (10: 1, 40 mL) Degas for 1 hour. Rh (PPh3) 3C1 (80 mg, 0.09 mmo) was added to the mixture. The solution thus obtained is refluxed to remove the solvent, and the residue is purified by flash chromatography and preparative HPLC purification on cerium oxide to give acetic acid (2-aminopyridine-4- (4-(Ph. 1,3-Butoxycarbonyl)-2-fluorophenyl)methyl ester, trifluoroacetic acid salt (185 mg, yield 42%) °MS (ESI+): m/z 376·26 (Μ + Η) +.

Ε) 4-((2-Aminopyridin-4-yl)methyl)-3-fluorophenylaminecarboxylic acid tert-butyl ester

Add 10% Pd/C (90 mg) to acetic acid (2-aminopyridin-4-yl)(4-(t-butoxycarbonyl)-2-fluorophenyl)methyl ester (in the form of trifluoroacetate) A solution of 180 mg, 0.37 mmol) in methanol (10 mL). The suspension was stirred for 1 hour under a hydrogen atmosphere. The catalyst was removed and the resulting filtrate was concentrated in vacuo. Then, the obtained residue was purified by flash chromatography on ruthenium dioxide (with 3% methanol / DCM elution) to give 4-((2-amino) as a trifluoroacetate salt. Tert-butyl pyridin-4-yl)methyl)-3-fluorophenylaminecarboxylate (73 mg, yield 46%) mp (ESI+): m/z 318.24 (M + H)+. 8 -264- (261) 1324926

Nh2 F) 4-(4-Amino-2-fluorophenyl)pyridin-2-amine

TFA (1.0 mL) was added to the tert-butyl 4-((2-aminopyridin-4-yl)methyl)-3-fluorophenylaminecarboxylate as a trifluoroacetic acid salt (73 mg, 0.17 mmol The solution formed in DCM (4.0 mL). The solution was stirred at room temperature for 2 hours and the solvent was removed in vacuo to give 4-(4-amino-2-fluorophenyl)pyridin-2-amine, bis-trifluoroacetic acid salt (70 mg , yield 93%). MS (ESI+): m/z 2 18.12 (M + H) + G) 1-(4-((2-aminopyridin-4-yl)methyl)-3-fluorophenyl)-3-(2) - (4-Fluorophenyl)ethinyl)urea, trifluoroacetate was prepared in a similar manner as described in Step F of Example 87. Conversion of 4-(4-amino-2-fluorobenzyl)pyridin-2-amine (19 mg, 0.042 mmol) in the form of bis-trifluoroacetate to 1-(4-((2-aminopyridine) 4-yl)methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate (19 mg yield 88%). iH NMR (DMSO-heart): 10.94 ( s, 1 Η ) , 1 0 · 4 7 ( s, 1 Η ) , 7 · 7 6 ( m, 3 Η ) &gt; 7.50 ( d, 1 H, J = 11 , 5Hz) &gt; 7.10-7.26 ( m, 4H ),

7. 1 0 ( m, 2H ) &gt; 6.65 ( d, 1 H, J = 6.5Hz ) &gt; 6.55 ( s, 1H ), 3.89 ( s, 2H) , 3.65 ( s, 2H) ; MS ( ESI+) : m/z -265- 8 (262) 1324926 3 97.26 ( M + H ) +. Example 90

1-(4-(2-Aminomethylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

Nh2

A) 4-(4-Amino-2-chlorophenoxy)pyridylcarboxamide Potassium tert-butoxide (352 mg, 3.2 mmol) was added to 4-amino-2- gas at room temperature A solution of the base (Aldrich, 430 mg, 3.0 mmol) in DMF (2.0 mL). The mixture was stirred for 1 hour at room temperature. Then, 4-chloropyridine carbenamide (468 mg, 3.0 mmol) and potassium carbonate (221 mg, 1.6 mmol) were added to the solution. The suspension thus obtained was heated overnight at 90 °C. After the suspension was cooled, it was diluted with 100 mL of ethyl acetate and 50 mL of water. The organic layer was separated, washed with brine (2×25 mL) and dried over magnesium sulfate. After filtration and concentration, 8 -266 - (263) 1324926 was obtained by solubilizing the solid thus obtained. Then, the solid was collected and washed with DCM (2×20 mL), ethyl acetate (5.0 mL) and dried to give 4-(4-amino-2-chlorophenoxy)pyridinamide (3 20 mg, yield 40%). MS ( ESI+): m/z 264.1 2 / 266.07 (M + H) +.

B) 1-(4-(2-Aminomethylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The preparation was carried out in the same manner as described in the step F of Example 87. Conversion of 4-(4-amino-2-chlorophenoxy)pyridinamide (79 mg, 0.30 mmol) (in 1.0 mL of DMF) to 1-(4-(2-amine) Pyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (65 mg, yield 49%). 'H NMR(DMSO-d6) δ 1 1 .05 ( s, 1 Η ) &gt; 1 0.58 ( s, 1 Η ) &gt; 8.52 ( d, 1H, J = 4.5Hz ) &gt; 8. 1 5 ( s , 1 H ) - 7.98 ( s, 1 H ) &gt; 7.70 ( s, 1 H ) &gt; 7.55 ( m, 1 H ) , 7.39 (m, 3H) · 7.27 ( m, 1H ) &gt; 7.16 (m, 3H ) , 3.73 ( s, 2H ) ; MS ( ESI+): m/z 443.1 7 ( M + H) + . Example 9 1 267 (264) 1324926

1-(4-(2-Aminopyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride

Water (2.2 mg, 0.12 mmol), pyridine (0.04 mL) and bis(trifluoroacetoxy)iodobenzene (Aldrich, 39 mg, 0.09 mmol) were added to 1-(4-() at room temperature. 2-Aminomethylpyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (Example 90, 27 mg, 0.06 mmol) In a solution formed by DMF (1.0 mL). The solution was stirred overnight and then purified by preparative HPLC to give the desired product. The product was further converted to 1 - ( 4 - ( 2 -amine) by adding IN HCl solution (0.5 mL) Pyridin-4-yloxy)-3-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride (19 mg, 70%). 'HNMRC DMSO-i/tf) &lt;5 13.50 (s, 1 Η ), 11.02 ( s, 1 Η ) , 10.57 ( s, 1 Η ) , 7.8 0- 7.95 ( m, 4H ), 7.55 ( m, 1H ) , 7.37 ( m,1H) , 7.30 ( m,2H), 7.11 (ro, 2H) &gt; 6.60 ( m, 1H ) - 6.00 ( s, 1 H ) , 3.70 ( s, 2H ) ; MS ( ESI+ ) :m/ z 415.16 (M + H)+. Example 92 8 -268- (265) 1324926

1-(4-(2-Aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

A) Bu (4-(2-Aminomethylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The preparation was carried out in a similar manner to that described in Step A of Example 90. Conversion of 4-(4-amino-3-chlorophenoxy)pyridinamide (39 mg, 0.19 mmol) (in 1.0 mL of DMF) to 1-(4-(2-amine-methylpyridylpyridine) 4--4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (18 mg, 41% yield) (purified by HPLC). MS (ESI+): m/z 443.1 3 / 445.1 4 (M + H) +. B) 1-(4-(2-Aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea according to Example 9 1 The preparation was carried out in a similar manner. -269- 8 (266) 1324926 1-(4-(2-Aminomethylpyridin-4-yloxy)-2.chlorophenyl)-3-(2-(4-fluorophenyl)ethyl Conversion of mercapto)urea (18 mg, 0.04 mmol) (in 1.0 mL of DMF) to 1-(4-(2-aminopyridin-4-yloxy)-2-chlorophenyl)-3-( 2- (4-fluorophenyl)ethylidene)urea (10 mg, yield 5 5%) ojNMRCDMSO-i/i) δ 13.47 ( s, 1 Η ) , 11.26 ( s, 1 Η ) , 11.08 ( s, 1 Η ) , 8.37 ( d,1 Η, J = 8.5Hz ), 7.95 (d,lH,J= 7.5Hz) 7.88 ( s, 2H ) - 7.62 ( s, 1 H )

, 7.35 ( m,3H) , 7.17 ( m,2H) , 6.64 ( d,1H, J = 7.5Hz ) &gt; 6. 1 3 ( s, 1 H ) &gt; 3.76 ( s, 2H ) ; MS ( ESI+ ): m/z 415.18 / 417.17 ( M + H ) +. Example 9 3

1-(4-(2-Aminomethylpyridin-4-yloxy)-3-methylphenyl 2-(4-fluorophenyl)ethenyl)urea

A) 4-(4-Amino-2-methylphenoxy)pyridinamide-270-8 (267) 1324926 Prepared in a similar manner as described in Step A of Example 90. Conversion of 4-amino-2-methylphenol (246 mg '2.0 mmol) to 4-(4-amino-2-methylphenoxy)pyridinamide (230 mg, yield 7%) . MS (ESI+): m/z 244.1 5 (M + H) +. B) 1-(4-(2-Aminomethylpyridinyl-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The preparation was carried out in the same manner as described in the step F of Example 87. Conversion of 4-(4-amino-2-methylphenoxy)pyridinamide (48 mg, 0.2 mmol) (in 1.0 mL of DMF) to 1-(4-(2-aminopyridylpyridine) -4-yloxy)-3-methylphenyl-3· (2-(4-fluorophenyl)

Ethyl) urea (35 mg, yield 4 1%). 1 Η NMR (DMSO -d6) δ 10.92 (S, 1 Η ), 1 0.44 (S, 1 H ) &gt; 8.44 (d, 1H, J 5.5Hz ) , 8.06 ( S,1Η), 7.63 (s,1H ), 7 • 5 0 ( s, 1H) &gt; 7.42 ( m, 1 Η ), 7.3 1 ( m, 2H ) &gt; 7.24 (d, 1H, J 2.0Hz ) &gt; 7.06-7. 1 2 ( m , 4H ) - 3.69 ( s, 2H ) , 2.02 ( s, 3H ) ; MS ( ESI+ ) : m/z 423.17 ( M + H) + . Example 9 4

F

1-(4-(2-Aminopyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-

-271- (D (268) 1324926 fluorophenyl)ethinyl)urea, hydrochloride

The preparation was carried out in the same manner as described in the step A of Example 91. 1-(4-(2-Aminomethylpyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorophenyl)ethenyl)urea (27 mg , 0.06 mmol) (in 1.0 mL of DMF) was converted to 1-(4-(2-aminopyridin-4-yloxy)-3-methylphenyl)-3-(2-(4-fluorobenzene) Ethyl hydrazide), hydrochloride (24 mg, yield 88%) (purified by HPLC). NMR ( DMSO-if^) δ 13.18 ( s, 1H) &gt; 10.93 (s, 1H)-

10.45 ( s,1 H ) , 7.88 ( d, 1H, J = 7.0Hz) , 7.73 ( s, 2H ), 7.50 ( m, 2H ) , 7.29 ( m, 2H ) , 7.10 ( m, 3H ), 6.56 ( d, 1 H, J = 7.0 Hz), 5.91 (d, 1 H, J = 2.5 Hz), 3.68 ( s, 2H ) , 2.02 ( s, 3H ) ; MS ( ESI+) : m/z 3 95.20 (M + H ) +. Example 9 5

1-(4-(2-Aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrogen Chlorate 8 (269) 1324926

F

NH2 A) 4-amino-3-(trifluoromethyl)phenol

10% Pd/C (100 mg) was added to a solution of 4-nitro-3-(trifluoromethyl)anthracene (Aldrich, 414 mg, 2.0 mmol) in 10 mL of methanol. The suspension was stirred under a hydrogen atmosphere for 12 hours, then filtered and concentrated in vacuo to give 4-amino-3-(trifluoromethyl)phenol (350 mg, yield 95%). The purity is pure enough to be used directly in the next step. MS ( ESI+): m/z 178.02 (M + H) +.

B) 4-(4-Amino-3-(trifluoromethyl)phenoxy)pyridinamide The preparation was carried out in a similar manner to that described in Step A of Example 90. Conversion of 4-amino-3-(trifluoromethyl)phenol (177 mg, 1.0 mmol) in 2.0 mL of DMF to 4-(4-amino-3-(trifluoromethyl)phenoxy Pyridine meglumine (180 mg, yield 61%). MS (ESI + ): m/z 298.20 (M + H) +. 8 -273 (270) 1324926

C) 1-(4-(2-Aminomethylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl Urea

The preparation was carried out in the same manner as described in the step F of Example 87. Conversion of 4-(4-amino-3-(trifluoromethyl)phenoxy)pyridinamide (30 mg, 0.1 mmol) in 1.0 mL of DMF to 1-(4-(2- Aminomethylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl)indole (30 mg, yield 63%) ). MS (ESI+): m/z 477.1 2 (M + H) +. D) 1-(4-(2-Aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The preparation was carried out in the same manner as described in the step A of Example 91. 1-(4-(2-Aminomethylpyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea (26 mg, 0.055 mmol) in 1.0 mL of DMF was converted to 1-(4-(2-aminopyridin-4-yloxy)-2-(trifluoromethyl)phenyl)-3 -(2-(4-Fluorophenyl)ethenyl)urea, hydrochloride (15 mg, yield 56%) (purified by HPLC). MMR (DMSO-heart) 6 13.40 ( s, 2H ), 11.28 ( s, 1 Η ) , 10.95 ( s, 1 Η ) , 8.25 ( d, 1 Η, J = -274- 8 (271) 1324926 8.5Hz ) &gt; 7.97 ( d, 1H, J = 7.0Hz ) , 7'88(s, 2H) &gt; 7.72 (d, 1 H, J = 2.5Hz ) , 7.65 (m, lH) , 7.35 (m, 2H) &gt; 7.1 9 ( m, 2H ) , 6.66 ( d, 1 H, J = 2.5 Hz ) , 3.75 ( s, 2H ); MS ( ESI+) · _ m/z 449.14 ( M + H) + . Example 96

1-(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate

A) 4-(3-Fluoro-4-trimethylacetamidophenoxy)pyridylcarboxamide Addition of 4-chloropyridinecarbamide (312 mg, 2.0 mmol) and DIEA (0.3 mL) To a solution of 4-amino-3-fluoroindole (Oakwood Products Inc., 252 mg, 2.0 mmol) in NMP (4.0 mL). The solution was heated at 250 t in a microwave oven. After the solution was cooled, it was diluted with water and the solution was extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with brine and dried over magnesium sulfate. After filtration and concentration at -275-(272) 1324926, the residue obtained is purified by flash chromatography on ruthenium dioxide (extracted with 0 - 30% methanol / DC). Fractions containing 4-(4-amino-3-fluorophenoxy)pyridinamide (50% purity, ΗPLC-UV detection) were obtained. M S ( E S I+ ) : m / ζ 2 4 8 · 1 2 ( M + H) +. Add 1N sodium hydroxide (5.0 mL) and trimethylacetamidine chloride (0.25 mL, 2 mmol) to the 4-(4-φ-amino-3-fluorobenzene) obtained in the previous step at room temperature. Oxy)pyridine carbenamide (3.0 mL) was taken in a solution of DCM (10.0 mL). The solution was stirred for 2 hours and then extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and concentration, the obtained residue was purified by flash chromatography (purified with 〇%-1 〇〇 / / ethyl acetate / hexane). 4-(3-Fluoro-4-trimethylacetamidophenoxy)pyridamide (110 mg, 17% yield in two steps). MS ( ESI+): m/z 3 3 2.1 8 (M + H) +.

B) TV-(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)trimethylacetamide was prepared in a similar manner to that described in Step 91 of Example 91 . 4-(3-Fluoro-4-trimethylacetamidophenoxy)pyridinamide (110 mg, 0-33 mmol) (in 4 mL of acetonitrile) was converted to #--276- (273) 1324926

(4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl)trimethylacetamide (70 mg, yield 70%). MS (ESI+) : m/z 3 04.2 1 ( M + H

F

NH2

C) 4-(4-Amino-3-fluorophenoxy)pyridin-2-amine 2 mL of 6N HC1 was added to iV-(4-(2-aminopyridin-4-yloxy)- 2-Fluorophenyl)trimethylacetamide (70 mg, 0.23 mmol) in a solution of 3 mL of methanol. Then, the mixture was heated to reflux for 48 hours. After the mixture is cooled, the solvent is removed under reduced pressure and the residue obtained is purified by solid-phase extraction (Waters Oasis® MCX extraction cartridge) to give 4-(4-amino-3- Fluorophenoxy)pyridine-2-amine (27 mg, yield 54%). MS (ESI+): m/z 220.2 (M + H) +. D) 1-(2-(2-aminopyridylpyran-4-yloxy)-2-(phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoro Acetate was prepared in a similar manner to that described in Step F of Example 87. 4-(4-Amino-3-fluorophenoxy)pyridin-2-amine (28 mg, 0.095 mmol) (in 2.0 mL of THF) was converted to b (4-(2-amino) -4 4--4-yloxy)-2 -oxyphenyl)-3-(2-(4-diphenyl)ethenyl)urea, trifluoroacetate (23 mg, yield 47%) Preparation 8-277- (274) (274) 1324926 HPLC after purification). NMR ( OMSO-d6 ) δ 1 1.20 ( s, 1H ) &gt; 10.77 ( s, 1 H ) &gt; 8.23 ( m, 1 H ) , 7.94 ( d, 1H, J = 6.5 Hz ) , 7.70 ( s, 2H ) - 7.45 ( m, 1 H ) &gt; 7.35 ( m, 2H ) , 7.16 ( m, 3H) &gt; 6.64 ( d, 1 H, J = 2.5Hz ) &gt; 6.11 ( s, 1 H ) , 3.75 ( s,2H) ; MS ( ESI+ ) :m/z 399.12 (M + H) +

1-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetic acid salt

A) 4·Amino-2,3-difluorophenol Potassium carbonate (17·6 g, 127.8 mmol) and benzyl alcohol (8.8 mL, 85.0 mmol) were added to 1,2,3-trifluoro-4 - Nitrobenzene (Aldrich, bO g ' 84.7 mmol) in a solution of DMF (25.0 mL). The resulting suspension was stirred overnight. Then, water (1 〇 〇 mL) was added to the reaction mixture, and the solution was kept at -278-8 (275) 1324926 overnight. Then, the precipitate was collected and rinsed with water to obtain a mixture of two isomers (22_4 g) [I _ (benzyloxy)-2,3-difluoro-4-nitrate in a ratio of 1:1 Benzobenzene and 2-(benzyloxy)·3,4-difluoro-1-nitrobenzene]. Add 10%?0/(:(1_0§) to [1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and 2-(benzyloxy)·3,4-di a solution of fluoro-p-nitrophenyl] (22.4 g, 84.5 mmol) in ethyl acetate (20.0 mL). </ RTI> </ RTI> </ RTI> </ RTI> Concentration in vacuo gave a mixture of two isomers (12.6 g) [1:1 ratio of 4 -amino-2,3-difluorophenol and

6-Amino-2,3-difluorophenol]. MS (ESI+): m/zl 46.00 (M + H \ +

B) #-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)trimethylacetamide in a similar manner to that described in Step A of Example 90 'Prepare. A mixture of 4-amino-2,3-difluorophenol and 6-amino-2,3-difluoroindole (580 mg '4.0 mmol) (in 3.0 mL of DMF) was converted to 4-( Mixture of 4-amino-2,3-difluorophenoxy)pyridinecarboxamide with 4-(6-amino-2,3-difluorophenoxy)pyridinamide (300 mg) ° MS ( ESI+) : m/z 266.1 3 ( M + H ) +. 8-279-(276) 1324926 Preparation was carried out in a similar manner to that described in Step A of Example 96. Mixture of 4-(4-amino-2,3-difluorophenoxy)pyridinamide with 4-(6-amino-2,3-difluorophenoxy)pyridinamide (300 mg, 1.13 mmol) converted to 4-(2,3-difluoro-4-trimethylacetamidophenoxy)pyridylcarboxamide and 4-(2,3-difluoro-6 a mixture of trimethylethylguanidinium phenoxy)pyridinecarboxamide (406 mg). MS (ESI+): m/z 3 5 0.20 (M + H) +.

The preparation was carried out in the same manner as described in the step A of Example 91. 4-(2,3-Difluoro-4-trimethylacetamidophenoxy)pyridylcarboxamide and 4-(2,3-difluoro-6-trimethylacetamidoamine A mixture of phenoxy)pyridinecarboxamide (400 mg) was reacted with bis(trifluoroacetoxy)iodobenzene to give #-(2-(aminopyridine)-4 after purification by preparative HPLC. -yloxy)-2,3-difluorophenyl)trimethylacetamide, trifluoroacetate (120 mg, yield 24%) °MS (ESI+): m/z 3 22.23 ( M + H ) +.

F

C) 4-(4-Amino-2,3-difluorophenoxy)pyridin-2-amine Prepared in a similar manner as described in Step C of Example 96. Conversion of #-(4-(2-aminopyridin-4-yloxy)-2,3-difluorophenyl)trimethylacetamide, trifluoroacetate (120 mg, 0.27 mmol) to 4 - (4-Amino-2,3-difluorophenoxy)pyridin-2-amine (52 mg, yield -280- 8 (277) 1324926 rate 81%) °MS (ESI+): m/z 238.11 ( M + H)+. D) 1-(4-(2-Aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, three Fluoroacetate

The preparation was carried out in the same manner as described in the step F of Example 87. Conversion of 4-(4-amino-2,3-difluorophenoxy)pyridin-2-amine (24 mg, 0.10 mmol) in 3.0 mL of THF to 1-(4-(2- Aminopyridin-4-yloxy)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate (21 mg, yield 40 %). 'H NMR ( DMSO-i/fi ) 6 11.27 ( s, 1H) , 10.84 ( s, 1 Η ) , 8.02 ( m, 1 Η ) , 7.96 ( d, 1H, J = 8.5 Hz ) , 7.73 ( s, 2H), 7.34(m,3H) &gt; 7.1 7 ( m, 2H ) &gt; 6.70 ( m, 1 H ), 6.20 ( d, 1 H, J = 2.0Hz ) , 3.75 ( s, 2H ) ; MS ( ESI+ ): m/z 4 1 7.1 0 ( M + H ) +. Example 9 8

7\/-(4-(2-Aminopyridinium [1疋-4-yloxy)-3-carbyl)-1-indolyl-5-methyl-1/f-pyrazole-3 -Procarbamide,Hydrate-281 - (278) 1324926

HO

A) 1-Benzyl-5-methyl-1//-pyrazole-3-carboxylic acid

Add DIEA (2_0 mL) and 2,4-dione pentanoic acid ethyl ester (0.70 mL, 5.0 mmol) to 1-benzylhydrazine dihydrochloride (Aldrich, 0.98 g, 5.0 mmol) in ethanol (30) mL) in the solution formed. The mixture was stirred at room temperature for 12 hours and concentrated in vacuo. The residue obtained was dissolved in 1N sodium hydroxide (1 mL). The solution was heated at 60 ° C for 1 hour. After the solution was cooled, the solution was extracted with DCM (3 X 50 mL). The aqueous layer was neutralized to pH 2.0 and then extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and concentration, benzyl-5-methyl-1//-pyrazole-3-carboxylic acid (1. g, yield: 92%). MS (ESI+): m/z 2 17.12 (M. + H) +. B) iV-(4_(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-bubenzyl-5-methyl-1//-pyrazole-3-carboxamide, hydrochloric acid The salt is ordered in a similar manner to that described in step C of Example 1 4-(

4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 25 mg, 0.11 mmol) and 1-pyryl-5-methyl-1//-哩- 3-Residual acid (25 mg, 0.11 mmol) was coupled and purified by preparative HPLC to give #-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl 5--5-methyl-1//-pyrazole-3-carboxamide hydrochloride (10 mg, yield 20 ° /.). -282- (279) 1324926 'H NMR(DMS0-i/«5) &lt;5 10.64 ( s, 1 Η ) , 7.8-7.98 (m,3H ), 7.00-7.65 (m, 9H) &gt; 6.7 1 ( m, 1 H ) , 6.15 ( s, 1H), 5.65 ( s, 2H ) &gt; 2.24 ( s, 3H ) ; MS ( ESI+ ) : m/z 4 1 8.2 1 ( M + H ) + . Example 9 9 Η

H2N 2-(4-Fluorobenzylsulfinyl)-TV-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride

φ A) 2-(4-Fluorobenzylthio)acetate to potassium carbonate (2.76 g, 20.0 mmol) and 1-(bromomethyl)-4-fluorobenzene (2.27 g, 12.0 mmol) Ethyl 2-hydrazinoacetate (Aldrich, 1.0 mL, 9.1 mmol) in EtOAc (10.0 mL). The mixture was stirred for 12 hours at room temperature. After filtration and concentration, the residue obtained was purified by flash column chromatography on EtOAc to yield ethyl 2-(4-fluorobenzylthio)acetate (1.89 g. Rate 91%) ° MS (ESI+): m/z 2 5 1.08 (M + H) +. -283- (280)1324926

FB) 2-(4-Fluorobenzylsulfinyl)acetate ethyl ester at - 40 ° C, w-CPBA (77%, 1.86 g, 8.29 mmol) in DCM (20.0 mL) Ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 8.29 mmol) in DCM (20.0)

mL) The solution formed. The solution was stirred overnight from -40 °C to room temperature. The solution was then quenched with di-ethyltriamine bound to the polymer. After filtration and concentration, the residue obtained is purified by flash chromatography on EtOAc to give ethyl 2-(4-fluorobenzylsulfinyl)acetate (2.0 g. , Yield 98%) ° MS (ESI+): m/z 266.09 (M + H) +.

F

C) 2-(4-Fluorobenzylsulfinyl)acetic acid

Add 1N sodium hydroxide (20.0 mmol) to ethyl 2-(4-fluorobenzylsulfinyl)acetate (1.60 g, 6.55 mmol) in THF (10.0 mL) and methanol (20.0 mL) In solution. The mixture was stirred for 2 hours at room temperature. After removing the organic solvent under reduced pressure, the remaining aqueous solution was neutralized with 1N hydrochloric acid (25.0 mL). It was extracted with ethyl acetate (3×1 〇〇 ml), and the combined organic layer was dried over magnesium sulfate. Then, the solution was filtered and concentrated under vacuum to give 2-(4-fluorobenzylsulfinyl)acetic acid (1.25 g, yield 88%). MS-284-(281) 1324926 (ESI+): m/z 2 17.05 (M + H) +. D) 2-(4-Fluorobenzylsulfinyl)(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride

4-(4-Amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (Compound B of Example 24, in a similar manner as described in Step C of Example 1 29 mg, 0.10 mmol) coupled with 2-(4-fluorobenzylsulfinyl) acetic acid (22 mg '0.1 mmol) to give 2-(4-oxobenzylsulfinyl)-# - (4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride (17 mg, yield 37%). 'H NMR (DMSO-i/6 ) (5 10.94 ( s, 1H) &gt; 7.97 ( d, 1H, J = 7.5 Hz ), 7.85 ( m, 3H ) , 7.39-7.45 ( m, 4H) &gt; 7.23 (t, 2H, J = 7.5Hz) &gt; 6.70 ( m, 1H ) &gt; 6.13 ( d, 1 H, J = 2.5Hz ), 4.32 ( d, 1H, J = 11. 0Hz ) &gt; 4.11 ( d , 1H, J = 11. 0Hz ), 3.98 (d, 1H, J = 1 3.0Hz ) , 3.65 (d, lH, /=11.0Hz), 9 4.11(d, 1H, J=11 .0Hz ) &gt; 3.98 ( d, 1H, J = 13.0 Hz ) &gt; 3.65 ( d, 1H, J = 13.0 Hz); MS ( ESI+ ) : m/z 4 18.26 ( M + H) + Example 1

H2n n -285- 3 (282) 1324926 2-(4-Fluorobenzylsulfonyl)-indole (4-(2-aminopyridin-4-yloxy)-3-fluorophenyl) Acetamine, hydrochloride

F A) 2-(4-Fluorobenzylsulfonyl)acetate

Adding w-CPBA (77%, 450 mg, 2.0 mmol) to ethyl 2-(4-fluorobenzylsulfinyl)acetate (3 70 mg ' 1.52 mmol) in DCM ( 5.0 mL) In solution. The mixture was stirred at room temperature for 2 hours and then quenched with di-ethyltriamine (1.5 g) bound to the polymer. The reaction mixture was filtered and concentrated in vacuo to afford ethyl <RTI ID=0.0>(4- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; M + H)+.

HO

F

B) 2-(4-Fluorobenzylsulfonyl)acetic acid Prepared in a similar manner to that described in Step C of Example 99. Ethyl 2-(4-fluorobenzylsulfonyl)acetate (340 mg, 1.31 mmol) was converted to 2-(4-fluorobenzylsulfonyl)acetic acid (270 mg, yield 81%) MS (ESI+): m/z 255.05 (M + H)+. C) 2-(4-Fluorobenzylsulfonyl)(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride salt according to the examples In a similar manner as described in Step C, 4-(-286-(283) 1324926 4-amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (50 mg, 0.17) Coupling with 2-(4-fluorobenzylsulfonyl)acetic acid (33 mg, 0.14 mmol) gives 2-(4-fluorobenzylsulfonyl) (4-(2-amino) Pyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride (30 mg, yield 45%). 'H NMR (DMSO-heart) J 13.40 (s, 1 Η), 11.15 (s, lH), 7.97 (d, lH, J = 7.0 Hz), 7.8 0- 7.90 (m, 3H), 7.47 (m, 4H) ) &gt; 7.26 ( t, 2H, J =

8.5 Hz ) , 6.72 ( d, 1 H, J = 7.0 Hz ) , 6.14 ( d, 1H, J = 2.0 Hz ) - 4.69 ( s, 2H ) &gt; 4.27 ( s, 2H ) ; MS ( ES Γ ): m/z 43 4.1 5 ( M + H ) +. Example 1 〇 1

#-( 4-(2-Aminopyridin-4-yloxy)-3.fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3 -carbamamine, hydrochloride

H3co2c A) methyl 1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxylate 4-fluoroaniline (1.67 g, 15 mmol) at rt Add 8-287-(284) 1324926 to methyl 2-keto-2/--piperan-3-carboxylate (Aldrich, 2.31 g, 15 mmol) in THF (40 mL) and DMF (10 mL) The resulting solution was stirred and the reaction mixture was stirred for 2.5 hours. A solid precipitate was observed. EDCI.HC1 (3.85 g, 20 mmol) and DMAP (120 mg) were added to the 4-fluoroaniline adduct obtained at the reaction site via Michael addition reaction at room temperature. Intermediate. The reaction mixture was stirred overnight at room temperature. 1 N aqueous salt #acid (50 mL) and ethyl acetate (150 mL) were added to the reaction mixture, the ethyl acetate layer was separated, and the aqueous layer was washed with ethyl acetate (150 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo to give a semi-solid material (~4.4 g). Diethyl ether (100 mL) and methanol (15 mL) were added to the crude product, which was stirred and filtered to give the desired product ( 870 mg). Concentration of the filtrate gave the crude product as a crude solid (2.95 g &apos;&apos;&apos;&apos;&apos;&quot;80%&quot;&apos;&apos;&apos; 4 NMR (DMSO-i/6) (5 8.23 ( dd, 1H, J = 7.2, 2.2 Hz) * 7.57 ( dd, 1H, J = 6.6, 1.7 Hz), 7.32 - 7.34 (m, 2H) . 7.17 ( t, 2H, J = 8.8 Hz) * 6.32 ( t, 1 H, J = 7.1 Hz ) &gt; 3.89 ( s, 3H ) ; MS ( ESI+ ) : m/z 248.2 ( M + H ) +.

B) 1-(4-Fluorophenyl)-2-keto-1,2-dihydroindole-3-residual acid 8 -288- (285) 1324926

Methyl 1-(4-fluorophenyl)-2-keto-1,2-dihydropyrrol-3-carboxylate (crude 2.45 g, 12 mmol) and 6N aqueous sodium hydroxide at room temperature The mixture formed in methanol (60 mL) was stirred for 4 hr. Concentrated hydrochloric acid (1 m L) was slowly added to the reaction mixture while stirring at room temperature, and the precipitated solid was filtered off, washed with a small amount of water and dried to give a yellow color. The desired acid product of the solid (2.1 g). The filtrate was concentrated in vacuo. The residue obtained was taken up in water (50 mL) and washed with ethyl acetate (2 x 130 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated in vacuo. A second crop of the product (195 mg, 2.30 g, 82% total) was obtained by triturating the residue obtained with a small amount of diethyl ether. 4 NMR (DMSO - heart) ¢5 8.47 ( dd, 1 H, y = 7.2, 2.2 Hz ) &gt; 8. 1 9 ( dd, 1 H, J = 6.6, 1.7 Hz) &gt; 7.62-7.60 ( m, 2H ) , 7 · 4 2 ( t, 2H, J = 8.8 Hz ) * 6.78 ( t, 1H, J = 7.1 Hz) ; MS ( ESI+) : m/z 234.2 ( M + H) +.

C) #-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine 3-carbalamine, hydrochloride, 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (in the same manner as described in Step C of Example 1) Compound B of Example 24, 58 mg, 0.20 mmol) was coupled with 1-(4-fluorophenyl)-2.one-1,2-dihydropyridine-3-carboxylic acid (47 mg, 0.20 mmol). W-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2·dihydropyridine- 3-carbalamine, hydrochloride (22 mg, yield -289- (286) 1324926 2 3%) o'HNMRCDMSO-i^) (5 13.40 (s, 1H), 12.13 (s, 1 H ) , 8.58 ( d, 1H, J = 5.0Hz) , 8.13 ( d,1H, J = 5.0Hz ) , 8.07 ( d, 1 H, J = 10.0Hz ) , 7.98 ( d,1 H, J = 7.5Hz ) , 7.89 ( s, 2H ) , 7.40-7.60 ( m, 6H ) - 6.72 ( m, 2H ) , 6.17 ( d,1 H, J = 2.5Hz ) ; MS ( ESI+ ) : m/z 43 5 . 1 8 ( M + H ) + φ Example 1 〇 2

H2N N (&lt;S) -A^-(2-Amino-2-keto-Phenylethyl)-W-(4-(2-Aminopyridin-4-yloxy)-3-fluoro Phenyl) propylenediamine, hydrochloride

A) 3-(4-(2-Aminomethylpyridin-4-yloxy)-3-fluorophenylamino)-3- ketopropanoic acid ethyl ester DIEA (2.0 mL) and 3-chloro Ethyl-3-ketopropionate (Aldrich, 0.75 mL, 6.0 mmol) was added to 4-(4-amino-2.fluorophenoxy)pyridinamide (Compound B of Example 24, 1.0 g, 4.0 -290- (287) 1324926 mmol) in a solution of DMF (10.0 mL). The mixture was stirred at room temperature for 12 hours, and more 3·chloro--3-propionic acid ethyl acetate (0.20 mL, 1.6 mmol) was added. The mixture was stirred while being then diluted with ethyl acetate (200 mL). It was rinsed with water and dried over magnesium sulfate. After filtration and concentration, the residue obtained is purified by DCM and filtered to give 3-(4-amine-carbazinidine-4-yloxy)-3-fluorophenylamino)-3- ketopropyl φ ester (900 mg, yield 62%). MS (ESI+) m/z 362.28 (

Lower, - copper base 2 small brine, with -(2-acid B M + H

B) 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)

Ethyl propyl propionate was prepared in a similar manner to that described in Step A of Example 91. 3-(4-(2-Aminomethylpyridin-4-yloxy)-3-fluoroamino)-3- olpropanoic acid ethyl ester (900 mg, 2.5 mmol) (in mL DMF) Conversion to ethyl 3-(4-(2-aminopyridin-4-yloxy)phenylamino)-3-ketopropanoate (710 mg, yield 86%) (ESI+) m/z 3 3 4.2 6 ( M + H ) +.

3-ketone is carried out as phenyl 10.0 3 -fluorine. MS (288) 1324926

C) 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3- ketopropionic acid

Preparation was carried out in a similar manner to that described in Step C of Example 99. Conversion of ethyl 3-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-3- ketopropanoate (700 mg, 2.10 mmol) to 3-(4) -(2-Aminopyridinium [1-4-yloxy)-3-phenylphenylamino)-3-mercaptopropionic acid (630 mg, yield 98%). MS ( ESI+) m/z 306.20 (M + H) +. D ) ( 5 &quot;) -iV, ( 2 -amino-2-mercapto-1-ethylidene)-•/V5- ( 4- ( 2 -moon-glyphthyridin-4-yloxy)-3 -fluorophenyl)propaneamine, hydrochloride, 3 -(4-(2-aminopyridine-4-yloxy)-3, in a similar manner to that described in Step C of Example 1. -fluorophenylamino)-3-ketopropionic acid (30 mg, 0.10 mmol) with (S)-2-amino-2-phenylacetamide hydrochloride (Acros, 28 mg, 0.15 mmol Coupling, (iS)-(2-amino-2-keto-1-phenylethyl)--(4-(2-aminopyridin-4-yloxy)-3-fluorobenzene Base propylene diamine, hydrochloride (25 mg, yield 5 3%) o'HNMRCDMSOO ό 10.68 ( s, 1H) &gt; 8.80 ( d, 1 H, J = 8.0 Hz ) , 7.96 (d, 1 H, J = 7.5 Hz ) , 7.77-7.90 ( m, 4H ) , 7.20-7.45 (m, 8H) &gt; 6.70 ( m, 1 H ) - 6.12 ( s, 1 H ) , 5.39 ( d, 1 H , J = 7.5Hz ) , 3.48 ( d, 1 H, J = 8 -292- (289) 1324926 1 5 , ΟΗζ ) , 3.4 1 ( d, 1 Η, J = 1 5 .ΟΗζ ) ; MS ( ESI+) m/z 43 8.26 ( M + H ) +.

(Λ) -W-(2-Amino-2-keto-1-phenylethyl)-W-(4-(2-aminopyridine-4-yloxy)-3-fluorophenyl)propane Diamine, hydrochloride

3 -( 4-(2-amino-2-inden-4-indolyl)-3-phenylene)-indenyl group was obtained in a similar manner to that described in Step C of Example 1. Propionic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (Λ)-2-amino-2-phenylacetamide hydrochloride (Bachem, 28 mg, 0.15 mmol). (Λ ) (2-Amino-2-keto-1-phenylethyl)-7V3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)propanediamine , hydrochloride (14 mg, yield 30%). iH NMR (DMSO-heart) δ 10.65 ( s, 1 Η ) , 8.76 ( d, 1 Η, J = 8.0 Hz), 7.92 (d,

1H, J = 7.0Hz), 7.7 5 - 7.8 8 ( m, 4H) - 7.20-7.43 ( m, 8H ), 6.66 ( m, 1H ) , 6.09 ( s, 1 H ) &gt; 5.35 ( d, 1H, J = 8.0 Hz), 3.45 (d, 1H, J = 1 5.0 Hz), 3.37 (d, 1H, J = 15.0 Hz); MS ( ESI+ ) m/z 43 8.23 ( M + H ) + 〇 Example 104 -293- 8 (290) 1324926

2-(3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-one-propionylamino)-2-phenylacetic acid (S)- Methyl ester, hydrochloride

3 -(4-(2-Aminopyridinium-4-yloxy)-3-aminophenylamino)-3-indenyl group was obtained in a similar manner to that described in Step C of Example 1. Copropionic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with 2-amino-2-phenylacetic acid (S)-methyl ester hydrochloride (Aldrich, 30 mg, 0.10 mmol) to give 2 -( 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-onepropanylamino)-2-phenylacetic acid (S)-A Ester, hydrochloride (21 mg, yield 43%). 1H NMR (DMSO-d6) δ 10.58 ( s, 1 Η ) &gt; 9.04 ( d, 1H, / = 7.0 Hz ) , 7.97 ( d, 1H, J = 7.0 Hz) , 7.7 5 -7.8 8 ( m, 3H) &gt; 7.42 ( m, 7H) , 6.72 ( d, 1H, J = 7.0Hz ) , 6.12 ( s, 1H ) &gt; 5.45 ( d, 1H, J = 7.0Hz) , 3.63 ( s, 3H ) , 3.43 3.38 (m, 2H); MS (ESI+): m/z 4 5 3.26 (M + H) +. Example 1 〇 5 8 -294- (291) 1324926

2-(3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3- ketopropylamino)-2-phenylacetic acid (/?) -methyl ester, hydrochloride

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-ketopropanoic acid was obtained in a similar manner to that described in Step C of Example 1. (Compound C of Example 12, 30 mg, 0.10 mmol) with 2-amino-2-phenylacetic acid (hydrazine)-methyl ester, hydrochloride (Aldrich, 30 mg, Ο.10 mm ο 1 ) Coupling gives 2 - ( 3 - ( 4 - ( 2 -aminopyridin-4-yloxy)-3-fluorophenylamino)-3- ketopropylamino)-2-phenylacetic acid ( Λ)-methyl ester, hydrochloride (25 mg, yield 51%) °1H NMR (DMS 〇-d6) δ 10.58 ( s, 1 Η ) , 9.03 ( d, 1 H, J = 7.0 Hz ) 7.96 ( d, 1H, J = 7.0Hz ) , 7.77-7.88 ( m,3H) , 7.42 ( m, 7H ) &gt; 6.71 ( d, 1 H, J = 7.5Hz ) &gt; 6.12 ( s, 1 H ) , 5.44 ( d, 1 H, J = 7.0 Hz ) , 3.63 ( s, 3H ) , 3.44 - 3.3 8 ( m, 2H ) ; MS ( ESI+ ) m/z 45 3.29 ( M + H ) + . Example 106 -295- (292) 1324926

H2N #- (4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)cyclopentylpropanediamine, hydrochloride

3 -(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-ketopropanoic acid was obtained in a similar manner to that described in Step C of Example 1. (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with cyclopentylamine (Aldrich, 17 mg, 0.2 mmol) to give #-(4-(2-aminopyridin-4-yloxy). 3-fluorophenyl)cyclopentylpropanediamine, hydrochloride (18 mg, yield 44%). 'H NMR ( DMSO-A) 5 13.34 ( s, 1 Η ) , 10.66 ( s, 1 Η ) , 8.15 ( d,1 Η, J = 7.0 Hz ), 7.96 ( d, 1 H, J = 7.0 Hz ) , 7.77-7.88 (m, 3H), 7.42

(m, 2H ) &gt; 6.70 ( d, 1H, J = 7.5Hz ) &gt; 6. 12 ( s, 1 H ), 3.98 ( m, 1 H ) , 3.69 ( s, 2H) , 1.78 ( m, 2H &gt; 1.63 (m, 2H), 1.49 (m, 2H), 1.37 (m, 2H); MS (ESI+): m/z 3 7 3.3 ( M + H ) + . Example 107 -296- 8 (293) 1324926 Η Η

(4-(2-Aminopyridinium-pyridin-4-yloxy)-3-carbyl)-cyclohexylpropanediamine, hydrochloride

3 -(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-ketopropanoic acid was obtained in a similar manner to that described in Step C of Example 1. (Compound C of Example 102, 30 mg '0.10 mmol) was coupled with cyclohexylamine (Aldrich, 20 mg, 0.2 mmol) to give (4-(2-aminopyridin-4-yloxy)- 3-fluorophenyl)-A^-cyclohexylpropanediamine, hydrochloride (22 mg, yield 52%). 'H NMR (DMSO-heart) ά 14.00 ( s, 1 Η ) , 10.72 ( s, 1H) &gt; 8.10 ( d, 1H, J = 7.0Hz )&gt; 7.97 ( d, 1 H, J = 7.0Hz ) , 7.88 ( m, 3H) , 7.44 ( m, 2H) , 6.70 (m, 1H) &gt; 6. 14 ( d, 1 H, J = 2.0 Hz ) , 3.54 ( m, 1H) - 3.27 ( s, 2H ) - 1 .66 - 1 .75 ( m, 4H ) &gt; 1 .52 ( m, 1H ) , 1.15 - 1.25 ( m, 5H) ; MS ( ESI+ ) m/z 3 87.3 2 ( M + H) + 〇Example 1 〇8 8 -297- (294) 1324926

&lt;-(4·(2-Aminopyridin-4-yloxy)·3-fluorophenyl: propylenediamine, hydrochloride is similar to the one described in the step C of Example 1 (2-Aminopyridin-4-yloxy)-3-fluorophenylamino) (Compound C of Example 102 C 30 mg, 0.10 mmc methylpropan-1-amine (Aldrich, 12 mg, 0_2 mmol {γ. (4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl: propanediamine, hydrochloride (13 mg, yield 32%) DMSO-i/6 ) δ 13.34 (s, 1H) &gt; 10.69 (s, 1H; 1 H ) &gt; 7.96 ( d, 1 H, J = 7.0Hz ) - 7.87 ( m, 3 m, 2H ) , 6.70 ( m, 1H) &gt; 6.13 ( d, 1H, J 3.34 ( s, 2H ) &gt; 2.9 1 ( d, 2H, J = 6.5Hz ) &gt;0; MS ( ESI+) : m/z 3 75.3 2 ( M + H ) + Example 109) Neopentyl ί-'- 3 -( -3 -mercaptopropionic acid) 1) is combined with 2,2-di-I to give &gt;-neopentyl. NMR ( ), 8 · 0 8 ( m, Η ) - 7.44 ( =2.0Hz ), • 84 ( s, 9H )

298- 8 (295) 1324926 (S) -2- (3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-onepropanylamino -2-phenylacetic acid, hydrochloride, according to a procedure similar to that described in Step C of Example 99, 2·(3-(4-(2-aminopyridin-4-yloxy)-) Hydrogenation of (S)-methyl ester hydrochloride (Compound D of Example 102, 14 mg, 0.028 mmol) of 3-fluorofluoroamino)-3-phenylpropanylamino)-2-phenylacetic acid, (51)-2-(3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-φ 3-ketopropylamino)-2- Phenylacetic acid, hydrochloride (13 mg, yield 9 7%) 〇! H NMR ( DMSO-^6 ) &lt;5 13.20 ( s, 1 Η ) , 10.57 ( s, 1 Η ) , 8.92 (d, 1 Η, J = 7.0Hz ) , 7.95 ( d, 1H, J = 7.0Hz ) , 7.87 ( d, 1H, J = ll.OHz) , 7.70 ( s, 2H ), 7.4 1 ( m, 8H ) &gt; 6.69 ( d, 1 H, J = 7.5 Hz ) , 6.12 ( d, 1H, J = 2.0 Hz ) &gt; 5.35 ( d, 1H, J = 7.5 Hz ) &gt; 3.42 ( s, 2H ); MS ( ESI+ ) : m/z 43 9.27 ( M + H ) +. %Example 1 1 〇

;V·( 4-(2-(3-dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide, hydrochloric acid Salt-299- (296) 1324926

A) #-( 4-(2-Chloropyridin-4-yloxy)-3-fluorophenyl)-2,6-difluoro.benzamide

2,6-- Daiki simmered chlorine (A丨drich 1 33// L, 0.27 mmol) was added dropwise to 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (Compound B of Example 20, 64 mg, 0.27 mmol), THF (1 mL), triethylamine (l.sup.#L), and the mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between EtOAc EtOAc (EtOAc m. 100%) » MS (ESI+): m/z 418.18 (M + H) +. B) #-(4-(2-(3-dimethylamino)propylamino)pyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide, Hydrochloride The acid salt was rinsed with chlorinated pyridyl-4-yloxy)-3-fluorophenyl)-2,6-difluoroylamine in a test tube covered with a screw cap (7 〇 mg &gt; 0.19). Methyl), 3-(dimethylamino)propylamine (〇mL 〇mm ο 1 ) ' C s 2 C Ο 3 ( 8 5 mg, 〇· 2 6 mm ο 1 ) and C u C 1 ( 1 g 0.17 mmol )mixture. Will NMP and 2,2,6,6-tetramethyl-3,5-heptane-300- (297) 1324926

Diketone (31 mg, 0. 7 mmol) was added to the mixture, which was then heated at 120 ° C for 4 hours. The mixture was cooled, and the residue was evaporated to ethyl acetate. The resulting residue was purified by EtOAc EtOAc EtOAcjjj: MS ( ESI+): m/z 5 17.37 (M + H) +. Example η 1

_ iV- ( 4-(2-Amino-3-(4-(2-amino-2-ketoethyl)phenyl)pyridin-4-yloxy)-3-fluorophenyl)-1 -(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxamide, 1-(4-fluorophenyl)-2-keto-1, hydrochloride 2-dihydropyridine-3-carboxylic acid (Compound B of Example 101, 11 mg, 0.05 mmol), DIPEA (10 // L ' 0.06 mmol) and TBTU (19 mg, 0_06 mmol) to treat 2- ( 4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide (Compound C of Example 78, 18 mg, 0.05 mmol) In a solution formed by DMF (1.5 mL). The mixture was stirred for 40 hours at room temperature. The mixture is concentrated in a vacuum,

-301 - (298) 1324926 and the residue obtained was purified by preparative HPLC (layer column A) to give the title compound as a trifluoroacetic acid salt. The trifluoroacetate salt was dissolved in anhydrous methanol and treated with &lt;EMILY&gt; The title compound (15 mg, 47%). 4 NMR (DMSO-heart) δ 12.11 ( s, 1 Η ) , 8.56 ( dd, 1H, J =

2.2, 7.1Hz) , 8.13 ( dd, 1 H, J = 2.2, 6.7Hz ) , 8.00 ( dd, 1 H, J = 2.2, 12.6Hz ) , 7.96 ( d,1 H, J = 7.7Hz ) , 7.60 -7.57 ( m, 2H ) , 7.4 8 - 7 · 3 3 ( m,1 0 H ) , 6 · 9 4 ( s, 1 H ), 6.72 ( dd, \H, J = 7.2, 7.2 Hz ) &gt; 6.38 ( d, IH, J = 7.2 Hz ) - 3.95 ( s, 2H ) ; MS ( ESI+ ) : m/z 5 68.23 ( M + H ) + Example 1 1 2

1-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloric acid salt

Α) 1·(2,5-Difluoro-4-nitrophenoxy)methyl)benzene-302-8 (299) 1324926 2,4,5-trifluoronitro group at weekly temperature A solution of benzene (5.4 g, 30.8 mmol), benzyl alcohol (3.2 mL, 30.8 mmol) and potassium carbonate (6.4 g, 46.1 mmol) in DMF (20 mL) was stirred for 72 hours. Water (60 m L ) was added to the mixture and it was cooled at 4 ° C for 24 hours. The resulting precipitate was filtered, washed with water and dried in vacuo to yield (yield: 7.5 g, 92%). 'H NMR (CDCI3) δ 7.90-7.94 (m,

1 Η ) &gt; 7.3 8-7.44 ( m, 5H ) &gt; 6.85-6.90 ( m, 1 H ) &gt; 5.22 ( s, 2H ).

B) 4-Amino-2,5-difluorophenol 10% palladium on carbon (〇.40g) was added to 1-((2,5-difluoro-4) in a flask In a solution of -nitrophenoxy)methyl)benzene (4.1 g, φ 15.6 mmol), the flask was continuously evacuated and then rinsed three times with nitrogen. Anhydrous methanol (1 〇〇 mL) was added to the solid under a nitrogen atmosphere. The mixture was stirred for 16 hours under a hydrogen atmosphere. Nitrogen was bubbled through the reaction mixture during 30 minutes and the mixture was filtered through a Celite® filter pad and then rinsed with methanol. The title compound (2·2 g '99%) was obtained as a dark brown solid. lH NMR ( DMSO-i/d) δ 9.05 ( br s, 1H) &gt; 6.5 3 -6.65 ( m, 2H) * 4.68 ( s, 2H) ; MS ( ESI+) m/z 1 46 ( M + H ) +. -303- 8 (300) 1324926

c) 4-(4-Amino-2,5-difluorophenoxy)pyridinamide

A solution of 4-amino-2,5-difluorophenol (1.7 g, 11.6 mmol) in DMF (5 mL) was added to potassium hydride (30-35 % dispersion in mineral oil, 1.9 g, 13.9 mmol) in a mixture of DMF (30 mL). After stirring at ambient temperature for 1 hour, 4-chloropyridine carbenamide (1.8 g, 11.6 mmol) was added, and the reaction mixture was heated at 100 ° C for 135 hours. The mixture was cooled to room temperature, quenched with 10% aqueous lithium chloride, and then extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solids were dissolved in chloroform and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. NMR ( DMSO-Je) (5 8.5 1 - 8.5 7 ( m, 1H) - 8.14 ( br s, 1H ), 7.74 ( br s, 1 H ) &gt; 7.3 7-7.3 8 ( m, 1H ) &gt; 7.17 -7.30 ( m, 2H) » 6.74-6.80 ( m, 1H ) , 5.62 ( s, 2H) ; MS ( ESI+) m/z 266 ( M + H) + .

-304- 8 (301) 1324926 D) 1-(4-(2-Aminomethylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluoro Phenyl)ethylidene)urea Diisopropylethylamine (0.10 mL, 0.57 mmol) was added to 4-(4-amino-2,5-difluorophenoxy)pyridinamide (0.15 g, 0.57 mmol) in a homogeneous mixture of THF (5 mL). The mixture was stirred for 2 minutes at ambient temperature, then 2·(4-fluorophenyl)ethenyl isocyanate (Compound D of Example 11, 0.36 Μ, in benzene, 2.0 mL, 0-72 mmol) ). After 3.5 hours, 2-(4-fluorophenyl)ethenium isocyanate (0.36 Torr in toluene, 2.0 mL, 0.72 m.sup.1) was added to the reaction mixture. After another 2 hours, 2-(4-oxophenyl)acetic acid isophthalic acid vinegar (0.36 Torr in toluene, 2.0 mL '0.72 mmol) was added to the reaction mixture 9 and then the mixture was stirred. 1 6 hours, then 'concentrate in vacuum. The resulting residue was treated with diethyl ether and ultrasonic, and a white solid produced was taken by filtration. The solid was treated twice more with diethyl ether and ultrasonic, and then filtered to give a white solid (0.23 g, 91.

〇'H NMR ( OMSO-de^ (5 1 1 · 2 9 ( s, 1 Η ) , 10.92 ( s, 1H )&gt; 8.56 ( d, 1 H, J = 5.6 Hz ) &gt; 8.21-8.26 ( m, 1 H ) « 8.16 (br s, 1H ) - 7.76 ( br s, 1H ) &gt; 7.66-7.71 ( m, 1 H ), 7.12-7.44 ( m, 6H ) &gt; 3.77 ( s, 2H ) MS ( ESI+) m/z 445 (M + H) + E) 1-( 4- (2-aminopyridin-4-yloxy)-2,5-difluorophenyl)-3·( 2-(4-Fluorophenyl)ethenyl)urea, hydrochloride-305-8 (302) 1324926 bis(trifluoroethyloxy)iodobenzene (Aldrich, 0.18 g) at room temperature '0.42 mmol) was added to 1-(4-(2-aminomethylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)ethyl Urea) urea (0.13 g' 0.30 mmol), water (0.01 mL, 0.60 mmol) and sputum (0.05 mL, 0.66 mmol) in DMF (2 mL). After 10 min, add another DMF (2 mL) was then stirred. The reaction mixture was stirred for 16 h then concentrated in vacuo to <RTI ID=0.0># </ RTI> </ RTI> </ RTI> to about half of the original volume. The resulting mixture was dissolved in 6N HCl and diethyl ether. Extracting the aqueous solution with diethyl ether and The combined organic layers were discarded, the aqueous layer was neutralized with sodium bicarbonate (aq.), filtered and concentrated in vacuo. EtOAc EtOAc EtOAc The residue obtained was purified 'and the appropriate fractions were concentrated in vacuo. The residue obtained was dissolved in THF (1 m L ) and cooled to 〇 ° C and HCl (4N' in the second D The reaction mixture was warmed to room temperature and allowed to stir for 1 hour '$ $ ' $ ίΐ # )东胃@ W ί# MS E1 stomach title compound (73 mg , 53%). 4 NMR (DMSO-i/&lt;i) 5 13.54 (br s, IH) , 11.35 (s, 1H), 10.95 (s, 1H) ' 8.24-8.28 ( m, 1H) ' 7.95-8.01 ( m, 3H &gt; 7.73 -7.77 ( m, 1H) &gt; 7.35-7.3 9 ( m, 2H ) ' 7 · 1 6 - 7.2 0 ( m,2 H ) '6.72- 6.74 ( m, 1H ) &gt; 6.25 ( s , 1H) - 3.78( s, 2H ) ; HRMS ( ESI+ ): Theoretical 値, 417·1175(Μ + Η)+: Measured 値: 4〗 7.1187 (Μ + Η ) +. -306- 8 (303) 1324926 Example 1 1 3

1-(4-(2-Aminopyridin-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetic acid salt

FA) 2,6-difluoro-4-nitrophenol 2,6-difluorophenol 10.0 according to conditions similar to those described by Kirk et al., J. Heterocyclic Chem. 1976, 13 3, 1253 g&gt; 76.9 mmol) was converted to the title compound (12.7 g, 94%). ]H NMR(

CDCls ) δ 1 2· 1 5 ( br s, 1 Η ) , 8. (Η-8· 1 Ο ( m, 2Η ).

ΝΗ2 Β) 4-Amino-2,6-difluorophenol 2,6-difluorofluoride in a similar manner as described in Demopoulos et a 1. J. Me d. Chem. 2004, 4 7, 2706 The group 4-nitrophenol (2.1 g, 12.1 mmol) was converted to the title compound (1·7 g, 99%). MS (ESI+): m/z 146 (M + H) +. 8 -307- (304) 1324926

C) 4-(4-Amino-2,6-difluorophenoxy)pyridamide

In a similar manner to the preparation of compound C of Example 1 1 2, however, 4-amino-2,6-difluorophenol (0.44 g, 3.0 mmol) was substituted for 4·amino-2,5-di The fluorophenol was converted to the title compound (0.23 g, 29%). 4 NMR ( DMSO-^6 ) δ 8.60 ( d, 1 H, J = 5.6 Hz ) ' 8,22 ( br s, 1 H ) , 7.83 ( br s, 1 H ) &gt; 7.45 -7.46 ( m, 1 H) &gt; 7.3 0-7.3 2 ( m, 1 H ) , 6.43-6.49 (m, 2H) &gt; 5.94 ( s, 2H ) ; MS ( ESI+ ) m/z 266 (M + H) + .

D) 1-(4-(2-Aminomethylpyridin-4-yloxy)-3,5-difluorophenyl)-3·(2-(4-fluorophenyl)ethenyl)urea

Conversion of 4-(4-Amino-2,6-difluorophenoxy)pyridinamide (104 mg, 0.39 mmol) to the title compound in a similar manner to the preparation of Compound D of Example 112 (91 mg, 52%). 4 NMR (DMSO-heart) δ 11.07 ( s, 1 Η ) , 10.62 (s, 1 Η ) , 8.50 ( d , 1 Η , J = 5.6 Η ζ ) , 8.11 (br s , 1 Η ) , 7.72 (br s, 1 Η ) -308- 8 (305) 1324926 , 7.61 ( m, 2H) , 7 · 3 6 · 7 · 3 7 ( d,1 Η, "7 = 2.3 Η z ) &gt; 7.23-

7.31 ( m, 3H) , 7.11 ( m,2H) ' 3.69 ( s, 2H) ; HRMS (ESI+): theoretical 値, 445.1124; measured 値 ' 445.1117 (M + H \ + E) 1- ( 4- ( 2 -aminopyridine-4-yloxy)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trifluoroacetate

In a similar manner to the preparation of the compound E of Example 1 1 2, 1-(4-(2-aminocarbazinyl)pyridin-4-yloxy)-3,5-fluorophenyl) -3-(2-(4-Fluorophenyl)ethenyl)urea (87 mg '0.20 mmol) was converted to the title compound 'but' using preparative HPLC (YMC S10 0DS' 30 乂 50 〇 111111, 5 8% to The eluted gradient of 90% aqueous methanol (containing hydrazine) was eluted for 30 minutes) and the crude product was purified. The title compound (23 mg » 22%) was obtained as a white solid. NMR (DMSO-heart) occupies 1]. 〇9 ( s, 1H) - 1 0 · 6 3 ( s, 1 Η ) , 7 · 9 2 ( d, 1 Η, "/ = 7.2 Η z ), 7 · 6 2 - 7.7 2 ( m,4Η ) &gt; 7.27-7.3 1 ( m, 2Η ) . 7.09-7.14 ( m, 2H ) ' 6.68-6.70 ( m,1H) , 6.17-6.18 ( m,1H) , 3.69 ( s, 2H) ; MS ( ESI+ ) m/z 417 ( M + H ) + » Example Π 4 -309- (306) 1324926

(4-(2-Aminoguanidine JtH-1,4-phenyloxy)-2,5-difluorophenyl)-2-keto-1-phenyl-1,2-dihydropyridine-3-methyl Guanamine, hydrochloride

A) 4-(5,5-Difluoro-4-(2-keto-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridinecarboxamide

1-Hydroxy-benzotriazine hydrate (22 mg, 0.16 mmol) was added to 2-mercapto-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (Compound C of Example 57) , 43 mg, 0.20 mmol) in a homogeneous mixture of DMF (4 mL). The mixture was stirred until homogeneous, then h(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (102 mg, 0.53 mmol) was added. After 2 minutes, 4-(4-amino-2,5-difluorophenoxy)pyridylcarzamide (Compound C of Example 112, 53 g, 0.20 mmol) was added and at ambient temperature The reaction mixture was stirred for 17 hours. Then, the reaction mixture was warmed to 40 ° C, and an additional M 3 hour was further stirred. After the mixture was cooled to ambient temperature, it was dissolved in ethyl acetate and 10% aqueous lithium chloride. The organic layer was washed with 1% aqueous lithium chloride, 8 - 310 - (307) 1324926 times, and then concentrated in vacuo. The title compound (45 mg, 49) was obtained eluted eluted elut elut elut elut elut elut elut elut %). MS ( ESI+) m/z 463 (M + H) +. B) #-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-2-one-1-phenyl-1,2-dihydropyridine-3 -carbamamine, hydrochloride

In a similar manner to the preparation of the compound E of Example 1 1 2, 4-(2,5- _-yl-4-(2-mercapto-1-phenyl-1,2-indolyl-1! Benzylamino)phenoxy)pyridylcarzamide (45 mg, 0.10 mmol) was converted to the title compound (19 mg, 40%). 'H NMR (DMSO-i^) &lt;5 13.40 ( br s, 1 Η ) , 12.47 ( s, 1 Η ) , 8.5 3 -8.5 7 ( m, 2H )

, 8.12-8.13 (m, 1H) &gt; 7.92-7.93 (m, 1H) &gt; 7.83 (s5 2H )-7.66-7.71 ( m, 1 H ) , 7 · 4 6 - 7.5 3 ( m, 5 H ) , 6.66-6.72 (m, 2H), 6.19 (s, lH); HRMS (ESI+): Theory 値, 43 5.1 269 (M + H) +; 値, 435.1258 (M + H) +. Example 1 1 5

(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-bu (4- 8 -311 (308) 1324926 fluorophenyl)-2-keto-1, 2-dihydropyridine-3-carboxamide, hydrochloride

A) 4-(2,5--Gasyl-4-(1-(4-(phenyl)phenyl)-2-indolyl-1,2-dichloropyridinium-3-carboxamido)phenoxy Pyridinecarbamide DIPEA (0.05 mL, 0.26 mmol) and hexafluorophosphoric acid &lt;7-benzotriazol-1-ylbis(tetramethylene)-quaternary urea (TBTU) (83 mg - 0.26 mmol) ), added to 1-(4-fluorophenyl)-2-keto-12-dihydropyridine-3-carboxylic acid (Compound B of Example 101, 50 mg, 0.21 mm〇l) and 4-( 4-Amino-2,5-difluorophenoxy)pyridylcarzamide (Compound C of Example Π2, 69 mg, 0.26 mmol) was taken in a homogeneous mixture of DMF (3 mL). The thus obtained solution of the solution was stirred for 18 hours, and then quenched with 1% by weight of aqueous lithium chloride. The mixture was partitioned between ethyl acetate and 10% lithium chloride (aq.). The organic layer of the hydrazine was washed twice with 1% aqueous lithium chloride and then concentrated in vacuo. The title compound (22 mg·, 22) was obtained from EtOAc (EtOAc) %). MS (ESI+) m/z 481 (M + H) + B) TV- (4- (2-aminopyridin-4-yloxy)-2,5-difluorophenyl)-1-(8 - 312-(309) 1324926 4-fluorophenyl)-2-mercapto-1,2-dihydropyridine-3-carboxamide, hydrochloride salt according to the preparation of compound E of Example 1 1 2 By way of 4-(2,5-difluoro-4-(1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxamido)phenoxy Pyridylcarbamide (22 mg, 0.04 mmol) was converted to the title compound (21 mg, 95%):1HNMR (DMSO-d6) δ 13.71 (br s, 1H) &gt; 12.43 ( s, 1H) - 8.48 - 8.5 7 ( m, 2H ) &gt; 8. 1 0-8. 1 3 ( m, 1 H ) , 7.9 3 - 7 · 9 5 ( m,3 H ), • 7.61-7.70 ( m, 1H) &gt; 7.53 -7.56 ( m, 2H) &gt; 7.29-7.39 ( m, 2H ) , 6.64 - 6.72 ( m, 2H ) , 6.1 0 ( s, 1 H ) ; HRMS ( ESI + ): Theoretical 値, 4 5 3 · 1 1 7 5 ( M + H ) + ; measured 値, 4 5 3 · 1 1 6 8 ( M + H) +.

(± ) (4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-(1-phenylethyl)propanediamine, hydrochloride

A) 3-(4-(2-Aminomethylpyridin-4-yloxy)-2,5-difluorophenylamine-313- 8 (310) 1324926 benzyl-3-ketopropionic acid Ester 4-(4-Amino-2,5-difluorophenoxy)pyridinamide (Compound C of Example 112, 1.0 g, in a similar manner to the preparation of Compound A of Example 102 , 3.9 mmol) was converted to the title compound (320 mg ' 22%). 'H NMR ( DMSO-c/6) &lt;5 10.32 ( s, 1 Η ) &gt; 8.54 ( d, 1 H, J = 5.5 Hz ) &gt; 8.14-8.17 ( m, 2H ) , 7.75 ( br s, 1 H ) » 7.61-7.65 (m, 1H) &gt; 7.42-7.43 ( m, 1H ),

7.24-7.25 ( m, 1H) &gt; 4.12 ( q, 2H, J = 7.2Hz) * 3.60 ( s, 2H ) , 1.20 ( t, 3H, J = 7.2Hz ) ; MS ( ESI+ ) m/z 3 80 (M + H) +.

B) 3·(4-(2-Aminomethylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-mercaptopropionic acid 1M aqueous sodium hydroxide (1.70 mL, 1.70 mmol) was added to ethyl 3-(4-(2-aminoformamidin-4-yloxy)-2,5-difluorophenylamino)-3- ketopropanoate (305 Mg, 0.80 mmol) in a heterogeneous mixture of methanol (8 mL). After stirring for 1 hour, the mixture was acidified with IN aqueous HCl (5 mL). The reaction mixture was extracted with EtOAc. EtOAc m. . HRMS ( ESI+ ): Theory 値, -314- (311) 1324926 3 5 2.0745 ( M + H ) + ; measured 値, 3 5 2.0 7 5 2 ( M + H ) +.

C) (±) -4-(2,5-difluoro-4-(3-keto-3-(1-phenylethylamino)pyridinium)phenoxy)pyridinecarboxamide DIPEA (0.07 mL, 0.38 mmol) and 0-benzotriazol-1-ylbis(tetramethylene)tetraurea hexahydrate (TBTU) (121 mg &gt; 0.38 mmol) were added to 3 · ( 4-(2-Aminomethylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-onepropanoic acid (89 mg, 0.25 mmol) and (±) -1- A homogeneous mixture of phenyl-ethylamine (Aldrich, 0.05 mL, 0.38 mmol) in DMF (3 mL). The resulting solution was stirred for 15 minutes and then quenched with 1 〇 % aqueous chlorinated φ lithium. The mixture was partitioned between ethyl acetate and 10% aqueous lithium chloride. The organic layer of the hydrazine was washed twice with 10% aqueous lithium chloride and then concentrated in vacuo. The residue obtained was purified by silica gel chromatography eluting with 1:3 hexane/ethyl acetate. The title compound (42 mg, 37%) was obtained. HRMS (ESI+): Theory 値-455.1532 (M + H) +, 値 45 - 455.1528 ( M + H) + ° 8 315 (312) 1324926 D ) ( ± ) -f- ( 4- ( 2-aminopyridine) 4--4-yloxy)-2,5-difluorophenyl)(1-phenethyl)propanediamine, hydrochloride in a similar manner to the preparation of compound E of Example 1 12 (±) -4- ( 2,5-Difluoro-4-(3-keto-3-(1-phenylethylamino)propanylamino)phenoxy)-pyridinecarboxamide (41 The title compound (26 mg, 62%) was obtained. 4 NMR (DMSOd6)

6 10.46 ( s, 1 Η ) , 8.70 ( d, 1 Η, J = 7·8 Ηζ) , 8.21 -8.26 (m,1 Η ) , 8.00 (d,1 Η, J = 7.2 Hz ) , 7.89 ( s? 2Η ), 7.67-7.72 (m,1Η), 7.22-7.3 6 (m,5Η), 6.73-6.76 ( m, 1 H ) &gt; 6.2 1 -6.22 ( m, 1 H ) &gt; 4.93 -4.96 ( m, 1 H ) , 3.57( s, 2H ) , 1.35 ( d, 3H, J = 7.0Hz ) ; HRMS ( ESI+ ): Theoretical 値, 427.1 5 82 ( M + H ) + ; Measured 値 ' 4 2 7. 1 5 7 4 ( Μ + Η ) +

(±) -#, (4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)-(cyano(phenyl)methyl)propanediamine, trifluoro Acetate-316- 8 (313) 1324926

A) (±) -4_(4-(3_(cyano(phenyl)methylamino)·3·ketopropylamino) 2,5-difluorophenoxy)pyridylcarboxamide according to Example 1 Preparation of Compound C of 1-6 In a similar manner, but using ((士)-February-2-phenylacetonitrile hydrochloride (Aldrich, 47 mg, 0.28 mmol substituted (±) d phenyl Ethylamine, 3-(4-(2-aminocarbazide-H-1,4-yloxy)-2,5-difluorophenylamino)-3-one-propionic acid (Compound B of Example 116) The title compound (67 mg, 72%).

B) (±) -,-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl)(hydroxy(phenyl)methyl)propanediamine, trifluoro Acetate was carried out in a similar manner to the preparation of compound E of Example 1 12, but using preparative HPLC (YMC S 10 ODS &gt; 3 0 x 5 00 mm, 34%-9 0% aqueous methanol (containing 0.1%) (30 minutes gradient of TFA), the crude product was purified, and (±)-4-(4-(3-(hydroxy(phenyl)methylamino)-3- ketopropylamino)-2, 5-Difluorophenoxy)D was converted to the title compound as the title compound (65 g, 0.14 mmol). The appropriate fractions were combined and lyophilized to give the title compound (38 mg, 4 9%) &quot;&quot;H NMR ( DMSO- ί ί ) 5 10.40 (s, 1 H ) ' 9.47 ( d, 1H, J = 7.63Hz ) ' 8.21-8.26 ( m, 1H ) * 7.99 ( -317- 8 (314) 1324926

d, 1H, J = 7.2Hz), 7.86 ( br s, 2H ) , 7.6 8 - 7.7 3 ( ms 1H ), 7.43 - 7.54 ( m, 5H ) » 6.74-6.77 ( m, 1H ) , 6.20-6.22 ( m, 2H), 3.55 (m, 2H); HRMS ( ESI + ) •• Theory 値, 43 8.1 3 78 ( M + H ) + ; measured 値, 438.1373 (M + H) +. Example 1 1 8

(± ) -iV, (2-amino-1-phenethyl)( 4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl)propanediamine, double (Trifluoroacetate) According to the conditions described in Campiani et al., Tetrahedron 2002, 58, 3689, (±) (4-(2-aminopyridin-4-yloxy)· 2,5·Difluorophenyl)-W3-(hydroxy(phenyl)methyl)propanediamine, trifluoroacetate (Compound for Example 117, 21 mg, 0.04 mmol). Cobalt boride was purchased from Alfa Aesar. The crude product was purified by preparative HP L C (YMC S 5 OD S, 10×2 5 0 m m, 10°/. to 90% aqueous methanol (with 0.1% TFA) gradient eluting for 30 min). The appropriate fractions were combined with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , J = 8.5Hz) , 8.12-8.17 ( m,1H ) &gt; 7.90-7.94 ( m, 3H ), 7.5 9-7.63 ( m, 2H) - 7.27-7.34 ( m, 4H) - 6.60-6.62 ( m , -318 - (315) (315)1324926 1 Η ) · 6.09-6.10 (m, 1Η) &gt; 5.09-5.1 0 ( m, 1 H ) &gt; 3.10- 3.50 ( m, 6H ) ; HRMS ( ESI+ ) : Theory 値, 442.1 69 1 ( M + H ) + ; measured 値, 4 4 2 · 1 6 7 8 »

4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-onepyrrolidin-3-carboxamide

A) 1-(4-Fluorophenyl)-2-ketopyrrolidine-3-carboxylic acid 4,fluoroaniline (Aldrich, 33 mg, 0.3 mmol) was added to 6,6-di at room temperature A solution of methyl-5,7-dioxaspiro[2.5]octane-4,8-dione (Aldrich, 51 mg, 0.3 mmol) in DMF (0.5 mL). The reaction mixture was stirred at 90 ° C for 2 hours, cooled to room temperature and used directly in the next step. B) #-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-furanyl D is more than hydrazin-3- EA (.) (316) 1324926 HATIJ (76 mg, 0.2 mmol) and diisoylamine (0.1 mL, 0.57 mmol) were added sequentially to 1-(4-fluorophenylylpyrrole) 3-Residual acid (0.3 mol), 4-(4-amino-2-fluoro)pyridine-2-amine (Compound B of Example 24, 21.9 mg, 〇.) in DMF (0.5 mL In the resulting mixture, the reaction mixture was stirred overnight at room temperature, and then purified by preparative HPLC using 2 mL of methanol to purify the reaction mixture to give the desired amount of hydrazine in a saturated aqueous solution of sodium hydrogencarbonate. And, and concentrated in the solvent to give the title compound (18 mg, 43%). 1 Η DMSO-heart) δ 10.76 ( br s, 1H ) , 7.95 ( d, 1H, J = ), 7.91 ( m, 1H) , 7.68 ( m,2H) , 7.50 ( m, 7.44 ( t, 1 H, 7 = 1 0.0 Hz ) , 7.24 (m, 2H) &gt; 6.70 )&gt; 6.11 ( d, 1H, J = 2.8Hz ) , 3.91 (m, 2H), 3 1 Hs J = 5.0 Hz), 2.4 1 (m, 2H); MS ( ESI+) m/z propyl </RTI> The fraction was taken into the NMR (= 7.2 Hz 1 Η ) &gt; (m, 1 Η .78 ( t, 425.15 (M + H ) +).

Fluorobenzene #-( 4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(yl)-2-keto-1,2-dihydropyridine-3-methyl Guanamine-320- (317) 1324926

A) iV-(3-carbo-4-(3-nitroindole ratio D-1,4-phenyloxy)phenyl)-1-(4-fluorophenyl)-2-keto-1,2 -dihydropyridine-3-carboxamide

Prepared in a similar manner to Example 62, from 3-fluoro-4-(3-nitropyridin-4-yloxy)aniline (Compound A of Example 72) to give a yellow-brown solid. The title compound (89%). NMR (CD3〇D) δ 9.13 ( s, 1Η ) , 8.72 (dd, 1Η, J = 8.4Hz ) , 8.60 ( d, 1H, J = 6Hz ) , 8.07 ( d, 1H, J = 12Hz ), 8.01- 7.99 ( m, 1H) &gt; 7.5 8 -7.5 5 ( m, 2H) &gt; 7.45 ( t, 1H, J =8Hz ) , 7.40-7.3 2 ( m,3H ) ,6.99 ( d,1 H, J = 4Hz ), 6.76 ( t, 1 H, J = 8Hz ) ; MS ( ESI+ ) m/z 46 5.1 8 ( M + H ) + B) iV- (4-(3-Aminopyridin-4-yloxy) , 3-fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxamide, in a similar manner to Step C of Example 59 preparation. The title compound (58%) was obtained as a white solid. 4 NMR (DMSO-heart) 5

12.07 ( s, 1 Η ) &gt; 8.59 ( dd, 1H, J = 7.6, 2.4Hz ) , 8.14 ( dd , 1H , J = 6.4 , 2Hz ) &gt; 8.04 ( s, 1 H ) &gt; 7.99 ( dd, 1H, J-321 - (318) 1324926 =13.2, 2·4Ηζ), 7.66 (d, 1 Η, J = 5.2 Hz), 7.63-7.60 (m, 2Η), 7.46-7.4 1 (m, 3H), 7.22 ( t, 1 H, J = 9.2 Hz ) , 6.74 ( t, 1 H, J = 7.2 Hz ) , 6.46 ( d, 1H, J = 5.2 Hz ), 5.26 ( br s, 2H ) ; MS ( ESI+ ) :m/z 435.26 (M + H)+. Example 1 2 1

#-( 3 -Fluoro-4 -( 3 -(pyrrolidin-3-ylmethylamino)pyridin-4-yloxy)phenyl)-1-( 4·fluorophenyl)-2- Keto-], 2-dihydropyridine-3-carboxamide, hydrochloride

3 -Metylpyrrolidine-1-carboxylic acid tert-butyl ester (CB Research and Development Inc., 28 mg, 0.14 mmol), acetic acid (5//L, 0.084 mmol) and triethylene oxide Sodium borohydride (23 mg, 0.104 mmol), added to #-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)- 2-keto-1,2-dihydropyridine-3-carboxamide (Example 120, 30 mg, 0.07 mmol) (in 1 mL DCE). After stirring at room temperature for 6 hours, a second portion (23 mg) of sodium triethoxyhydride borohydride was added. After stirring at room temperature for 2 hours, 4N HCl (5 mL) in dioxane was added to the mixture and stirred at room temperature for an additional hour. The reaction solution was diluted with 1% methanol/ethyl acetate (1 〇 mL) and was taken with saturated sodium bicarbonate (1 mL).

-322- (319) 1324926 Wash. The aqueous phase was back-extracted with 10 mL of 10% MeOH/EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude product obtained was purified by preparative HPLC. The appropriate fractions were concentrated to remove methanol and then basified with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with 10% methanol / ethyl acetate (3 x 20 mL), and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue obtained was purified by EtOAc EtOAc (EtOAc) 4 NMR ( DMSO-i/, 5 ) δ 12.17 ( s, 1 Η ) ' 8.59 ( dd, 1H, J = 7.6, 2Hz )&gt; 8.30 ( s, 1H ) » 8.16 ( dd, 1H, J = 6.4, 2Hz &gt; 8.10 (dd, 1 H, J = 12.8, 2Hz) &gt; 8.00 ( d, 1H, J = 6.4Hz) -7.64-7.5 8 ( m, 3H) » 7.52 ( t, 1H, J = 9.2Hz » 7.46-7.42 ( m, 2H ) , 7.00 ( d,1 H, J = 6Hz ) , 6.75 ( t, 1H, J = 7.2Hz) &gt; 3.72-3.64 ( m, 3H ) - 3.3 7-3.26 ( m, 1H ), • 3.17-3.10 (m,lH) « 2.97-2.92 ( m, 1 H ), 2.74-2.66 (m, 1H) &gt; 2.10-2.03 ( m, 1H ) * 1.75-1.68 ( m, 1H) ; MS ( ESI+ ): m/z 5 18.29 (M + H) +. Example 122

(320) 1324926 JV-(4-(3-(2-Aminoethylamino)pyridin-4-yloxy-3-fluorophenyl)-1-(4-fluorophenyl)-2-one -1,2-dihydropyridine-3-carbamidamine, hydrochloride

The title compound (52%) was obtained as a white solid. NMR (DMSO-ofd) δ 12.10 (s, 1H) &gt; 8.52 (dd, 1H, J = 7.6, 4.2 Hz) - 8.25 ( s, 1 H ) &gt; 8.09 ( dd, 1 H, J = 6.8, 2.4 Hz)

&gt; 8.06-8.02 ( m, 1H) &gt; 7.96 ( d, 1H, J = 6.4Hz) &gt; 7.56- 7.52 ( m, 3H ) , 7.42 - 7.34 ( m, 3H ) , 6.92 ( d, 1 H, J = 6Hz ) , 6.68 ( t, 1 H, J = 6.8Hz ) , 3.50-3.48 (m, 2H), 3.00-2.99 ( m, 2H) ; MS ( ESI+) : m/z 47 8.29 ( M + H ) + Example 1 2 3

(3-Fluoro-4-(3-(hexahydropyridin-2-ylmethylamino)pyridin-4-yloxy)phenyl)-1-(4-indolyl)-2-indenyl- 1,2-carbazide-3-tosaline, hydrochloride was prepared in a similar manner to Example 1 2 1 to give

The title compound (71%) NMR (DMSO-A) δ 12.17 ( s, 1 Η ) - 8.59 ( dd, 1H, J = 7.2, -324- (321) 1324926

2Hz) , 8.5 1 ( s, 1 H ) , 8.16 ( dd, 1 H, J = 6.8, 2Hz ), 8.11 ( dd, 1H, J = 13.2, 2.4Hz) , 8.02 ( d,1 H, J = 6.4 Hz ), 7.63 - 7.5 8 ( m, 3H) &gt; 7.51 ( t, 1H, J = 8.8Hz) - 7.46 - 7.41 ( m, 2H) , 7.01 ( d, 1H, J = 6Hz) , 6.75 ( t, 1H, J = 6.8Hz), 3.70-3.63 (m, 1H) - 3.52-3.45 (m, 1H ), 3.30-3.27 (m, 2H) &gt; 2.8 6-2.84 ( m, 1 H ) &gt; 1.95- 1 .93 (m, 1H) &gt; 1.80-1.62 (m, 3H) &gt; 1 .5 8 - 1 .44 ( m, 2H ); • MS ( ESI+ ) m/z 532.31 ( M + H) + . Example 124

φ (4-(3-(3-dimethylamino)-2,2-dimethylpropylamino)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl) 2-keto-1,2-dihydropyridin-3-carboximine, hydrochloride was prepared in a similar manner to Example 1 2 1 to give

The title compound (58%) was obtained as a white solid. 'H NMR (DMSO-^d) δ 12.10 ( s, 1H) &gt; 8.57 ( s, 1H) &gt; 8.52 ( dd, 1 H, J = 7.6, 2Hz ) , 8.09 ( dd, 1 H, J = 6.8 , 2.4Hz ) &gt; 8.03 ( dd, 1H, J = 13.2, 2.4Hz ) , 7.90 ( d, 1H, J = 6.4Hz ), 7.56-7.5 1 ( m,3H ) , 7.44 ( t, 1 H,= 8.8Hz ), 7.39-7.35 (m,2H) , 6.92 (d,1H,J = 6.4Hz) ,6.68 (t, 8 -325- (322) 1324926 1H, J - 7.2Hz ) ,3.33 ( s,2H ), 3.10 ( s, 2H ) , 2.77 ( s, 3H) &gt; 2.76 ( s, 3H ) , 1.07 (s, 6H) ; MS ( ESI+ ) m/z 5 4 8.3 4 ( M + H ) + . Example 1 2 5

iV-( 4-(3-(2-Amino-3-hydroxypropylamino)pyridin-4-yloxy)-3-phenylphenyl)-1-(4-fluoro(phenyl)-2 - Mercapto-1,2 - one gas oxime hydrazine-3-carboxylic acid amine, hydrochloride

The title compound (65%) was obtained as a white solid. H NMR

(DMSOO δ 12.10 ( s, 1H) &gt; 8.52 ( dd, 1H, J = 1.2, 2Hz) &gt; 8.30 ( s, 1 H ) , 8.09 ( dd, 1H, / =6.8, 2.4Hz), 8.03 ( dd , 1H, J = 12.8, 2Hz ) , 7.96 ( d, 1 H, J = 6.4Hz ) , 7.5 6-7.5 2 ( m, 3H ) , 7.4 3 - 7 · 3 5 ( m,3 H ) , 6.93 ( d, 1 H, J = 6Hz ) , 6.68 ( t, 1H, J = 7.2Hz) , 3.6 5 -3.5 6 ( m, 2H ) , 3.4 8 -3.45 ( m, 3H ) ; MS ( ESI+ ) m/z 5 0 8.2 7 ( M + H) +. Example 126

-326- (323) 1324926

1-(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl) Urea, hydrochloride

A) tert-butyl 4-chloro-3-carbamidinyl-2-ylcarbamate n-butyllithium (13·7 mL, 21.9 mmol, 1.6 Μ) at -78 ° C under nitrogen atmosphere , added to hexane (4-chloropyridin-2-yl)amine carboxylic acid terpene vinegar (CB Research and Development Inc., 2.0 g, 8,75 mmol) (in 18 mL THF) ). After stirring at -78 ° C for 45 φ minutes, a solution of DMF (1.93 mL) in THF (2 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 30 minutes, then allowed to slowly warm to room temperature. The reaction mixture was quenched with 1N aqueous hydrochloric acid and then saturated aqueous sodium bicarbonate ( 50 mL) was basified and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The title compound (0.95 g, 42%) was obtained as a white solid. NMR ( DMSO-A ) δ 10.44 ( s, 1H ), -327- (324) 1324926 10.13 (s,lH) &gt; 8.47 ( d, 1H, J = 5.2 Hz) , 7.40 (d, lH, J = 5.6 Hz), 1.48 (s, 9H).

B) tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-carboxyridin-2-ylcarbamate, sodium hydride (60%, 180 mg, 4.44 mmol) 2-fluoro-nitroguanidine (Aldrich, 700 mg, 4.44 mmol) (in 5 mL DMF). After stirring at room temperature for 5 minutes, a solution of 4-chloro-3-methylpyridylpyridin-2-ylaminecarboxylic acid tert-butyl ester (0.95 g, 3.7 mmol) in 5 mL of DMF was added to the mixture. in. The reaction mixture was stirred at 60 ° C for 20 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate (50 mL), and then washed with 10% aqueous lithium chloride solution (2×40 mL) and aqueous sodium hydrogen carbonate (40 mL). Dry over anhydrous magnesium sulfate and concentrate in vacuo. The title compound (1.0 g, 72%) was obtained as a yellow oil. NMR (CD3OD) δ 10.59 ( s, 1 Η ), 8. 3 7 - 8.2 5 ( m, 2 Η ) , 7.6 7 ( t,1 Η,·· = 7 · 6 Η z ) ' 6.6 0 ( d, 1 Η, J = 6Hz ) &gt; 1.59 (s, 9H). (325) 1324926

C) 4-(2-Fluoro-4-nitrophenoxy)-3-(hydroxymethyl)pyridin-2-ylamine tert-butyl formate

Sodium borohydride (7.6 mg, 0.20 mmol) was added to 4-(2-fluoro-4-nitrophenoxy)-3-carboxyridin-2-ylamine formic acid at 〇 ° C A solution of butyl vinegar (75 mg, 0.2 mmol) in methanol (1 mL). After stirring at 0 °C for 30 minutes, the reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL). The reaction was diluted with ethyl acetate (5 mL) and the layers were separated. The organic layer was dried with EtOAc EtOAc m. 4 NMR ( CD3 〇 D ) δ 8.28 ( dd, 1H, J = 1 0.4, 2.8 Hz ) &gt; 8.22-8.18 ( m, 2Η ) - 7.45 ( t, 1H, J = 8.4Hz) , 6.68 (d, 1 H, J = 6 Hz), 4.8 1 (s, 2H), 1.57 (s, 9H); MS ( ESI+ ) m/z 3 80.27 ( M + H ) + .

D) 4-(4-Amino-2-fluorophenoxy)-3-(hydroxymethyl)pyridin-2-ylaminecarboxylic acid tert-butyl ester-329-8 (326) 1324926 according to Example 5 The title compound was obtained as a white solid. 4 NMR (CD3OD) 5 8.14 (d, 1H, J = 6Hz), 6.97 (t, 1H, J = 8.8Hz) ’ 6.62-

6.54 ( m, 2H ) , 6_46 ( d, 1H, J = 6.4 Hz ) , 4.64 ( s, 2H ), 1.55 ( s, 9H ) ; MS ( E S Γ ) m/z 350.11 (M + H) +. E ) I - (4-(2-amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorobenzene#yl)-3-(2-(4-fluorophenyl)ethyl The title compound was obtained as a white solid in the form of the hydrochloride as a white solid. 1 Η NMR ( DMSO-^6 ) δ 10.99 ( s, 1 Η ) * 1 0.56 ( s, 1 Η ), 7.82 ( d, 1 H, J = 7.2 Ηζ), 7.74 ( dd, 1 Η, y = 13.6 , 2·8Ηζ )&gt; 7.31-26 (m, 3H) &gt; 7. 1 9-7.02 ( m, 3H ) , 6.16 ( d, 1H, J = 7.2Hz) , 4.57 ( s, 2H) , 3.69 ( s, 2H) ; MS ( ESI+ ) m/z 429.1 6 ( M + H ) + .

-330- 1 (4-(2-Amino-3-((methylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorobenzene) Base) ethyl hydrazide) urea, hydrochloride (327) 1324926

A) (2-Bis-B-Ethyl-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)methyl(methyl)aminecarboxylic acid tert-butyl ester

Under 〇t: successively, methylamine (240//L, 0.24 mmol, 2M' in THF), acetic acid (14//L, 0.24 mmol) and sodium triethoxy borohydride (400 mg) , 1.89 mmol), added to the tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-carbenylpiperidine-2-ylcarbamate (Compound 126, Example 126, 75 Mg, 0.2 mmol) (in 1 mL of dichloroethane). After stirring at room temperature for 16 hours, the EtOAc EtOAc EtOAc m. . Purification of the crude product obtained by flash column chromatography (20%MeOH /EtOAc) Butyloxy)-3-(methylamino)methyl)pyridin-2-ylaminecarboxylic acid tert-butyl ester (37 mg, 47%). Adding di(tert-butyl) dicarbonate (Aldrich, 32 mg, 0.15 mmol) to 4-(2-fluoro-4-nitrophenoxy)-3-((methylamino)methyl)pyridine T-butyl 2-methylglycolate (48 mg, 0.122 mmol) and DMAP (16 mg, 0.134 mmol) (in 1 mL of dichloromethane). After stirring at room temperature for 30 minutes, a bis- and oxime-BOC substance (2:1) was observed. Add another DMAP and dicarbonate (T-butyl ester -331 - 8 (328) 1324926). After stirring for 30 minutes at room temperature, EtOAc EtOAc m. %). 4 NMR ( CD3OD ) δ 8.50 ( d, 1H, J = 5.2Hz) , 8.15-7.97 ( m, 2Η ), 7.43 ( d, 1H, J = 5.6Hz ) &gt; 7.07 ( t, 1 H, J = 8 , 4 Hz ) &gt; 4.64 ( s, 2H ) &gt; 2.83 ( s, 3 H ) &gt; 1.44 ( s, 27H ) ; MS ( ESI+ ) m/z 5 93.3 4 ( M + H ) + .

B) 1-(4-(2-Amino-3-((methylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorobenzene) The title compound (60%) was obtained as a white solid in the form of the hydrochloride as a white solid. 1 H NMR ( DMSO-ί/, ί ) &lt;5 1 0.8 8 ( s, 1 Η ) &gt; 10.35 (s, 1H) &gt; 7.45-7.42 ( m, 1H ) &gt; 7.30 ( m, 3H ) &gt 7.11-7.07 ( m, 4H ) &gt; 6.52 ( d, 1H, J = 7.2Hz ) &gt; 4.02 ( s, 2H ) &gt; 3.66 ( s, 2H ) &gt; 2.54 ( s, 3H ) ; MS ( ESI+ m/z 442.3 0 ( M + H ) + Example 1 2 8

F HO, /^

- 332 - 8 (329) 1324926 pyridine-4-yloxyurea, trifluoro-I(4-(2-amino-3-((2-hydroxyethylamino)methyl)pyridyl)-3- Fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)acetate

A) (2-80(:-Amino-4-(2-fluoro-4-nitrophenoxy))methyl(2-hydroxyethyl)aminecarboxylic acid tert-butyl ester according to Example 1 27 In a similar manner to Step A, the title compound (14%) was obtained as a yellow oil. 1 CD3 〇D ) (5 8.30 ( dd, 1 H, J = 10.4, 2.8 Hz ) &gt; 8. m, 2 H ), 7.52 ( t, 1 H, J = 8.4 H z ) , 6.64 ( d: 7.2 Hz ) , 4.71 (s, 2H) &gt; 3.65 ( t, 2H, J = 6Hz ) m, 2H ) &gt; 1.57 ( s, 18H) ; MS ( ESI+ ) m/z 523 x + B) 1-(4-(2-amino-3-((2-hydroxyethylamino)methyl)oxy)-3-fluoro Phenyl)-3-(2-(4-fluorophenyl)acetamidine trifluoroacetate was obtained in the same manner as in the step C of Example 59. NMR ( DMSO-i/tf ) δ 11.12 ( s, 1 Η ), 1 Η ) &gt; 8.01 ( d, \U, J = 6.8Hz ) &gt; 7.87 ( dd, 1H, mouth pyridine-3 - Base preparation, H NMR ( 23-8.20 ( , 1H, J = , 3.40 ( • 32 ( M + H ) 陡 steep - 4 -) urea, preparation, - (43% 10.69 (s, J = 12.8) , -333- 8 (330) 1324926 2.4Hz ) , 7.5 3 - 7.40 ( m, 4H ) , 7.26-7.20 (m, 2H) 6.68 ( d, 1H, J = 7.2Hz ) &gt; 4.34 ( s, 2H ) , 3.81 ( s, 2H) , 3.75 ( t, 2H, J = 7.2Hz ) &gt; 3.18 ( m, 2H ) ; MS ( ESI + ) m/z 472.24 ( M + H ) +. Example 1 2 9

iV-(4-(2-Amino-3-((2-aminoethylamino)methyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl) -2-keto-1,2-dihydropyridine-3-carboxamide, trifluoroacetate

N〇2 A) (2-BOC-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)methyl(2-BOC-aminoethyl)aminecarboxylic acid III The title compound (] 9%) was obtained as a yellow oil. 4 NMR ( CD3 〇 D ) 0 8.3 0 ( dd, 1 H, J = 10, 2.4 Hz ) &gt; 8.2 3 - 8.20 ( m, 2H ) - 7.52 ( t, 1 H, J = 8.4 Hz ) - 6.61 ( d, 1 H, J = 7.2 Hz ) &gt; 4.65 ( s, 2H ) , 3.39 ( m, 2H ) , 3.25 ( m, 2H ),

-334- (331) 1324926 1.61 ( s, 27H ) ; MS ( ESI+) m/z 622.4 7 ( M + H ) B ) ( 4- ( 2-Amino-3-((2-aminoethylamino)) Methyl oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-keto-1 pyridine-3-carboxamide, trifluoroacetate according to Example 59 Step C In a similar manner, then, in the same manner as in Example 62, 醯# was formed, thus, a material (28%) as a white solid in the form of trifluoroacetic acid was obtained. Η NMR (DMSO- Heart) δ 12.09 ( s 8.52 ( dd, 1H, J = 7.2, 2Hz ) , 8.09 ( dd, 1 H, J = ), 7.99 ( dd, 1H, J = 12.8Hz ) , 7.89 ( d, 1 H, ) , 7.5 6-7.5 2 ( m, 2H ) &gt; 7.49-7.47 ( m, 1 H ), (m, 3H ) , 6.68 ( t,1 H, J = 7.2Hz ) , 6·07 ( d 7.2Hz ) &gt; 4.25 ( s, 2H ) , 3.20 ( m, 2H ) , 3.08 ; MS ( ESI+ ) m/z 5 0 7.2 3 ( M + H ) +. + 〇) 卩 Β疋 -4 - , 2- Hydropyridyl-reduced amine compound title compound, 1Η), =6.4, 2Hz J = 6.4Hz 7.39-7.33 ,1Η, J = (m, 2H )

#- (4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy))-1-(4-fluorophenyl)-2-one-1,2-dihydropyridine 3-methylindole 3-fluorophenylamine, trifluoro 8 - 335- (332) 1324926 acetate

A) 3-((t-butyldimethylsilyloxy)methyl)-4-(2.fluoro-4-n-nitrophenoxy)pyridine-2-ylcarbamic acid tert-butyl ester Imidazole (21 mg '0·31 mm〇l) and tert-butyldimethylsilyl chloride (40 mg, 0.26 mmol) were added to 4-(2-fluoro-4-nitrophenoxy)- T-butyl 3-(hydroxymethyl)pyridin-2-ylaminecarboxylate (Compound C of Example 126, 100 mg, 0.26 mmol) (3 mL dichloromethane). After stirring at room temperature for 1 hour, a second portion of tert-butyldimethylsilyl chloride (40 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then diluted with dichloromethane (10 mL), washed with water (1 〇m), dried over anhydrous sodium sulfate and concentrated in vacuo . The title compound (1 〇 2 mg, 79%) was obtained as a white solid. . 4 NMR ( CD3OD ) &lt;5 8.16 ( dd, 1H, J = 10.4, 2.8 Hz ) , 8.09 · 8.05 ( m, 2H ) , 7.29 (t, 1H, J = 8.4 Hz ) &gt; 6.53 ( d, 1H, J = 5.6 Hz ) &gt; 4.84( s, 2H ) · 1.43( s, 9H ) , 0.84 ( s, 9H ) , 0.00 ( s, 6H ) ; MS ( ESI+ ) m/z 494.29 ( M + H ) + ( 333) 1324926

Nh2 B) 4-(4-Amino-2-fluorophenoxy)-3-((t-butyldimethylammoniumoxy)methyl)pyridine 2-ylaminecarboxylic acid tert-butyl ester

The title compound (95 mg, 98%). 4

NMR (CD3OD) δ 7.90 ( d, 1 H, J = 6 Hz), 6.76 (t, 1 Η, J = 8.8 Hz), 6.43 ( dd, 1 H, J = 12.8, 2.8 Hz), 6.3 9-6.3 7 ( m, 1 H ) , 6.21 ( d,1H, J = 5.6 Hz ) , 4.85 ( s, 2H ), 1.39 ( s, 9H) , 0.81 ( s, 9H) , 0.01 ( s, 6H) ; MS ( ESI+ ) m/z 464.34 ( M + H ) +.

C) 3-((Tertiary butyl dimethyl decyloxy)methyl)-4-(2-fluoro-4-(1·(4-fluorophenyl)-2- keto-I,2 -Dihydropyridine-3-carboxamido) phenoxy)pyridin-2-ylaminecarboxylic acid tert-butyl ester was prepared in a similar manner as Example 62 to give the title compound ( 86%). 4 NMR (CD3OD) 6 8.5 1 ( dd, 1H, J = 7.6, 2.4 Hz ) &gt; 7.93 ( d, 1H, J - 6Hz ) (334) 1324926 , 7.84 - 7.80 ( m, 2H) - 7.40-7.3 7 ( m, 2H ) &gt; 7.21-7.15 ( m, 3H ) &gt; 7.06(t, 1 H, J = 8.8Hz ) &gt; 6.57 ( t, 1H, J = 6.8Hz ) &gt; 6.26 ( d, 1 H , J = 5.6Hz ) &gt; 4.86 ( s, 2H ) &gt; 1.40 (s, 9H ) - 0.82 ( s, 9H ) &gt; 0.00 ( s, 6H ) ; MS ( ES1+ ) m/z 679.34 ( M + H ) +.

D) 4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-methylamino)phenoxy)·3- (Hydroxymethyl)pyridin-2-ylaminecarboxylic acid tert-butyl ester Gasification of tetrabutyl saddle (260 / / L, 0.264 mmol, 1 M in THF) was added to 3-(( Third butyl dimethyl decyloxymethyl) methyl)-4-(2-fluoro-4-(i(4-fluorophenyl))-2-keto-1,2-dihydropyridine-3 -Methylamino)phenoxy)pyridin-2-ylaminecarboxylic acid tert-butyl ester (119 mg, 0.176 mmol) (in 2 mL THF). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate (20 mL), then washed with water and brine (10 mL each) and dried over magnesium sulfate Concentrate. The title compound (66 mg, 66%) was obtained eluted elute NMR (CD3OD) δ 8.62 ( dd, 1H, J = 7.2, 2Hz ) , 8.04 ( d, 1 H, J = 6Hz ) , 7.94-7.90 ( m, 2H ) &gt; 8 -338- (335) 1324926

7.50-7.46 ( m, 2H) · 7.33-7.25 (m, 3H) &gt; 7.20 ( t, 1H, J =8.8Hz ) , 6.67 ( t,1 H, J = 6_8Hz) , 6.40 ( d,1H, J = 5.2 Hz), 4.78 ( s, 2H) , 1.49 ( s, 9H) ; MS ( ESI+) m/z 565.17 ( M + H) + 〇 E) #-(4-(2-Amino- 3-(( Hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-one-1,2-dihydropyridine-3-carboxamide 'three • Fluoroacetate is added to 4-(2-fluoro-4-(1-fluorophenyl)-2-one) at room temperature in 4 NH C1 (in 10 m L of dioxane) Tert-butyl-1,2-dihydropyridine-3-carbamido)phenenyl)-3-(hydroxymethyl)pyridin-2-ylaminecarboxylate (33 mg, 0.058 mmol) (on 2 In mL THF). The reaction mixture was stirred at room temperature for 8 hours and then concentrated in vacuo. The obtained crude product was purified by preparative HPLC. The appropriate fractions were concentrated, and toluene (2×3 mL) was added and the obtained mixture was concentrated again. The residue obtained was purified by EtOAc EtOAc (EtOAc) NMR (DMSO·heart) δ 1 2.0 8 ( s, I Η ) , 8.5 2 ( dd, 1 Η,·· = 7.2, 2 Η ζ ) , 8.0 9 ( dd, 1 Η, J = 6.8, 2 Hz ), 7.99 ( dd,1Η, J = 12.8, 2_4Hz) , 7.8 1 ( d, 1 H, J = 7.2Hz ) , 7.5 6 - 7.5 2 ( m, 2 H ) &gt; 7.48- 7.46 ( m, 1 H ) , 7 · 3 9 - 7.3 4 ( m,2 H ) - 7.30 ( t, 1H, J = 9.2Hz ) , 6.67 ( t, 1 H, J = 7.2Hz ) , 6.2 1 ( d,1H, J =

7.2 Hz) , 4.58 ( s, 2H ) ; MS ( ESI+ ) m/z 465.1 7 ( M + H -339- (336) 1324926 + Example 1 3 1

1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4- Fluorophenyl)ethylidene)urea, dihydrochloride

N〇2

A) 4-(2-Fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridine-2.amine was rinsed with vacuum/argon to give 4-( 2-Fluoro-4-nitrophenoxy)-3.iodopyridin-2-amine (Compound C of Example 34, 100 mg, 0.27 mmol) '2-Ethynyl 11 is steeper (Aldrich, 56〆) A solution of L, 0.54 mmol), triethylamine (2 mL), and THF (2 mL) was degassed and then treated with Cul (6 mg, 0.032 mmol) and (Ph3P) 4pd (20 mg, 0.017 mmol) . The reaction mixture was heated at 60 ° C for 45 minutes, cooled to room temperature and diluted with ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then evaporated and evaporated. The title compound was obtained as an olive green solid (5 mg, 57%). ). NMR (DMSO-heart) &lt;5 8.53 (d, 1 H, J = 5.1 Hz), 8.42-8.3 7 (m, 1 H), 8..19-8.12 (m, lH), 7.96 (d, lH) , J=5.6Hz) , 7.85-7.78 (m,lH) 7.71 ( d, 1H, J = =7.6Hz ), 7.52 ( t, 1 H, J =8.6Hz ), 36 ( ddd, 1 H, J = 7.6, 5.1 , 1.0 Hz ) , 6.71 (s, 2H ) &gt; 21 ( d, 1H, J = 5.6 Hz ); MS ( ESI+ ) : mi/z 3 5 1.25 (

M + H) +.

B) 4-(4-Amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridine-2.amine in the same manner as in the step C of Example 4-(2-Fluoro-4-nitrophenoxy)-3-(2-(pyridine) by using zinc powder (65 mg, 1.0 mmol) and chlorinated saddle (53 mg, 1.0 mmol) Reduction of 2-yl)ethynylpyridin-2-amine (35 mg, 0.10 mmol) afforded the title compound. The title compound (25 mg, 78%) mp. C) 1-(4-(2-Amino-3-(2-(pyridin-2-yl)ethynyl)pyridin-4-yl-341- (338) 1324926 oxy)-3-fluorophenyl) 3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride, in the same manner as in the step E of Example 11, from 4-(4-amino-2-fluoro) Phenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (25 mg, 0.078 mmol) and 2-(4-fluorophenyl)ethenyl isocyanate formed in toluene The title compound was prepared as a EtOAc solution (Comp. D. The obtained crude product was purified by preparative HPLC (layer B). The title compound (1 8 mg, 40%) was obtained as a brown oil. 'H NMR ( DMSO-^6 ) &lt;5 11.06 (s,1Η ),

10.63 ( s, 1 Η ) , 8.62 ( d, 1H, J = 4.6Hz ) , 8.23 ( s, 1H ), 7.99 ( d, 1 H, J = 7.1Hz) &gt; 7.94-7.84 ( m, 3H ), 7.87-7.76 ( m, 1H) · 7.51-7.42 ( m, 3H) &gt; 7.39-7.32 ( m, 2H ) &gt; 7.21 -7. 1 3 ( m, 2H ) &gt; 6.30(d, 1H, J = 7.1 Hz) &gt; _ 3.74 (s, 2H) ; MS ( ESI+ ) : m/z 498.11 (M + H)+. Example 〖3 2

(4-(2-Amino-3-(4-(2-amino-2-mercaptoethyl)phenyl)D) is 8-83-(339) 1324926 pyridine-4-yloxy)-3 -fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxamide, hydrochloride in the same manner as in Example 62, from 2 -(4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)phenyl)acetamide (Compound C of Example 78, 18 mg, 0.05 The title compound was prepared as the title compound (m.p.). The obtained crude product was purified by preparative φ HPLC (layer B), and then the trifluoroacetic acid salt was converted to hydrochloride (15 mg, 50%). H NMR( DMSO-i/e ) δ 12.11 ( s, 1 Η ) , 8.58-8.54 ( m,1H) &gt; 8.13 (dd, 1 H, J = 6.6, 2.2 Hz), 8.00 ( dd, 1H, J = 12.6, 2.2 Hz) &gt; 7.96 ( d, 1H, J = 7.7 Hz) &gt;· 7.5 9 ( dd, 2H, J = 8.8, 4_9Hz) &gt; 7.47-7.41 ( m, 6H ) &gt; 7.40- 7.3 5 ( m, 3H ) , 6.94 ( s, 1 H ) , 6.72 ( t, 1 H, J = 7.1 Hz) &gt; 6.38 ( d, 1H, J = 7.1 Hz ) , 3.44 ( s, 2H ) ; MS ( ESI+ ) : m/z ® 568.23 ( M + H ) +. Example 1 3 3

1 - ( 4 -( 2 -amino-3-(2-(5-aminopyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3- (2 - (4-fluorophenyl)ethenyl) -343- 8 (340) 1324926 Urea, dihydrochloride

A) 6-(2-(Trimethyldecyl)ethynyl)pyridin-3-amine

Treatment of 3-amino-6-bromopyridine with Cul (60 mg, 0.32 mmο 1 ) and (Ph3 P ) 4P d (1 1 4 mg &gt; 0.10 mmol) (A1 fa A esar &gt; 1.0 g &gt 5.8 mmol ), a mixture of ethynyl trimethyl decane (1.7 mL, 17.3 mmol) 'CH3CN (3 mL), DMF (2 mL) and triethylamine (2 mL), and the mixture was stirred at 45t 1.5 hours. More ethynyltrimethylnonane (1.7 mL, 17.3 mmol) was added to the reaction mixture, and the mixture was stirred for 2 hr. The mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The title compound (0.75 g, 68%) was obtained eluted eluted eluted eluted . 'H NMRC DMSO-rftf) δ 7.85 (s, 1H ) , 7.15 (d, 1H, J = 8.1 Hz), 6.81 (d, 1 H, J = 8.1 Hz), 5.76 (s, 2H), 0.19 (s, 9H) ; MS ( ESI+): m/z 191.20 ( M + H ) + »

BocHN

Si(CH3)3 -344- (341) 1324926 B) 6-(2-(Trimethyldecyl)ethynyl)pyridin-3-ylcarbamic acid tert-butyl ester

The solution of 6·(2-(trimethyldecyl)ethynyl)pyridine-3-amine (〇5 g '2.6 mmol) in THF was cooled to -5 ° C, and 1·0 M NaHMDS (5.3 mL, 5.5 mmol in THF) was added dropwise thereto. The mixture was warmed to -20 ° C, and the BOC anhydride was added all at once, and the mixture was allowed to warm to room temperature over a period of 25 minutes. The mixture was dissolved in ethyl acetate and a saturated aqueous solution of sodium bicarbonate, and ethyl acetate layer was separated and rinsed with brine. The ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the crude product obtained by flash chromatography on EtOAc (EtOAc: EtOAc:EtOAc -i^) &lt;5 9.80 ( s, 1H ), 8.58 ( d, 1H, J = 2.0Hz) , 7.8 6 ( dd, · / = 8.6,2 · 5 Hz, 1H ) &gt; 7.44 ( d, 1H , J = 8.6 Hz ) , 1.47 ( s, 9H) * 0.22 ( S, 9H) ; MS ( ESI+ ) : m/z 291.34 (M + H)+.

BocHN c) 6-ethynylpyridin-3-ylaminecarboxylic acid tert-butyl ester 6-(2-(trimethyldecyl)ethynyl)pyridin-3-ylaminecarboxylic acid tert-butyl ester (62 mg, 0.21 The solution of mmol) in THF (5 mL) was cooled to -15 ° C and treated with 1.0 四 tetrabutylammonium fluoride (Aldrich' 0.25 mL, 0.25 mmol) and stirred 40-345-8 ( 342) 1324926 minutes. The mixture was concentrated in vacuo and taken up in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The title compound (45 mg, 100%) was obtained eluted elute 4 NMR (DMSO-d6) δ 9.78 ( s, 1 Η ) , 8.58 ( d, 1H, J = 2.5 Hz ) , 7.92 - 7.84 ( m, 1H ) &gt; 7.46 ( d, 1H, J = 8.6 Hz) - 4.17 ( s, 1 H ), 1.47 ( s, 9H) ; MS ( ESI+) : m/z 2 19.20 ( M + H ) +

D) 6-(2-(2-Amino-4-nitrophenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylaminecarboxylic acid tert-butyl ester

In the same manner as in the step A of Example 46, the third butyl 6-ethynylpyridin-3-ylcarbamate and the 4-(2-fluoro-4-nitrophenoxy)-3·iodine The pyridin-2-amine (Compound C of Example 34) gave the title compound. 4 NMR (DMSO-iZd) &lt;5 9.77 (s, 1H) &gt; 8.56 (s, 1H) . 8.40-8.36 ( m, 1H ) &gt; 8.14 ( d, 1H, J = 8.8 Hz ) &gt; 7.94 ( d, 1H, J = 5.5Hz) * 7.89 ( d, 1H, J = 8.2Hz ) , 7.59 ( d, 1H, J = 8.8Hz ) . 7.5 3 -7.47 ( m, 1 H ) , 6.63 ( br s, 2H), 6.21 (d, 1H, J = 6.0Hz) &gt; 1.47 ( s, 9H ) ; MS ( ESI+ ) : m/z 466.22 ( M + H) + . -346- 8 (343) 1324926

E) 6-(2-(2-Amino-4-(4-amino-2-fluorophenoxy))ethynyl)pyridin-3-ylaminecarboxylic acid tert-butyl ester according to Example 11 In the same manner as in the step C, the title was prepared from the tert-butyl φ 2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)pyridin-3-ylaminecarboxylate. Compound ( ). MS ( ESI+): m/z 43 6.29 (M + H) +. Pyridine-3-yl 6-(2-(ethynyl) quantitative yield

F) 6-(2-(2-Amino-4-(2-fluoro) 4-(3-(2-(4-g(indolyl)))yloxy)pyridin-3-yl) Ethyl acetyl)pyridic acid tert-butyl ester in the same manner as in the step E of Example 11, from 2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)pyridine The title compound ( ) was prepared as the -3 - butyl carbamic acid tert-butyl ester. NMR ( DMSO-^6 ) δ 11.02 ( s, 1 Η ), 1 Η ) &gt; 9.78 ( s, 1 Η ) &gt; 8.59 ( d, 1 Η, J = 2.5 Hz ) dd, 1 Η, J = 8.6, 2.5Hz), 7.81 ( d, 1H, J =: 7.75 ( dd, 1H, J = 12.7, 2.5Hz ) , 7.68 ( d, 1 H, , phenyl) b-stamp-3 -ylamine 6-(2- (ethynyl) yield 80% 10.56 (s, , 7.91 ( ;.6Hz), J = 8.6 Η z -347- (344) 1324926 ).7.44-7.2 7 ( m, 5H ) &gt; 7.19-7.13 ( m, 2H ) &gt; 6.47 ( s, 2H ) &gt; 5.86-5.81 (m, 1H) &gt; 1.48 (s5 9H) ; MS(ESI+) :m/z 61 5.34 ( M + H ) +. G ) (4-(2-Amino-3-(2-(5-aminocyclopyridin-2-yl)ethynyl)pyridin-4-yloxy)-3-fluorophenyl)-3- ( 2- (4-fluorophenyl)ethinyl)urea, dihydrochloride

Treatment of 6-(2-(2-amino-4-(2-fluoro-4-(3-(2-)4-fluorophenyl)ethinyl))yloxy) with TFA (0_5 mL) a solution of tert-butyl pyridin-3-yl)ethynyl)pyridin-3-ylaminocarbamate (23 mg, 0.037 mmol) in dichloromethane (2 mL·) and was taken at room temperature Stir for 1 hour. The mixture was concentrated in vacuo, and the obtained crude product was purified by preparative ΗPLC (Layer B) and converted to the hydrochloride salt in the same manner as in the procedure of Example 36. 11 mg, 52%). H NMR (DMSO - heart) &lt;5 11.05 (s, 1 Η ) » 1 0.62 ( s, 1H ) &gt; 8.05 ( s, 1H ) ' 7.97 ( d, 1 H, J = 2.7 Hz ) · 7.94 ( d , 1H, J = 7.1Hz) , 7.82 ( d, 1H, J = 12.1Hz) , 7.66 ( d, 1H, J = 8.8Hz) '7.45-7.45 (m, 2H ) , 7.35 ( dd, 2H, J = 8.2, 5.5Hz ) &gt; 7.20 ( d, 1 H, 7 = 6.6Hz ) &gt; 7.1 6 ( t, 2H, J = 8.8Hz ) &gt; 6.24 ( d, 1H, J = 6.6Hz ) » 3.74 ( s , 2H); MS (ESI+): m/z 515.19 (M + H) +. Example 134 8 -348- (345) 1324926

#-( 4-(2-Amino-3-(3-((3Λ,4Λ)-3-hydroxy-4-(pyrrolidin-1 -φ)pyrrolidin-1)yl)-3-methyl But-1-ynyl)pyridin-4-yloxy)· 3-fluorophenyl)-1-(4-fluorophenyl)-2-keto-1,2·dihydropyridine-3-carboxamidine Amine, trihydrochloride

A ) ( 3Λ,4Λ) -1- ( 2·methylbutan-3·yn-2-yl)-4-(pyrrolidine-1-

Pyrrolidin-3-ol treated with Cul (77 mg, 0.78 mmol) (3 and 47?) -4-(pyrrolidine D-l-yl)pyridinyl D-but-3-ol (Lexicon Pharma) , 1.56 g, 10.0 mmol) and 3-chloro-3-methyl-1-butanthene (GFS Chemical, Inc., 1.36 g, 13.2 mmol), THF (15 mL) and triethylamine (13.3 mmol) mixture. At the same time as the exothermic reaction occurs, precipitates form. After the mixture was stirred for 15 hours at room temperature, it was concentrated in vacuo and evaporated and evaporated. The aqueous phase was extracted twice with ethyl acetate and the ethyl acetate phase was dried over magnesium sulfate and concentrated to afford a pale brown solid (1. 〇g 8 -349 - (346) 1324926 , 4 5 %). 'H NMR ( CDC13 ) δ 4.20 ( br s,1 H ) , 3.13 - 3.04 ( m, 1 H ) - 2.95 ( dd, 1 H, J = 10.1, 6.6 Hz ) , 2.77 (

Dd, 1H, J = 10.1, 2.6 Hz), 2.64 (m, 3H) &gt; 2.61 ( m, 2 H )&gt; 2.5 5-2.46 ( m, 1 H ) , 2.26 ( s, 1H) &gt; 1 . 8 5 - 1 .74 (m, 4H), 1.38 (s, 3H), 1.36 (s, 3H); MS (ESI+): m/z 223.29 ( M + H ) + .

B) (3Λ,47?) -I - (4-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)-2-methylbutene-3 -alkyn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidin-3-ol

In the same manner as in the step D of Example 35, from (3/?,47?)-1-(2-methylbut-3-acetyl-2-yl)-4-(pyrrolidin-1-yl) Pyrrolidin-3-ol and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C of Example 34) gave the title compound (yield 57 %). 1H NMR (CDCI3) 5 8. 1 0 ( dd, 1H, J = 10.2, 2·5Ηζ), 8.03 ( d, 1 H, J = 9.2Hz ) , 7.99 ( d, 1H, J = 5,6Hz ),

7.13-7.06 ( m, 1H) &gt; 6.26 (d, 1H, J = 6.1Hz) &gt; 5.18 ( br s, 2H ) , 4.21(m,1H) &gt; 3. 1 0-2.99 ( m, 1 H &gt; 2.96 ( s, 1 H ) , 2.70 ( dd, 2H, J = 9.7, 3.1 Hz) &gt; 2.66-1.15 ( m, 2H )&gt; 1 .8 7 - 1 .76 ( m, 5H ) &gt ; 1 .3 3 - 1 .3 2 ( m, 2H ) &gt; 1.32 ( m, 8 -350- (347) 1324926

3H ) , 1.34 ( m, 3H ) ; MS ( ESI+) : m/z 4 70.20 ( M + H

C) (3Λ,4Λ)-1-(4-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)-2-methylbut-3- Alkyn-2-yl)-4-(pyrrolidinyl-pyridyl)pyrrolidin-3-ol was obtained from (3Λ,4Λ)-1-(4-(2-) in the same manner as in Step C of Example 11. Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1.yl) Pyrrolidin-3-ol, the title compound was obtained (yield 95%). MS ( ESI+ ) : m/z

440.3 7 ( M + H ) +. D) #-( 4-(2-amino-3-(3·((3i?,4/〇-3-hydroxy-4-(pyrrole II))pyrrolidine D-l-yl)-3 -methylbutan-1-fastyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-mercapto-1,2-dihydro Pyridine-3-carboxamide, trihydrochloride, in the same manner as in Example 62, from (3Λ,4Λ)-1-(4-(2-amino-4-(4-amino-2-) Fluorophenoxy)Djt-3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidin-1-yl)pyrrolidine-3-ol and 4-(4- Fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxylic acid (Compound 8 -351 - (348) 1324926 B of Example 101) gave the title compound (yield 50%) 1H NMR (DMSO-d6) δ 12.1 4 ( s, 1 Η ) , 8.62 - 8.5 4 ( m, 1H ) &gt; 8.14 ( dd, 3H, J = 6.6, 2.0 Hz ) &gt; 8.05 ( d, 1H, J = 13.2Hz), 7.99 (

d, 1 H, J = 7.1 Hz) , 7.62 - 7.51 ( m, 5H) &gt; 7.42 (t, 2H, J = 8.6 Hz) &gt; 6.78-6.70 ( m, 1 H ) , 6.32 ( d, 1 H , J = 7.1Hz ) -4.65 ( br s, 1 H ) , 3.94 - 3.84 ( m, 1H) &gt; 3.7 1 ( d, 2H, J = 16.8Hz) &gt; 3.60 ( m, 2H ) , 3.52 ( m , 1 H ),

3.22-3.08 ( m, 2H) &gt; 2.00-1.91 ( m, 2H) &gt; 1.88-1.78 ( m, 2H ) , 1.70 ( s, 6H ) ; MS ( ESI+) : m/z 6 5 5.40 ( M + H) Example 1 3 5

-352- 8 1 (4-( 2 -Amino-3-( 3-(( 3Λ,4Λ) -3 -hydroxy-4-(pyrrolidin-1-yl)pyrrolidin-1-yl)-3- Methylbut-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, trihydrochloride In the same manner as in the step E of Example 11, from (3;?,4/?)-1-(4-(2-amino-4-(4-amino-2-fluorophenoxy)pyridine- 3-yl)-2-methylbut-3-yn-2-yl)-4-(pyrrolidinyl-pyridyl)pyrrolidin-3-ol, the title compound was obtained (yield 40%). 4 NMR (DMSO-heart) (349) 1324926 ά 1 1 .06 ( s, 1 Η ) - 1 0.62 ( s, 1 Η ) - 7.97 ( d, 2Η, J = 6.6Hz ) , 7.80 ( d, 1 H , J = 11.7Hz) , 7 · 5 1 - 7.4 0 ( m, 2 H )&gt; 7.38-7.32 ( m, 2H) &gt; 7. 1 6 ( t, 2H, J = 8.6Hz ) - 6.25 (d , 1 H, J = 6.6 Hz ) , 4.63 -4.5 3 ( m, 1H ) , 3.79 - 3.68 ( m, 1 H ) &gt; 3.74 ( s, 2H ) &gt; 3.6 8-3.5 6 ( m, 2H ) , 3.51-3.43 (m, 2H) , 3.08-2.99 (m, 4H) &gt; 1.98-1.92 (m, 2H), 1.89- 1.7 7 ( m, 2H) , 1.64 ( s, 6H) ; MS ( ESI+) : m/z

Example 1 3 6

1-(3-Fluoro-4-(3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetonitrile Urea, hydrochloride

N〇2 A) 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)propan-2-alkyn-1-ol in the same manner as in the step A of Example 36 Prepared from 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine (Compound A of Example 33) 8-353-(350) 1324926 and propargyl alcohol (Aldrich). The title compound (yield 77%). H NMR ( DMSO-A ) δ 8.69 ( s5 1 Η ) , 8.49 ( d, 1 Η, J = 5.6 Hz) , 8.43 ( dd, 1 H, J = 1 0 · 7 , 2.5 H z ) , 8 · 1 7 ( d, 1 H, J = 9.2Hz ) , 7.57 ( t, \H, J = 8.6Hz ) , 7.04 ( d,1H, J = 5.6Hz ) &gt; 5.40 (t, 1H, 7 = 6.1Hz) &gt; 4.28 ( d, 2H, J = 6.1 Hz); MS (ES I+ ) : m/z 289.15 (M + H)+.

B) 3-(4-(4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol was obtained in the same manner as in the step C of Example 11. 3-(4-(2-Fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol, the title compound was obtained (yield: 95%). MS ( ESI + ) : m/z 25 9.2 1 (

M + H) +. C) 1-(3-Fluoro-4-(3-(3-hydroxypropan-1-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl) Ethyl hydrazide, urea, hydrochloride, in the same manner as in the step E of Example ,, from 3-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)- 2-yn-1-ol, the title compound was prepared (yield 36%) «hNMRCDMSO-A) &lt;5 11.06 (s, 1 Η ) &gt; 1 0.63 ( s, 1 Η ) - 8.79 ( s, 1 Η ) , 8.49 ( d, 1H, J = 6.1Hz), 7.82 ( d, 1 H, J = 1 2.2Hz ) , 7.45-7.40 8 -354- (351) 1324926 (m, 2H ) &gt; 7.38-7.33 (m, 2H ), 7.23-7.13 (m, 2H) &gt; 6.89 ( d, 1H, J = 6.1Hz) , 4.37 ( s, 2H) , 3.74 ( s, 2H) ; MS ( ESI+ ) : m/z 43 8.23 ( M + H ) +.

#- (4-(2-Amino-3-(3-aminopropan-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl) 2-keto-1,2-dihydropyridine-3-carboxamide, dihydrochloride

N〇2 A) 3-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylaminecarboxylic acid tert-butyl ester according to and implementation In the same manner as in Step A of Example 42, Bo c-propargylamine (Compound A of Example 42) and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (Compound C of Example 34) gave the title compound (yield: 59%). 4 NMR (DMSO-heart) 08.35 (dd, 1H, J = 1 0.7, 2·5Ηζ), 8. 1 2 (d, 1H, J = 9.2Hz), 7.88 ( d, 1H, J = 5·6Ηζ) , 7.39 ( t, 1H, J = 8·6Ηζ), -355 - 8 (352) 1324926 (d, 1H, J s, 9H ); 7.3 1 ( t, 1 H, J = 5.1Hz) &gt; 6.53 ( s, 2H ) - 6.15 = 5.6 Hz ) - 3.92 ( d, 2H, J = 5.6 Hz ) &gt; 1.36 ( MS ( ESI+ ) : m/z 4 03.3 4 ( M + H ) +.

Nh2

B) 3-(2-Amino-4-(4-amino-2-fluorophenoxy)pyran-2-ynylaminecarboxylic acid tert-butyl ester according to the same procedure as in Step C of Example 11. The title compound (quantitative yield) was prepared from the benzyl 4-(2-carbyl-4-nitrophenoxy) 11-but-3-yl)propan-2-butyrate. ): m/z 3 73.3 5 ( M + H ) +.

Π定-3 -yl) 3- (2-amine-alkynylamine MS (EST

C) 3-(2-Amino-4-(2-fluoro-4-(1-(4-fluorophenyl) 1,2-dihydropyridine-3-carboxamido)phenoxy)pyridine 3-butyl benzyl carbamate in the same manner as in Example 62, from 3-(2-aminoamino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl Amine methyl ketone and (4-(phenyl)-2-indolyl-1,2 - one gas oxime ratio steep-3-竣•2-mercapto-)prop-2-ynyl-4-(4-acid Tributyric acid (implementation 8 -356- (353) 1324926

The title compound (yield 48%) was obtained. 'H NMR (DMSO-heart) (5 12.07 ( s, 1H ) , 8.57 ( dd, 1H, J = 7.1, 2.0 Hz) - 8.12 ( dd, 1H, J = 6.6, 2.0 Hz ) &gt; 8.00-

7.93 (m, 1H), 7.75 (d, 1H, J = 6.1Hz) &gt; 7.61 ( d, 2H, J = 5.1Hz) &gt; 7.59 ( d5 1 H, J = 4.6Hz ) , 7.4 8 - 7.3 7 ( m, 4H ), 7.3 0-7.2 5 ( m, 1 H ) , 6.72 ( t, 1 H, J = 7.1 Hz) , 6.3 7 (br s, 1 H ) , 5.80 ( d,1 H, J = 6.1 Hz) , 4.00 ( d, 2H, J • = 5.1 Hz) &gt; 1 .3 8 ( s, 9H ) ; MS ( ESI+ ) : m/z 5 8 8.26 ( M + H) +. D) TV-(4-(2-Amino-3-(3-aminopropy-1-ynyl)pyridin-4-yloxy)-3-phenyl)-1-(4-benzene (2)-mercapto-1,2. a sulphate of 11-formyl-3-carboxamide, dihydrochlorate in the same manner as in step E of Example 36, from 3-(2-amino)- 4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-keto-1,2-dihydropyridine-% 3-carboxamido)phenoxy)rudomidine-3 The title compound was obtained as the title compound (yield: 80%). 'H NMR ( DMSO-A) δ 12.13 ( s, 1 Η ) - 8.57 ( dd, 1 Η, J = 7.1, 2.0 Hz) , 8.51 (s, 2H) , 8.14 ( dd, 1 H, J = 6.6, 2.0 Hz ) &gt; 8. 1 1 -8.02 ( m, 1H ) &gt; 7.9 8-7.90 ( m, 1 H ) &gt; 7.60 ( dd, 2H, J = 9.2, 5.1Hz) &gt; 7.53 ( d, 1H, J = 9.2Hz ) - 7.46-7.37 ( m, 3H ) &gt; 6.76-6.71 ( m, 1H ) , 6.20 ( d, 1H, J = 6.6Hz ) - 4.1 1 -4.04 ( m, 2H ) ; MS ( ESI+ ) : m/z 4 8 8.1 6 (M + H) +. 8 357 (354) 1324926 Example 1 3 8

1-(4-(2-Amino-3-(3-aminopropy-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluoro) Phenyl)ethylidene)urea, dihydrochloride

A) 3-(2-Amino-4-(2-fluoro)-4-(3-(2-(4-fluorophenyl)ethenyl)ureido)phenoxy)pyridin-3-yl) Propane-2-ynylaminecarboxylic acid tert-butyl ester

3 - (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-ynyl, in the same manner as in the step E of Example 11. The title compound was obtained as a title compound (yield: 38%). NMR (DMSO-ί/ί ) δ 11.02 ( s, 1Η ) - 10.55 ( s, 1Η ) &gt; 7.80- 7.73 - 7.69 ( m,2Η) , 7.3 8-7.29 ( m,3Η) , 7.33 ( d,1Η , J = 5.1Hz) - 7.30-7.2 1 ( m, 1H ) &gt; 7.2 1-7.13 ( m, 2H) &gt; 6.37 ( br s, 1 H ) &gt; 5.76 ( d, 1H, 7 = 6.1Hz ) &gt; 4.00 ( s, 2H ), 3.73 ( s, 2H) , 1.38 ( s, 9H) ; MS ( ESI+) : m/z 5 5 2.24 ( M + H ) + . 8 -358- (355) 1324926 B ) 1-(4-(2-Amino-3-(3-aminopropy-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl) 3-(2-(4-fluorophenyl)ethenyl)urea, dihydrochloride salt, in the same manner as in the step E of Example 11, from 3-(2-amino-4- 4-(2) -fluoro-(3-(2-(4-fluorophenyl)ethenyl)ureido)phenoxy)pyridin-3-yl)prop-2-ynylaminecarboxylic acid tert-butyl ester, preparation The compound with the title φ (yield 65%). NMR (DMSO-heart) 5 11.05 ( s, 1 Η ) , 1 0.61 ( s, 1 Η ) &gt; 8.48 ( br s, 3H ) &gt; 7.90 ( d, 1H, J = 6.6Hz ) &gt; 7.84-7.76 ( m, 2H ) , 7.4 5 -7.3 9 ( m, 1 H )-7.3 9-7.3 2 ( m, 3H ) &gt; 7.20-7.13 ( m, 2H ) &gt; 6.11 ( d, 1 H, J = 6.1 Hz) &gt; 4.09-4.03 (m, 2H), 3.74 (s, 2H); MS (ESI+): m/z 452.12 (M + H) +. Example 1 3 9

1-(4-(2-Amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorobenzene) Ethyl hydrazide), hydrochloride - 359- 8 (356) 1324926

No2 A) 3-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol according to the procedure of Example 36 A the same way, by propargyl alcohol (

The title compound was obtained from Aldrich) and 4-(2-Chrysin-4-ylphenyl)-3-propenylpyridinium U疋-2-amine (Compound C of Example 34) 4 6% ) o'HNMRCDMSO-A) δ 8.40-8.34 ( m, 1H ), 8.13 ( d, 1H, J = 8.6Hz ) , 7.88 ( d,1H, J = 5.6Hz ), 7.42 ( t, 1 H , J = 8.6Hz ) , 6.49 ( s, 2H ) , 6.14 ( d,1 H, J =6.1Hz) , 5.26-5.20 ( m, 1H ) , 4.26 ( d, 2H, J = 6.1Hz ); MS ( ESI.) : m/z 3 04.23 ( M + H ) +.

B) 3-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol from 3-(2-Amino- 4-(2-Fluoro-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol, the title compound was obtained (yield 6 5%) 〇MS(ESI+) : m/z 274.21 (M + H)+. -360- 8 (357) 1324926 C) 1-(4-(2-amino-3-(3-hydroxyprop-1-) Pyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride salt from 3-(2-amino-4 - (4-Amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-propanol gave the title compound (yield: 48%). 4 NMR (DMSO-heart) &lt;5 11.05 ( s, 1 Η ) , 10.60 ( s, 1 Η ), 7.86 ( d, 1 Η, J = 7.1 Hz) &gt; 7.83 -7.77 ( m, 1H ) , 7.44 -

• 7.37 ( m, 2H ), 7.3 7-7.3 2 ( m, 3H) &gt; 7.20-7.13 ( m, 2H )-6.1 4 ( d, J = 6.6Hz, 1 H ) , 4.37 ( s, 2H) - 3.74 ( s, 2H ) ; MS ( ESI+ ) : m/z 45 3.2 8 ( M + H ) + . Example 1 4 0

(3-(Dimethylamino) iV-(4-(2-amino-3-yloxy)-3-fluorophenylpyridin-3-carboxamide, dihydropropan-1·ynyl)pyridine -4-•2-keto·1,2-dihydropyridin-1-(4-fluorophenyl) chlorate

8 361 - (358) 1324926 A ) 3-( 3-(Dimethylamino)prop-1-ynyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine In the same manner as in Step A of Example 42, from 1-dimethylamino-2-propyne (Aldrich) and 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridine- 2-Amine (Compound C of Example 34) gave the title compound (yield: 64%). NMR (DMSO-heart) δ 8.36 ( dd, 1 H, J = 10.7, 2.5 Hz), 8.11 (d, 1 H, / - 8.6 Hz), 7.93 (d, 1 H, φ J = 5.6 Hz) &gt; 7.30 ( t, 1 H, J = 8.6Hz ) &gt; 6.4 3 ( brs, 2 H )

-6.28 ( d, 1H, J = 6.1 Hz) - 3.4 1 ( s, 2H ) , 2.05 ( s, 6H ); MS ( ESI+ ) : m/z 331.28 (M + H)+.

B) 4-(4-Amino-2-fluorophenoxy)-3-(3-(dimethylamino)prop-1-ynyl)pyridin-2-amine according to Step C of Example 11 In the same manner, the title compound was prepared from 3-(3-(dimethylamino)propan-1 -ynyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine. Yield 77%) 〇MS (ESI+): m/z 3 0 1.3 (M + H) +. C) #-( 4-(2-Amino-3-(3-(dimethylamino)prop-1-ynyl)pyridin-4-yloxy)-3-phenyl)-1-( 4-(phenyl)-2-mercapto-1,2-monopyridine-3-carbamide, dihydrochloride 8 (359) 1324926

In the same manner as in Example 62, 4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino)prop-1-ynyl)pyridin-2-amine and 1-(4-Fluorophenyl)-2-keto-1,2-dihydropyridine-3-carboxylic acid (Compound B of Example 101) gave the title compound (yield 71%). 1 H NMR (DMS-ί/ί ) &lt;5 1 2.1 4 ( s, 1 Η ) - 11.39 (s, 1Η) &gt; 8.60- 8.53 ( m, 1 H ) &gt; 8.33 ( s, 1 H ) &gt ; 8.1 4 ( dd, 1H, J = 6.6, 2.2Hz ) , 8.05 ( dd, 1 H, J = 12.7, 2.2Hz ) , 7.98 ( d, 1 H, φ J = 7.0Hz ) - 7.61 ( d, 1 H, J = 5.3Hz ) &gt; 7.5 8 ( d, 1 H, J = 4.8Hz ) , 7.5 6-7.5 0 ( m, 1H ) , 7.3 7-7.47 ( m, 3H ), 6.76-6.69 ( m, 1H) &gt; 6.30 ( d, 1H, J = 7.0Hz) &gt; 4.39 ( s, 2H) , 2.84 ( s, 6H ) ; MS ( ESI+ ) : m/z 4 8 0.2 8 ( M + H ) +

1-(4-(2-Amino-3-(3-(dimethylamino)propanyl)pyridin-4-yloxy)-3-fluorophenyl)-3-(2-( 4-fluorophenyl)ethinyl)urea, dihydrochloride, in the same manner as in the step E of Example 11, from 4-(4-amino-2-fluorophenoxy)-3- (3-(Dimethylamino)prop-1-ynyl)pyridine-2-amine, the title compound was obtained (yield: 70%). 4 NMR ( DMSO - 8 - 363 - (360) (360) 1324926 d6 ) δ 11.46 ( br s, 1 H ) , 1 1 .07 ( s, 1 H ) , 10.64 ( s, 1 H )&gt; 8.3 7 ( br s, 1 H ) , 7.98 (t, lH, &gt; 7 = 7.5 Hz) &gt; 7.81 ( d,1 H, J = 1 3.6 Hz ) , 7.43 -7.3 2 ( m,4H ) , 7.20-7.09 ( m, 2H ) , 6.27 ( d, 1 H, J = 7.0Hz ) , 4.3 8 ( s, 2H ) , 3.75 ( s, 2H ) , 2.84 ( s, 6H ) ; MS ( ESI+ ) : m/z 5 16.31 (M + H Example 142

1-(4-(2-Aminopyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea, hydrochloride

A) 4-(4-Aminophenoxy)pyridylcarboxamide The title compound was obtained from 4-aminophenol in a similar manner to that described in step B. Yield: 85%. MS ( ESI+ ) m/z 2 3 0 (M + H) +. 8 -364- (361) 1324926

B) 1-(4-(2-Aminomethylpyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethenyl)urea

The title compound was prepared in a similar manner to that described in the step C' of Example 24. Yield: 95%. MS (ESI+): m/z 409 (M + HC) 1-(4-(2-aminopyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)ethylhydrazine The title compound was prepared in a similar manner to that described in Step D' of Example 24. Yield: 58%. 4 NMR ( DMSO-A ) 5 12.86 ( s, 1H) , 10.97 ( s, 1H) , 10.51 ( s, 1H) , 7.91

(d, 1H, J = 6.0Hz), 7.67 ( d, 3H, J = 9.0Hz ) , 7.34 ( dd, 2H, J = 9.0, 5.0Hz ) &gt; 7.2 1 ( d, 2H, J = 9.0Hz ) , 7.16 ( t, 2H, J = 9.0Hz ) &gt; 6.6 3 ( dd, 1 H , J = 9.5 , 2.0Hz ) &gt; 6.05 ( d, 1H, J = 2.0Hz ) 3.73 ( s, 2H ) ; MS ( ESI+ ) : m/z 3 8 1 ( M + H ) +. Example 143 365- 8 (362) 1324926

1-(4-(2-aminopyridin-4-yloxy)-3-phenyl)-3-(2-(3-phenyl)ethenyl)urea

OBn A) 2-(3-Benzyloxy)phenyl)acetic acid

Potassium carbonate (6·90 g, 50 mmol) and benzyl bromide (4,75 mL, 40 mmol) were added to 3-phenylacetic acid (Acros, 3.04 g, 20 mmol) at 20 In the solution formed by mL DMF. The reaction mixture was stirred for 24 hours. The suspension was filtered and washed with diethyl ether. Then, the filtrate was washed with brine and dried over magnesium sulfate. After filtration and concentration, the crude benzyl (3-(benzyloxy)phenyl)acetate was obtained which was used directly in the next step. MS ( ESI+ ) m/z 3 5 5 (M + Na) +. The crude benzyl 2-(3-(benzyloxy)phenyl)acetate was dissolved in a mixture of methanol (20 mL) and THF (50 mL). 40 mL of 1 N NaOH (40 mmol) was added to the solution. The reaction mixture was stirred for 2 hours at room temperature. The organic solvent was removed in vacuo. The remaining aqueous solution was extracted with diethyl ether (2 X 50 mL). Then, the aqueous solution was acidified with IN HCl (50 m L ), and the title compound was precipitated. The solid was recovered (4.35 g, two steps 90%) using -366- (363) 1324926 filtration. MS ( ESI+) m/Z 26 5 (M + Na) +.

B) 2-(3-(Benzyloxy)phenyl)ethenyl isocyanate 1 drop of DMF and sulfinium chloride (0.30 mL, 4 ^ mmol) was added to 2-(3-(benzyl) at room temperature A solution of oxy)phenyl)acetic acid (484 mg, 2.0 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour and then, at 50 ° C, stirred for 5 hours. The mixture was cooled and the solvent was removed in vacuo. The residue obtained was dissolved in 5 mL of toluene, and AgOCN (600 mg &gt; 4.0 mmol) was added. The suspension was stirred for 0.5 hours, and filtered to give a solution (0.40 M) of 2-(3-(benzyloxy)phenyl)ethyl succinyl isocyanate in toluene.

C) 1-(2·(3-(Benzyloxy)phenyl)ethenyl)-3-(4-(2-aminocarboxyridin-4-yloxy)-3-fluorophenyl The title compound was prepared in the same manner as described in the step C' of Example 24 using the solution of the step B of this example. Yield··63%. MS ( ESI + ) m/z 5 1 5 (M + H) +. 8 -367- (364) 1324926

D) 1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-(benzyloxy)phenyl)ethenyl)urea

The title compound was prepared in a similar manner to that described in step D' Yield: 61%. MS ( ESI+ ) m/z 48 7 ( M + H ) + E) 1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3) -Hydroxyphenyl)ethinyl)urea 10% Pd/C (200 mg) was added to 1-(4-(2-aminopyridine-4-yloxy)-3-fluorophenyl)-3-( A solution of 2-(3-(benzyloxy)phenyl)ethenyl)urea (150 mg, 0.31 mmol) in a mixture of 5 mL ethyl acetate and 3 mL methanol. The suspension was stirred for 1 hour under a hydrogen atmosphere. After filtration and concentration, the title compound (7 7 mg ' 63%) &quot; 'HNMRC DMSO · heart) δ 10.95 ( s, 1 Η ), 1 〇 · 5 4 ( s, 1 Η ) , 9.3 5 ( s , 1 Η ) , 7 · 7 4 ( d,1 Η,·/ = 6 _ 0 Η ζ ), 7.68 ( dd, 1Η, J = 13.0, 2·0Ηζ), 7.30 ( dd, 1Η, J = 9.0, 1 . ΙΗζ ) , 7.23 (t, 1Η, «/ = 9.0Ηζ) · 7.07 ( t5 1 Η, y = 8.0Hz) » 6.69 ( s, 1 H ) &gt; 6.68 ( d, 1H, J = 7.0Hz) &gt; 6.62 (dd, 1H, J = 7.0, 2.0Hz ) &gt; 6.10 ( dd, 1H, J = 6.0, 2.0Hz ), 5_90 ( s, 2H) , 5.73 ( d,1H, J = 2.0Hz) , 3.27 ( s, -368- (365) 1324926 2H) ; MS ( ES Γ ) : m/z 397 (M + H)+. Example 144

3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)ethenyl)-1-methylurea, hydrogen Chlorate

HN

F A ) 2-(4-fluorophenyl)-#-methylacetamide

4·Fluorophenylethylidene chloride (518 mg, 3.0 mmol) was added to a solution of methylamine in THF (2.0 Μ, 5 mL • 10 mmol) at -78 °C. The reaction mixture was stirred at -7 8 t: to room temperature for 1 hour. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The title compound (490 mg, 98%) mp (ESI+): m/z 1 69 (M + H) +

-369- 8 (366) 1324926 B) 3-(4-(2-Aminomethylpyridin-4-yloxy)-3-fluorophenyl)-1·( 2-(4-fluorophenyl) Ethyl)-1-methyl gland at -78. (:, methyl lithium (1.6 Μ, 0.34 mL, 0.5 5 mmol) in diethyl ether was added to 2 -(4-fluorophenyl)methylacetamide (8 9 mg, 0.53 mmol) in 2 mL THF In the solution formed, the solution was stirred at -78 °C for 5 minutes' and then rapidly introduced into 20% phosgene (in toluene, 1.9 Μ, 0.29 mL, 0.55 mmol). After 2 minutes, 依# 4-(4-Amino-2-fluorophenoxy)pyridylcarzamide (Compound B of Example 24, 100 mg, 0.40 mmol) and DMF (2 mL) and DIEA (0.4 mL) were added sequentially. The reaction mixture was stirred for 1 hour at room temperature and quenched with water. Then, the solution was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The title compound (77 mg, 33%), m.

C) 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(2-(4-fluorophenyl)ethenyl)-1-methylurea The hydrochloride salt was prepared in a similar manner to that described in the step D' of Example 24 to give the title compound. Yield: 24%. 'H NMR ( DMSO-A ) &lt;5 13.20 ( s, 1 Η ) , 11.17 ( s, 1 Η ) , 7.90 ( d, 1H, J = 7.0 Hz ) - 7.78 - 7.74 ( m, 3H ) , 7 · 3 9 - 7 · 3 4 ( m, 2 H ) &gt; 7.23-7.21 (m, 2H ) &gt; 7.10-7.05 ( m, 2H ) &gt; 6.63 ( dd, 1H, J = 7.0, 2.0Hz ) &gt; 6.08 ( D5 1H, J = 2.0 Hz) · 4.00 ( s, 2H ) &gt; 3.24 8 -370- (367) 1324926 (s, 3H ) ; MS ( ESI+ ) m/z 4 13 ( M + H ) + . Example 1 4 5

(i?) -#-(2-Amino-2-keto-1-phenylethyl)(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl) Propylamine, trifluoroacetate

A) Ethyl 3-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenylamino)-φ 3-ketopropanoate according to the compound E of Example 112 Preparation of 3-(4-(2-Aminomethylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-ketopropanoic acid ethyl ester in a similar manner (implementation) Compound A of Example 116, 0.73 g (1.0 mmol) was converted to the title compound (0.24 g, 35%). MS (ESI+): m/z 3 5 2 (M + H) +. -371 - 8 (368) 1324926

OH B) 3-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-ketopropanoic acid

3-(4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-, in a similar manner to the preparation of Compound B of Example 1 16 Ethyl ketopropionate (0.24 g, 0.68 mmol) was HRMS (ESI+): theory 値, 324.0796 (M + H) + ; 値 3, 3 24.0795 ( M + H ) + .

〇

C ) ( /? ) -f - (2-Amino-2-keto-1-phenylethyl)-f - ( 4-(2-aminopyridin-4-yloxy)-2,5- Difluorophenyl)propanediamine, trifluoroacetate, in a similar manner to the preparation of Example 103, 3·(4-(2-Aminopyridin-4-yloxy)-2,5-di Fluorophenylamino)-3-ketopropionic acid (0.039 g, 0.12 mmol) and (/?)-2-amino-2-phenylacetamide hydrochloride (Bachem, 0.023 g, 0.12 mmol The coupling gave the title compound (0.0048 g, 7%). NMR (DMSO - core) δ 10.33 (s, 1 Η ) &gt; 8.77 ( d, 1 Η, J = 7.8 Hz ) , 8.10-8.19 (m,1Η -372- (369) 1324926 ), 7.90 ( d, 1 H, J = 7.2Hz ) , 7.60- 7.7 5 ( m, 4H ) &gt; 7.17-7.39 ( m,6H) , 6.66-6.69 ( m, 1H) , 6.11 ( s,1H) , 5.35 ( d, 1H, J = 7.8 Hz); HRMS ( ESI+ ): Theoretical 値, 456.1483 (M + H) +; measured 値, 456.1487 (M + H) +. Example 146

TV-(4-(2-Amino DjiD-1,4-ethoxy)phenyl)-2-indolyl-1-phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloric acid salt

A) 4-(4-(2-keto-1-yl-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridinecarboxamide according to the compound of Example 1 15 Preparation of A in a similar manner, 4-(4-aminophenoxy)pyridinamide (Compound A of Example 142, 0.030 g, 0.13 mmol) and Compound C of Example 57 (0.028 g, 0.13 mmol Coupling, the title compound (0.057 g, 100%) was obtained, which can be used directly without further purification. MS ( ESI+ ) m/z

-373- (370) 1324926 427 ( M + H ) +.

B) iV-(4-(2-amino-2-ethylidene-4-yloxy)phenyl)-2-indolyl-1-benzyl-1,2-dihydropyridine-3-carboxamidine Amine, Hydrochloric Acid 4-(4·(2-keto-1-phenyl-1,2-dihydropyridine-3-methyl) was obtained in a similar manner to the preparation of Compound E of Example 1 1 2 The indoleamino)phenoxy)pyridylcarzamide (0.055 g, 0.13 mmol) was converted to the title compound. 'H NMR(CD3OD) δ 12.10 ( s, 1Η ) - 8.59-8.61 ( m, 1H ) &gt; 7.8 8 -7.90 ( m, 1H ) , 7.69-

7.76 ( m, 3H ) , 7 · 3 9 - 7 · 5 3 ( m, 5 H ) &gt; 7.10-7.13 ( m, 2H ), 6.66 ( t, 1H, J = 6.9Hz ) - 6.5 3 -6.5 5 ( m, 1 H ), 6.07-6.08 ( m, 1H) &gt; 4.75 ( br s, 2H) ; HRMS ( ESI+)

: Theory 値, 399.1457 (M + H) + ; measured 値, 399.1453 (M + H N + Example 1 4 7

374- 8 (371) 1324926 #- (4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-2-indenyl-1,2-dihydropyridine 3-carbamamine, hydrochloride

A) Methyl 1-benzyl-2-keto-1,2-dihydropyridine-3-carboxylate φ 2-keto-27--pyran-3-carboxylic acid methyl ester at room temperature (Aldrich, 2.0 g, 13 mmol, 1.0 eq.) and a heterogeneous mixture of 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq.) in DMF (10 mL). The reaction mixture was treated with EDCI (3.4 g, 1 8 mmol, 1.4 eq.) and DMAP (0.11 g, 9.91 mmol' 0.07 eq.) at room temperature, and the solution thus obtained was stirred for 12 hours. The reaction mixture was quenched with 1 N aqueous HCl and the solution was extracted with ethyl acetate (4 X 50 mL). The combined organic extracts were washed with 10% aqueous lithium chloride (3.times.ss.sssssssssssssssssssssssssssssssssssss &gt; 73%), which can be used directly without further purification. NMR ( DMSO-i/&lt;j) ^ 8.17-8.20 ( m, 1H) » 8.03-8.05 ( m, 1 η ) &gt; 7.38-7.46 (m, 2H) * 7.16-7.22 ( m, 2H) &gt; 6.37 ( dd,1H, J = 6.94Hz) * 5.13 ( s, 2H ) · 3.73 (s, 3H); HRMS ( ESI+ ): Theory 値 ' 262.08 79 ; measured 値 ' 262.08 8 5 . -375- 8 (372) 1324926

B) 1-Benzyl-2-keto-1,2-dihydropyridine-3-carboxylic acid The benzyl group was treated with 5N aqueous sodium hydroxide (4.6 mL, 24 mmol, 2.6 eq. A solution of 2-keto-1,2-dihydropyridine-3-carboxylic acid methyl ester (2.4 g, 9.2 mmol, 1.0 eq.) in MeOH (25 mL). Then, the reaction mixture was concentrated in vacuo, diluted with water and then extracted with ethyl acetate. The aqueous portion was cooled to 〇t and acidified with concentrated hydrochloric acid. The solid thus obtained was filtered, washed with water and dried and evaporated tolulululululululululululululululululululululululululu 1H NMR (DMSO-heart) δ 8.39-8.44 (m, 2H), 7.42-7.46 ( _ m, 2H), 7. 1 8-7.24 ( m, 2H ) , 6.78 ( dd, 1 H, J = 6· 98Ηζ ), 5.3 1 ( s, 2H ) : HRMS ( ESI+): Theoretical 値, 248.0723 ; measured 値, 248.07 1 8 °

C) 4-(4-(1-benzyl-2-keto-1,2-dihydropyridine-3-carboxamido)-2--376-8 (373) 1324926 fluorophenoxy) Pyridylcarbamide treatment of 1-benzyl-2-keto-1,2-dihydropyridine-3-carboxylic acid (〇.10) with DIPEA (0.18 mL, 1.0 mmol, 2.5 eq.) at rt. g, 0·41 mmol, 1.0 eq.), 4-(4-amino-2-fluoro-fluorophenoxy)pyridinamide (0.10 g, 0.41 mmol, 1.0 eq.) and TBTU (0,17 g) , 0.45 mmol, 1.1 eq.) homogeneous solution formed in DMF (2 mL), and the mixture was stirred for 12 hr. The reaction mixture was quenched with 10% aqueous lithium chloride (15 mL), and the resulting solution was extracted with ethyl acetate (4×40 m1). The organic extract of the combined hydrazine was washed with 1 〇 % aqueous lithium chloride (4 X 50 mL), dried (sodium sulfate), and the mixture was concentrated in vacuo. Purification of the residue obtained by flash column chromatography (eluent eluting with ethyl acetate) afforded the product as a solid ( 〇·1 3 g, 67%). iH NMR (DMSO-heart) &lt;5 12.26 ( s, 1H ) , 8.49 - 8.56 ( m, 2H ) * 8.33 - 8.36 ( m, 1H ) &gt; 8. 1 5 ( br m, 1H ) &gt; 8.03- 8.07 ( m, 1H )

' 7.74-7.75 ( m,1 H ) » 7.5 1 -7.54 ( m, 1H ) &gt; 7.41-7.46 ( m, 4H ) , 7.20-7.24 ( m,3H ) , 6.71 ( dd,1H,·/ = 6.89 Hz ), 5.32 (s, 2H) ; HRMS ( ESI+ ): theoretical 値, 477.1374 ; measured 値, 4 7 7.1 3 7 8 . 〇)#-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-benzyl-2-keto-1,2-dihydropyridine-3-carboxamidine Amine, hydrochloride, bis(trifluoroethyloxy)iodobenzene (0.12 g, 0.28 mmol, 1_1 eq.) added to 4-(4-(1-benzyl-2-one) at room temperature Base-1,2- 8 -377- (374) Dihydropyridine-3-carboxamido)-2·fluorophenoxy)pyridinecarboxamide (0.12 g, 0.26 mmol, 1.0 eq.) and water ( 0.01 mL, 0.51 mmol, 2.0 eq.) in a solution of DMF (1 mL). Pyridyl (0.065 mL, 0.77 mmol, 3.0 eq.) was added to the homogeneous mixture&apos; and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with 1 mL of aqueous hydrochloric acid (1 mL), and the thus obtained solution was extracted with diethyl ether (3 X 5 mL) and the organic layer was discarded. The aqueous portion was neutralized with 1N aqueous sodium hydroxide, and the thus obtained solution was extracted with 9 / 1 CHCI3 / methanol (4 X 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (EtOAc, eluting with EtOAc:EtOAc) The free base was dissolved in THF, cooled to 〇 ° C, and the homogeneous solution was treated with anhydrous 4N hydrochloric acid (in dioxane). The reaction mixture was warmed to room temperature, concentrated in vacuo and EtOAc evaporated. The title compound (0.082 g, 66%) was obtained as crystals. hNMRCDMSOdtf) &lt;5 13.66 ( br s, 1H) &gt; 8.49-8.51 ( ms 1H) &gt; 8.3 9- 8.49 ( m, 1H) , 8.3 7-8.3 9 ( m,1 H ) « 8.00-8.09 ( m , 3H ) &gt; 7.54-7.56 ( m, 1H ) &gt; 7.43-7.48 ( m, 3H ) * 7.19-7.24 (m, 2H )&gt; 6.69-6.72 (m, 2H ) &gt; 6.21-6.22 ( m, 1H ) , 5.32 ( s, 2H ) ; HRMS ( ESI+ ): Theoretical 値, 4 4 9 _ 1 4 2 5 ; measured 値, 449.1406 〇-378-

Claims (1)

Patent application scope βΑ Attachment: Patent application No. 94112594 Chinese patent application scope is replaced by the Republic of China on February 26, 1999 Or a mirror image isomer, a non-mironomer or a pharmaceutically acceptable salt thereof, wherein: each R 2 is independently or a quinone; η is 0 to 4; R3 is Η; R4 is pyridone, pyridyl, pyridyl-indole-oxide, or pyrazolyl, which is substituted with hydrazine or a substituent selected from the group consisting of halogen, - CH3, phenyl, benzyl, fluorophenyl, or -NH(fluorophenyl); 1324926 wherein R16 represents hydrazine, -CH2OH, NH2, -NHCH2CH2NH2, -NHCH2C(CH3)2CH2N(CH3)2, -NHCH2CH(NH2 CH2〇H, -CH2NHCH2CH2NH2, -NHCH2(pyrrolidinyl), -NHCH2(hexahydropyridyl), pyridyl group substituted with hexahydropyrazinyl, phenyl substituted with hexahydropyrazinyl, -CH2CH2OH, -CH2CH2NH2,·&lt;:Η2(:(0)ΝΗ2, -c(o)nhch2ch2nh2, -c(o)nhch2ch2nhch3, or -C(0)NHCH2CH2N(CH3)2, -CsC-CH2NH2, -CsC-CH2N(CH3)2, or -c^cc(ch3)2-(hydroxypyrrolidyl group substituted with pyrrolidinyl); R17 Η or NH2; R18 shows Η; and R19 shows Η. 2. A compound as claimed in claim 1 wherein R2 indicates F or F 〇 3. A compound according to claim 1, wherein R4 is substituted by phenyl, fluorophenyl, -CH3, CM, or Br. 4. A compound as claimed in claim 1 wherein R17 represents -ΝΗ2. 5. A compound according to claim 1, wherein R16 represents Η, -CH2OH, ΝΗ2, -NHCH2CH2NH2, -NHCH2C(CH3)2CH2N(CH3)2, -NHCH2CH(NH2)CH2OH, or -CH2NHCH2CH2NH2 ο 6. A compound of claim 1 wherein R4 represents pyridyl substituted by 0-2-1324926 or a substituent selected from the group consisting of halogen, -CH3, phenyl, benzyl, fluorophenyl, or NH (fluorophenyl). 7. The compound of claim 1, wherein R4 represents pyridone or pyridyl-N-oxide, each of which is substituted with 0 or 1 substituent selected from the group consisting of halogen, -CH3, phenyl, Benzyl, fluorophenyl, or -NH (fluorophenyl). 8. A compound according to claim 1 which has an IC5Q値 of less than about 1·〇 V 抑制 in inhibition of Met kinase. 9. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of cancer. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. -3-