Monocyclic heterocycles as kinase inhibitors

Technical Field [0002] The present invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors such as c-Met, and thus are useful as anti-cancer drugs. Pharmaceutical compositions that contain these compounds are also useful in the treatment of non-cancer diseases that are associated with signal transduction pathways acting through growth factor and anti-angiogenesis receptors such as c-Met.

Summary of the Invention [0003] The present invention relates to compounds of formula II as described below, which are useful in the treatment of cancer.

<img file="PL1737451T3_D0001.tif" />

or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, in which:

each R² is independently H, halogen, cyano, NO₂, OR⁵, NO⁶R⁷, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl;

B is O, S, SO or SO2;

W and X are each independently C or N;

n is 0 to 4 if both W and X are C, 0 to 3 if one of X or W is N and 0 to 2 if both X and W are N;

R³, R⁵, R⁶, and R⁷ are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle;

- 2 _R4 means optionally substituted pyridinone, pyridyl, pyridyl-N-oxide or pyrazolyl, provided that:

(a) if R⁴ is pyridyl, R⁴ is not substituted with both hydroxy and methoxy;

A is selected from one of the following:

<img file="PL1737451T3_D0002.tif" />

wherein

D is S or O;

m is 0 to 6;

17 18 19 20 21 22 23 24 25 26 27 R, R, R, R, R, R, R, R, R, R, R and R are independently selected from H, halogen, NR³⁰R³¹, OR³², CO2R³³, SO2R³⁶, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

R²⁸ and R²⁹ are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or joined together to form a carbocyclic or heterocyclic ring having from 3 to 8 atoms;

R³⁰, R³¹, R³², R³³, and R³⁶ are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, heterocycloalkyl or substituted heterocycloalkyl or substituted heterocycloalkyl.

Description of the disclosure [0004] The present disclosure includes compounds of formulas I and II as defined herein, pharmaceutical compositions employing such compounds, and methods of using such compounds in the treatment of cancer, provided that compounds of formula II with the substituent definitions above and as defined in claim 1 , and compositions and methods for using such compounds are embodiments of the present invention.

[0005] The term "alkyl" used alone or as part of another group refers to a monovalent alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, unless otherwise specified. Preferred alkyl groups are lower alkyl groups having from 1 to 6 carbon atoms. The alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. Alkyl groups can be substituted at any point of attachment. An alkyl group substituted with another alkyl group is also called a "branched alkyl group". Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents include, but are not limited to, one or more of the following groups: alkyl, cycloalkyl, heterocycloalkyl, -CN, aryl, heteroaryl, halogens (such

- 3 like F, Cl, Bar, I), haloalkyl (such as CCl3 or CF3), hydroxy, alkoxy, alkylthio, alkylamino, COOH, -COOR, -C (O) R, -OCOR, amino, carbamoyl (-NHCOOR -or-OCONHR-), urea (NHCONHR-) or thiol (-SH).

[0006] The term "alkenyl" alone or as part of another group refers to a hydrocarbon radical having a straight, branched or cyclic chain containing from 2 to 12 carbon atoms and at least one double carbon bond. Alkenyl groups can be substituted at any point of attachment. Exemplary substituents for alkenyl groups include those set forth above for alkyl groups.

[0007] The term "alkynyl", alone or as part of another group, refers to a straight, branched or cyclic hydrocarbon radical having 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be substituted at any point of attachment. Exemplary substituents for alkynyl groups include those set forth above for alkyl groups.

[0008] The numbers in the index after the "C" symbol indicate the number of carbon atoms that a particular group may contain. For example, "C 1-6 alkyl" means a saturated straight or branched carbon chain having from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, secpentyl, isopentyl, and n-hexanyl. Depending on the context, "C1-6 alkyl" may also be C16 alkylene that connects two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methyl-butane-1,4-diyl, etc. "C2-6 alkenyl" means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. Depending on the context, "C2-6 alkenyl" may also be C2-6 alkenediyl, which connects two groups; examples include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl, etc. "C2-6 alkynyl" means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to six carbon atoms; examples include ethynyl, propynyl, butynyl, and hexinyl.

[0009] The term "cycloalkyl" alone or as part of another group is a type of alkyl having from 3 to 15 carbon atoms, without changing or resonance of the double bonds between carbon atoms. May contain from 1 to 4 rings. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Cycloalkyl groups can be substituted at any available attachment point. Exemplary substituents include one or more of the following groups: halogen such as F, Br or Cl, hydroxy, alkyl, alkoxy, amino, nitro, cyano, thiol, alkylthio, and any of the substituents described above for alkyl groups.

[0010] The terms "alkoxy" or "alkylthio" alone or as part of another group mean an alkyl group as described above bonded by oxygen (-O-) bond or sulfur (S-) bond, respectively.

[0011] The term "alkyloxycarbonyl" alone or as part of another group means an alkoxy group bonded through a carbonyl group. The alkoxycarbonyl radical is represented by the formula: -C (O) OR, wherein the R group is a straight or branched C 1-6 alkyl, cycloalkyl, aryl or heteroaryl group.

[0012] The term "alkylcarbonyl" alone or as part of another group refers to an alkyl group bonded through a carbonyl group.

[0013] The term "alkylcarbonyloxy" alone or as part of another group means an alkylcarbonyl group bonded through an oxygen bond.

[0014] The term "aryl" alone or as part of another group refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups that are fused, e.g., naphthyl, phenantrenyl and the like. An aryl group therefore contains at least one ring having at least 6 atoms, with five such rings containing up to 22 atoms, with variable (resonant) double bonds between adjacent carbon atoms or corresponding heteroatoms. Aryl groups may optionally be substituted with one or more groups including, without limitation, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S ( O) m (m = 0, 1.2) or thiol.

[0015] The term "arylalkyl" or "aralkyl" alone or as part of another group means an aryl group, as described above, bonded through an alkyl group, as described above. And an example of an aralkyl group is a benzyl group.

[0016] The term "amino" alone or as part of another group refers to -NH2. The "amino" group may optionally be substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, aralkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl or carboxy. These substituents may be further substituted with a carboxylic acid, any of the alkyl or aryl substituents provided herein. In some embodiments, amino groups are substituted with carboxy or carbonyl to form N-acyl or N-carbamoyl derivatives.

[0017] The term "heteroaryl" alone or as part of another group refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups that have at least one heteroatom (O, S or N) in at least one of the rings. Each ring from a heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom . Fused rings forming bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms can optionally be oxidized and the nitrogen atoms can optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic

They must include at least one completely aromatic ring, but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group can be attached to any nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from the group consisting of halogens, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxy, alkoxy, thioalkyl, = O, -CO2H-C (= O ) H, -CO2alkyl, C (= O) alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclic group, heteroaryl, -NR'R ", - C (= O) NR'R", -CO2NR'R ", - C (= O) NR'R", - NR'CO2R ", NR'C (= O) R", - SO2NR'R "and NR'SO2R", wherein R 'and R "are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R' and R" together form a heterocyclic or heteroaryl ring.

[0018] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, olsazolyl, diazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, and pyrimidinyl, pyrimidinyl,

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, pyrolinyl, benzinurinyl, benzinurinyl, chininyl, tetrahydroquinolinyl and the like.

[0020] Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenantrollinyl, acridinyl, phenantridinyl, xanthenyl and the like.

[0021] The term "heterocyclic ring" alone or as part of another group refers to a stable, saturated or partially unsaturated monocyclic ring system containing 5 to 7 ring members from carbon atoms and other atoms selected from nitrogen, sulfur and / or oxygen. Preferably, the heterocyclic shadow ring is a 5 or 6 membered monocyclic ring and contains one, two or three heteroatoms selected from nitrogen, oxygen and / or sulfur. The heterocyclic ring may be optionally substituted, which means that the heterocyclic ring may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably di [lower] alkylamino), cyano, halogens, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amide (preferably lower alkyl amide), alkoxyalkyl (preferably lower alkoxy [lower] alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl (preferably phenyl), substituted aryl optionally substituted , lower alkyl and lower alkoxy groups. Examples of such heterocyclic rings are isoxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrolinyl, pyranyl, pyrazinyl, piperidyl, morpholinyl and triazolyl. The heterocyclic ring may be attached to the parent structure via a carbon atom or via any heterocycle heteroatom that results in a stable structure.

[0022] The term "heteroatom" means O, S or N, selected independently. It should be noted that any heteroatom with unfilled valences is assumed to have a hydrogen atom to fill the valence.

[0023] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine selected independently.

[0024] If the functional group is termed "protected", it means that the group is in a modified form to exclude undesirable side reactions at the protected site. Suitable protecting groups for compounds of the invention are recognized in this application, given the level of skill in the field, and with reference to standard textbooks such as Greene, TW and colleagues, Protective Groups in Organic Synthesis, Wiley, NY (1991).

[0025] As used herein, the term "patient" includes all mammalian species.

[0026] Suitable examples of salts of the compounds of the invention with inorganic and organic acids are hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, fumarate and phosphate. Salts that are not suitable for pharmaceutical applications but which can be used, for example, to isolate or purify free compounds I and II, their pharmaceutically acceptable salts, are also included.

[0027] In general, the present disclosure includes compounds of formula I or II:

<img file="PL1737451T3_D0003.tif" />

or an enantiomer, diastereomer, hydrate, solvate or pharmaceutically acceptable salt thereof, in which:

R¹ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, heteroarylalkyl, substituted heteroarylalkyl heterocycloalkyl or substituted heterocycloalkyl;

each R² is independently H, halogen, cyano, NO₂, OR⁵, NO⁶R⁷, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl;

B is O, NR⁸, NO⁸CH2, S, SO, SO2 or CR⁹R¹⁰;

- 7 11 37 38 1 V is NR or - (CR R) p - provided that if V is N, R is alkyl or cycloalkyl;

W and X are each independently C or N;

Y is selected from O, S, and NR¹²;

Z is-CR¹³R¹⁴ or- (CR¹³R¹⁴)₁NO¹⁵;

is 0 to 2;

n is 0 to 4 if both W and X are C, 0 to 3 if one of X or W is N, and 0 to 2 if both X and W are N; p is 1 to 4;

R³, R⁵, R⁶, R⁷, R⁸, R¹¹ and R¹⁵ are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group;

R⁴ is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, provided that (a) if R⁴ is phenyl (i) R⁴ is not substituted with both hydroxy and amido; and (ii) R⁴ is not substituted with -NRSO2R- wherein R is alkyl or aryl;

(b) if R⁴ is pyridyl, R⁴ is not substituted with both hydroxy and methoxy; and (c) if R⁴ is pyrimidinyl, it is not substituted with = O;

R⁹ and R¹⁰ are independently selected from H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

R is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CN, NO2 or SO2NH2;

R¹³ and R¹⁴ are independently selected from H, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl or together form a carbocyclic or heterocyclic ring having 3 to 8 atoms;

A is selected from one of the following:

<img file="PL1737451T3_D0004.tif" />

- 8 in which

D is S or O;

m is 0 to 6;

R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are independently selected from H, halogen, NR³⁰R³¹, OR³², CO2R³³, CONR³⁴R³⁵, SO2R³⁶, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

R²⁸ and R²⁹ are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or joined together to form a carbocyclic or heterocyclic ring having from 3 to 8 atoms;

R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, heterocycloalkyl or substituted heterocycloalkyl or substituted and

R³⁷ and R³⁸ each independently H, halogen or alkyl.

[0028] In some embodiments of the present disclosure, R¹ is substituted or unsubstituted phenyl, such as fluoro-phenyl, substituted or unsubstituted C1 to C4 alkyl, such as methyl or substituted or unsubstituted C3 to C8 cycloalkyl, such as cyclohexyl or cyclopentyl.

[0029] In some embodiments of the present disclosure, R² is C1 to C4 alkyl, halogen or haloalkyl.

[0030] In some embodiments of the present disclosure, R⁴ is an optionally substituted phenyl or a 5 or 6 membered nitrogen-containing heteraryl group such as pyridyl, pyridinone, pyrazolyl or pyrrolidyl.

[0031] According to one embodiment of the present disclosure, B is O, NHCH2, CH₂ or CH (OH); Y is O or S and Z is-CR¹³R¹⁴ or-NR¹⁵ in which R¹³, R¹⁴, and R¹⁵make up every H.

[0032] In some embodiments of the present disclosure, A is optionally substituted pyridine or pyrimidine wherein the substituent is alkyl, alkenyl, alkynyl, halogen, cycloalkyl, heterocycloalkyl, -NR³⁹COR⁴⁰, -NR³⁹WHAT)₂R⁴⁰, NR⁴¹R⁴² or-C (O) NR⁴³R⁴⁴in which R³⁹ R⁴⁰ , R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently H, lower alkyl, substituted lower alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or -NR⁴³R⁴⁴ form heterocycloalkyl.

[0033] According to some embodiments of the present disclosure, A is z-NR substituted pyridine⁴¹R⁴², -NR³⁹COR⁴⁰, -C (O) NR⁴³R⁴⁴, halogen, C.₁ to C.₄ alkyl, optionally substituted with hydroxy, hydroxyalkylamino, alkylamino, aminoalkylamino or heteroarylalkyl; or -C = CR⁴⁵, -C = CR¹⁶in which R⁴⁵ and R⁴⁶ are alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, -C (O) R⁴⁷, -NR³⁹COR⁴⁰, aryl or heteroaryl; or pyridine is substituted with aryl, such as phenyl, which may be further substituted with CONH2, methyl, aminoethyl, hydroxyethyl, -CONHCH2CH2NHCH3 or CH2CONH2; pyridines can also be substituted with pyridyl or piperidyl groups.

[0034] According to some embodiments of the present disclosure, A is optionally substituted pyrimidine. Preferred substituents include -NR⁴¹R⁴² lubNR³⁹WHAT₂R⁴⁰in which R⁴¹ and R² are preferably H or methyl and R³⁹ and R⁴⁰ are preferably H or alkyl.

[0035] In one embodiment of the present disclosure, the compounds have the following formula III:

<img file="PL1737451T3_D0005.tif" />

wherein

R is optionally substituted phenyl or alkyl; Z is NH or NCH3; R is F,₃

Cl, CH3 or CF3, R is H; and Y is O or S. In some embodiments, R¹ is C3 to C7 cycloalkyl, substituted or unsubstituted phenyl or (CH2) nR⁵⁰ where n is 1 to 3, R⁵⁰ is H, substituted or unsubstituted phenyl, amino, amido, CN, -C (O) 2H or -C (O) 2CH3.

In some embodiments of the present disclosure, the compounds have the following Formula IV formula:

<img file="PL1737451T3_D0006.tif" />

3 Wherein R is halo or H; R is H; R is optionally substituted phenyl, optionally substituted pyrazole or optionally substituted pyridyl, pyridinone or pyridine-N-oxide.

In one embodiment of the present disclosure, the compounds have the following formula V:

<img file="PL1737451T3_D0007.tif" />

in which R¹ is optionally alkyl or cycloalkyl; A is optionally substituted pyrimidine or pyridine; and R2 is halo or H; and R¹³ and R¹⁴ are either H or together with the carbon to which they are attached form a cycloalkyl such as cyclopropyl.

[0035] The disclosure also provides methods of treating a proliferative disease such as cancer by administering to a mammalian species in need of such treatment an effective amount of a compound of formulas I or II as defined above. In another embodiment, the disclosure provides a method of treating proliferative disease by modulating Met kinase by administering to mammalian species in need of such treatment an effective amount of a compound of formulas I or II as defined above in combination (simultaneously or sequentially) with at least one other anti-cancer agent. In a preferred embodiment, the proliferative disease is cancer.

[0036] Some compounds of Formulas I and II may generally be prepared according to the following Schemes 1-14. Compounds are easily synthesized using synthetic methods known to those skilled in the art. Solvates (e.g., hydrates) of compounds of formulas I and II are also within the scope of this disclosure. Methods of solvation are generally known in the art. Accordingly, the compounds of this disclosure may be in free or hydrate form, and may be prepared according to methods exemplified in the following schemes below.

[0037] The general routes to the pyridine and pyrimidine analogues described in the disclosure are illustrated in Scheme 1. The suitably substituted pyridine or pyrimidine 1 can be treated with functionalized phenols 2, 4, and 8 in the presence of a base such as sodium hydride, sodium hydroxide or potassium carbonate, providing the desired ethers 3, 5, and 9, respectively. Removal of the acetamide protecting group 3 with aqueous HCl in methanol provides the key intermediate 5. Alternatively, aniline 5 can be obtained from compound 9 by reducing the nitro group with either zinc dust and ammonium chloride or an Adams catalyst (platinum (IV) oxide) under hydrogenation conditions. Analogs 6 and 7 can then be obtained by acylation of aniline 5 with, for example, isocyanates, acid chlorides or by the action of a carboxylic acid and a coupling reagent such as: benzotriazol-1-yloxytris (trimethylamino) phosphonium hexafluorophosphate (BOP reagent), bromotripirophosphorophosphorophosphorophosphorophosphine ), O- (1H-benzotriazol-1-yl) -N, N, N; N'-tetramethyluronium tetrafluoroborate (TBTU). Acylthiourea 6 (Y = S, Z = NH) formation can be achieved by treating aniline 5 with an appropriately substituted isothiocyanate.

<img file="PL1737451T3_D0008.tif" />

[0038] Two different regioisomeric analogs of aminopyrimidine 14 and 19 can be obtained using the synthetic routes shown in schemes 2 and 3. PMB-protected aminopyrimidine 11, obtained from commercially available 2,4-dichloropyrimidine (10, Aldrich), can be converted to ether 13 via aniline 12 using the same chemistry shown in Scheme 1. Removal of the PMB group from 13 can be done with trifluoroacetic acid and anisole to produce compound 14.

<img file="PL1737451T3_D0009.tif" />

[0039] Similarly, PMB-protected aminopyrimidine 16, obtained from commercially available 4,6-dichloropyrimidine (15, TCI America), can be converted to ether 17 with the PMB deprotection step (Scheme 3). Bis-Boc (t-butyloxycarbonyl) protection of amine 17 with an excess of di-tert-butyl dicarbonate, followed by hydrogenation with an Adams catalyst provides aniline 18. Amine 19 can be obtained from compound 18 followed by acylation or a thiourea formation step and removal of Boc protecting groups under acidic conditions.

<img file="PL1737451T3_D0010.tif" />

[0040] The aminopyridazine derivative 26 can be obtained using the synthetic route shown in Scheme 4, which is based on similar chemistry cited in the following references: Chung, H.-A. and co-workers J. Heterocyclic Chem. 1999, 36, 905-910 and Bryant RD and co-workers J. Heterocyclic Chem. 1995, 32, 1473-1476, the disclosures of which are incorporated herein by reference. 4,5-Dichloropyridazine-3 (2H) -one (20, Aldrich) can be protected with, for example, a tetrahydropyran group (THP) to give intermediate 21. Treatment of compound 21 with an appropriately substituted phenol and base (i.e., hydride sodium), followed by reduction of the intermediate containing a nitro group, under catalytic hydrogenation conditions, may provide aniline 22. Protection of aniline group 22 as bis-benzyl carbamate (Cbz), followed by removal of the THP group under acidic conditions can provide compound 23. Treatment of compound 23 with either trifluoroacetic anhydride (TFAA), phosphorus oxychloride or phosphorus oxybromide in the presence of a base such as triethylamine or diisopropylethylamine may introduce the needed leaving group at the 3-position of compound 24. Replacement of the leaving group X of compound 24 with an appropriately substituted amine, then removal of the Cbz group can produce intermediate 25. Aniline 25 can be converted to the desired 3-aminopyridazine analogue 26 using the chemistry previously described in Schemes 1-3.

<img file="PL1737451T3_D0011.tif" />

[0041] 2-Aminopyridine derivatives can be obtained using the synthetic routes shown in Schemes 5 and 6. Aniline 27, obtained from the chemistry described in Scheme 1, can be converted to intermediate 28 after heating with Cu powder and potassium carbonate in benzylamine (Scheme 5 ). Removal of the benzyl protecting group of compound 28 under catalytic hydrogenation with palladium on carbon provides aminopyridine 29. Intermediates 28 or 29 can be treated with isothiocyanates 30, isocyanates 32, and carboxylic acids 34 in the presence of a coupling reagent to give acylthiourea 31, acylurea 33, and amide 35, respectively.

<img file="PL1737451T3_D0012.tif" />

[0042] In a similar approach, the 2-chloropyridine intermediate 36, obtained using the chemistry described in scheme 1, can be converted to N-oxide 37 using acid

3-chloroperbenzoate (m-CPBA) in chloroform (see WO2004 / 002410) (Scheme 6). Treatment of compound 37 with an appropriately substituted amine can provide intermediate 38. Reduction of N-oxide of compound 38, e.g., triphenylphosphine, then removal of the acetamide protecting group under acidic conditions can provide aniline 39. Conversion of aniline 39 to the desired analog 40 can be accomplished using the chemistry previously described in diagrams 1-5.

DIAGRAM 6

<img file="PL1737451T3_D0013.tif" />

[0043] In an alternative approach to compounds similar to 40, 2aminopyridine derivatives 47 and 48 can be obtained according to the synthetic sequence illustrated in Scheme 7. To this end, 4-chloropicolinic acid (41, TCI America) can be converted to 4- chloropicolinamide (42) using a two-step procedure involving thionyl chloride followed by ammonia in methanol. Coupling of intermediate 42 with a 4aminophenol 43 derivative in the presence of a base such as potassium t-butoxide can provide a picolinamide 44 derivative. Acylation or formation of an acylurea intermediate 44 can provide intermediates such as 45 and 46. Treatment of picolinamide derivatives 45 and 46 with either bis- (trifluoroacetoxy) iiodenzene, pyridine and water in DMF or bromine, potassium hydroxide in water promotes Hofmann rearrangement to produce the desired 2-aminopyridine derivatives 47 and 48.

<img file="PL1737451T3_D0014.tif" />

[0044] Compounds containing thiazoles 53, 57 and 62 can be obtained using the synthetic routes described in schemes 8-10. Replacement of leaving group 49 (Scheme 8) or 54 (Scheme 9) with aniline / phenol 50 can provide intermediates 51 and 55, respectively. Reduction of the nitro substituents in 51 and 55 with zinc dust and ammonium chloride in a mixture of THF-MeOH produces anilines 52 and 56, respectively. Conversion of anilines 52 and 56 to the desired compounds 53 and 57 can be carried out using the chemistry previously described (vide supra).

<img file="PL1737451T3_D0015.tif" />

[0045] Reductive amination of aldehyde 58 can be achieved using the methods described in WO 2004/001059, incorporated herein in full by reference, using properly substituted aniline 59, nitro intermediate 60 (Scheme 10) can be provided. The desired aminothiazole derivative 62 can then be obtained using chemistry similar to that described in Schemes 8 and 9.

DIAGRAM 10

<img file="PL1737451T3_D0016.tif" />

[0046] The inclusion of various substituents at the 3-position of the pyridine core can be carried out using the chemistry depicted in scheme 11. To this end, 4-chloro-3-iodopyridine (63,

- 17 Tabanella, S. and co-workers of Org. Biomol. Chem. 2003, 1, 4254-4261.) Can be coupled to a 4-nitrophenol derivative 8 in the presence of a base such as diisopropylethylamine (Hunig's base) to give the desired iodide intermediate 64. Various coupling reactions involving organometallic agents can then be performed with the iodide derivative

64, examples of which are illustrated in Scheme 11. Iodide 64 can be treated with amines (R "R'NH), substituted alkynes 66, arylborons 67, vinyl stannanes, and α, β-unsaturated esters in the presence of a palladium or copper catalyst, yielding intermediates 65 , 6871, respectively. The nitro moiety of compounds 65 and 68-71 can be reduced with, for example, zinc dust and ammonium chloride in a THF-MeOH mixture, and the resulting aniline intermediates can be acylated using the chemistry previously described in Schemes 1-5.

[0047] Intermediate 71 can then be converted to α, β-unsaturated amides 73 (Scheme 12). Compound 72, Obtained from acid catalyzed ester 71 hydrolysis, can be coupled with various amines (R "R'NH) in the presence of a coupling reagent such as, but not limited to, EDCI, TBTU, DCC, providing the desired amide intermediate 73. Reduction of the nitro moiety 73 and subsequent acylation of the required aniline intermediate can be carried out using the chemistry previously described in schemes 1-5.

<img file="PL1737451T3_D0017.tif" />

<img file="PL1737451T3_D0018.tif" />

[0048] Intermediate 74 can also be further modified to obtain propargyl amines 76 (Scheme 13). Mesylation of propargyl alcohol 74 can be accomplished with methanesulfonyl chloride in the presence of a base such as diisopropylethylamine (Hunig's Base) to give mesylate 75. Replacement of the mesylate group of compound 75 with various amines (R "R'NH) can provide propargyl amines 76. The reduction of the nitro moiety 76 and subsequent acylation of the required aniline intermediate can be carried out using the chemistry previously described in schemes 1-5.

<img file="PL1737451T3_D0019.tif" />

[0049] 3-Aminopyridine derivatives 79 and 80 can be obtained according to the synthetic route described in Scheme 14. To this end, 4-chloro-3-nitropyridine (77, Lancaster Synthesis Ltd.) can be coupled with 4-aminophenol in the presence of a base such as sodium hydride in DMF to yield the nitro intermediate 78. The chemistry previously described above can be used to convert intermediate 78 to the desired compounds 79 and 80. The amino substituent 79 and 80 can also be further modified, for example by alkylation, acylation, arylation or sulfonylation.

DIAGRAM 14

<img file="PL1737451T3_D0020.tif" />

[0050] The introduction of substituents at the 5 or 3 position of the 2-aminopyridine ring can be carried out using iodide intermediates 83 and 86, respectively (Schemes 15 and 16). The 2-carboxamide derivative 81 can be converted to the 2aminopyridine 82 derivative using the Hofmann rearrangement protocol previously described in Scheme 7. Iodination of position 5 of compound 82 can be achieved with N-iodosuccinimide in acetonitrile-isopropanol mixtures to give the desired iodide intermediate 83. Alternatively, t-butyl-4-chloropyridin-2-ylcarbamate (84, CB Research and Development Inc.) can be converted to t-butyl-4-chloro-3-iodo-pyridin-2-ylcarbamate (85) in a two-step process involving n- butyllithium in THF at low temperature followed by the addition of iodine. Removal of the N-Boc (t-butylcarbamate) protecting group with 85 boiling aqueous hydrogen bromide, then coupling the chloride intermediate with a 4-nitrophenol derivative 8 in the presence of diisopropylamine (Hunig's Base) in N-methylpyrrolidinone (NMP) at temperature can provide the iodide intermediate 86. The iodide intermediates 83 and 86 m can be further processed using chemistry similar to that previously described in Scheme 11.

<img file="PL1737451T3_D0021.tif" />

[0051] Methylene (B = CH2) linked analogs 93 and 94 can be obtained according to the synthetic sequence shown in scheme 17. Compound 88, Obtained from N-Boc protected 4-bromoaniline derivative 87, can be treated with methylmagnesium bromide, then tert-butyllithium and 2-chloroisisonotinaldehyde (Frey, LF et al. Tetrahedron Lett. 2001, 42, 6815-6818) at low temperature to obtain intermediate 90. Oxidation of the pyridine ring 90 with 3-chloroperbenzoic acid (m-CPBA), then replacement of the chloro substituent with amine (R'NH2) and then reduction of the intermediate N-oxide with zinc and ammonium formate in methanol can provide the compound

Intermediate 91. If allylamine is used as the nucleophilic amine (R'NH2), the allyl group can be removed from amine 91 using a rhodium catalyst in an ethanol-water mixture. The removal of the hydroxyl group 91 can be carried out in two different ways. For example, hydrogenolysis of compound 91 in the presence of a palladium catalyst, followed by deprotection of the N-Boc group in aniline under acidic conditions (HCl in methanol) can provide compound 92. Alternatively, compound 92 can be obtained by acylating alcohol 91 and then hydrogenating the intermediate in the presence of a palladium catalyst and removing the N-Boc protecting group under acidic conditions (trifluoroacetic acid in methylene chloride). Intermediate 92 can then be acylated to provide the desired compounds 93 and 94 using the chemistry previously described in Schemes 1-5.

<img file="PL1737451T3_D0022.tif" />

[0052] Derivatives of heterocyclic amide 100 and 105 can be obtained according to the synthetic routes described in schemes 18 and 19. For this purpose, methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (97) can be obtained in a two-stage process starting from from commercially available (E) -dimethyl 2- (3-methoxyallylidene) malonate (95) (Scheme 18). In this way, treatment of compound 95 with aniline at room temperature can provide intermediate 96, which can then cyclize in the presence of a base such as sodium hydride in dimethyl sulfoxide to produce 97. Hydrolysis of intermediate 97 under basic conditions can provide 2-oxo-1 acid -phenyl-1,2-di-21-pyridine-3-carboxylic acid (98). Carboxylic acid 98 can then be conjugated to aniline derivative 99 in the presence of a coupling reagent such as 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt) in DMF to provide the desired compound 100.

<img file="PL1737451T3_D0023.tif" />

[0053] The intermediate N-pyridyl 104 (Scheme 19) can be obtained by a two-stage process in which the commercially available 6-bromopicolinic acid (101) by coupling with phenyl-1,3,2-dioxaborinate 102 (Aldrich) in the presence of palladium (0) catalyst and sodium carbonate, followed by oxidation of the required intermediate 103 at elevated temperature. Coupling of intermediate 104 with aniline derivative 99 can provide the desired compound 105.

<img file="PL1737451T3_D0024.tif" />

[0054] Compounds of Formulas I and II are useful in the treatment of various cancers, including but not limited to the following:

- 22 (a) cancer, including bladder, breast, intestine, liver, lung cancer, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;

(b) hematologic malignancies of the lymphoma origin, including leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma and Burkett's lymphoma;

hematopoietic malignancies including acute and chronic (c) myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; hematopoietic cancers including those of plasma origin, such as multiple myeloma;

(d) tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

(e) tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and neuroblastoma; and (f) other cancers including melanoma, seminoma, teratocarcinoma, osteosarcoma, parchment skin, squamous cell keratosis, thyroid follicular cancer, and Kaposi's sarcoma.

[0055] Because of the key role of protein kinases in regulating cell proliferation in general, inhibitors may act as reversible cytostatics that may be useful in the treatment of any disease processes that are characterized by a cell proliferative disorder process, e.g. benign prostatic hyperplasia, familial adenomatous polyposis , neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scars, inflammatory bowel diseases, transplant rejection, endotoxic shock and fungal infections.

[0056] Compounds of Formulas I and II as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned above), viral infections (including, but not limited to, herpes virus, pox virus, Epstein virus -Barra, Sindbis virus and adenovirus), preventing the development of AIDS in people infected with HIV, autoimmune diseases (including but not limited to lupus, erythematosus, autoimmune glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and autoimmune diabetes), neurodegenerative diseases (including but not limited to Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, pigmentary retinopathy, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injuries associated with myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin or alcohol-induced liver disease, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), cavity mucositis nose and paranasal sinuses,

- 23 sensitive to acetylsalicylic acid, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

[0057] Compounds of Formulas I and II may regulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including, but not limited to, HIV, human papillomavirus, herpes virus, smallpox virus, Epstein-Barr virus, Sindbis virus and adenovirus).

[0058] Compounds of Formulas I and II may be useful in cancer chemoprevention. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-cancer cells that have already been affected or inhibiting tumor recurrence.

[0059] Compounds of Formulas I and II may also be useful in inhibiting angiogenesis and tumor metastasis.

[0060] The term "anti-cancer" agent includes any known agent that is useful in the treatment of cancer, including 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyl testosterone, prednisolon, triamcinolone, chlorotrianisen, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, Zoladex, matrix metalloproteinase inhibitors, VEGF inhibitors, including anti-VEGF antibodies such as Avastin, and small molecules such as ZD6474 and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055 are also included. Genentech anti-HER2 antibodies (e.g., Herceptin) can also be used. Suitable EGFR inhibitors include gefitinib, erlotinib, and cetuximab. Pan Her inhibitors include canertinib, EKB-569, and GW-572016. Src inhibitors as well as Casodex are also included^® (bicalutamide, Astra Zeneca), tamoxifen, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 inhibitors, and PDGF inhibitors such as imatinib. Also included are anti-angiogenic and anti-vascular agents that, by interrupting the blood supply to solid tumors, inactivate cancer cells by depriving them of nutrition. Castration, which also makes androgen-dependent cancers nonproliferative, can also be used. IGF1R, non-receptor and receptor tyrosine kinase inhibitors and integrin signaling inhibitors are also available. Additional anti-cancer drugs include microtubule stabilizing agents such as paclitaxel (also known as Taxol^®), docetaxel (also known as Taxotere^®), 7-Methylthiomethylpaclitaxel (disclosed in US 5,646,176), 4-desacetyl-4-methylcarbonylpaclitaxel, 3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-defenyl-3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in USSN 09/712, 352 filed November 14, 2000, C-4-methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, deoxyepotilon A, deoxyepotilon B, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 165 *]] - 7-11dihydroksy-8,8,10,12,16-pentamethyl-3- [1 -methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17oxabicyclo [14.1.0] heptadecane-5,9-dione (disclosed in WO 99/02514), [1S [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 3- [2- [2- (aminomethyl) -4-thiazolyl] -1-methylethenyl] -7,11-dihydroxy -8,8,10,12,16-pentamethyl-4-17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (disclosed in USP 6,262,094) and their derivatives; and microtubule-breaking agents. Also suitable are CDK inhibitors, antiproliferative cell cycle inhibitor, epidophyllotoxin; anti-cancer enzyme, topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platinum and carboplatin; biological response modifiers; growth inhibitors; therapeutic antihormonal agents; leucovorin; tegafur and hematopoietic growth factors.

[0061] Additional cytotoxic agents include melphalan, hexamethylmelamine, thiotepa, cytarabine, idatreksta, trimetrexate, dacarbazine, L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide, leuprolide, pyridobenzone derivatives.

[0062] Pharmaceutical compositions containing the active substance may be in a form suitable for oral administration, for example in the form of tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions intended for oral administration may be prepared according to any method known in the art for the preparation of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavors, dyes and preservatives to provide pharmaceutically pleasant and tasty preparations . The tablets contain the active substance in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the production of tablets. Such excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, for example starch, gelatin, polyvinylpyrrolidone or excipients and lubricants, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated according to known methods of masking the unpleasant taste of the drug or delaying the disintegration and absorption in the gastrointestinal tract and thus providing a sustained effect. For example, a water-soluble taste masking material such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or a retarder material such as ethyl cellulose, cellulose acetate butyrate may be used. [0063] Formulations for oral use may also be presented in the form of hard gelatin capsules in which the active substance is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active substance is mixed with a water-soluble carrier, such as polyethylene glycol or an oil environment, for example peanut oil, liquid paraffin or olive oil.

[0064] Aqueous suspensions contain the active ingredient in admixture with suitable excipients for the manufacture of aqueous suspensions. Such excipients are suspending agents, e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia, the dispersing or wetting agents can be a naturally occurring phosphatide, e.g. lecithin, or

- alkylene oxide condensation products with fatty acids, for example polyoxyethylene stearate, or ethylene oxide condensation products with long-chain aliphatic alcohols, for example heptadekaethylene-oxycetanol or ethylene oxide condensation products with partial fatty acids and hexitol esters such as monooleate polyoxyethylene, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0065] Oily suspensions may be prepared by suspending the active ingredient in vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above and flavoring agents may be added to provide a tasty oral formulation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0066] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are, for example, those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0067] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring phosphatides, for example, soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitol monooleate, and condensation products of said partial esters with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0068] Syrups and elixirs may be prepared with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain soothing, preserving, flavoring and coloring agents and an antioxidant.

[0069] The pharmaceutical compositions may be in the form of sterile injectable aqueous solutions. Acceptable substrates and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.

[0070] Sterile injectable preparations may also be sterile oil-in-water microemulsions in which the active ingredient has been dissolved in the oil phase. For example, the active substance may first be dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerin and processed into a microemulsion.

[0071] Injectable solutions or microemulsions can be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compound. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is Deltec CADD-PLUS.TM. model 5400 intravenous pump.

[0072] The pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be prepared according to a method known in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectable preparations may be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1,3-butandiol. In addition, sterile solid oils are commonly used as a solvent or suspending medium. For this purpose any mild oil can be used, including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may find use in the preparation of injectables.

[0073] Compounds of Formulas I and II may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be obtained by mixing the drug with a suitable non-irritating excipient which is a solid at ambient temperatures but a liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols with different molecular weights, and polyethylene glycol fatty acid esters.

[0074] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of formula I are used. (For the purposes of this application, topical application includes mouthwash and gargle.) [0075] The compounds of the present invention may be administered in intranasal form by topical application of suitable nasal vehicles and delivery devices, or by transdermal routes using these forms of transdermal patches. well known to those skilled in the art. For administration in the form of a transdermal delivery system, the dosage to be administered will of course be continuous rather than batch in the dosage regimen. The compounds of the present invention may also be provided as suppositories using substrates such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular weights, and polyethylene glycol fatty acid esters.

[0076] If the compound of the present invention is administered to a human, the daily dose will normally be determined by the prescribing physician, with the dose generally

- 27 varied depending on the age, body weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.

[0077] If prepared as a fixed dose, such product combinations use the compounds of the present invention within the dosage range described above and another pharmaceutically active agent or treatment within its approved dosage range. Compounds of formulas I and II may also be administered sequentially with known anti-cancer or cytotoxic agents if the combination formulation is unsuitable. The disclosure is not limited in the administration sequence; compounds of formulas I and 11 may be administered either before or after administration of known anti-cancer or cytotoxic agents.

Tests [0078] The pharmacological properties of the compounds of this invention can be confirmed in many pharmacological tests. The exemplary pharmacological tests listed below were carried out using the compounds of the invention and their salts.

Met kinase assay [0079]

<td>reagents</td><td>Final concentration of the substrate mixture</td>

<td>Stock solution</td><td></td>

<td>Tris-HCl, (1M, pH 7.4)</td><td>20 mM</td>

<td>MnCl2 (1M)</td><td>1 mM</td>

<td>DTT (1M)</td><td>1 mM</td>

<td>BSA (100mg / ml)</td><td>0.1 mg / ml</td>

<td>polyGlu₄/ tyr (10mg / ml)</td><td>0.1 mg / ml</td>

<td>ATP (1mM)</td><td>1 μΜ</td>

<td>γ-ATP (10) gCi / gl)</td><td>0.2 μθ / ml</td>

<td>Buffer</td><td>A mixture of enzymes</td>

<td>20ul 1M DTT</td><td>4ul GST / Met enzyme (3.2mg / ml) = 10ng / rxn</td>

<td>200ul 1M Tris-HCL, pH 7.4</td><td>qs 12ml buffer</td>

<td>20ul 100mg / ml BSA</td><td></td>

<td>qs 20ml H₂0</td><td></td>

[0080] Incubation of mixtures used in the Met kinase assay contains a synthetic polyGlu substrate: Tyr, (4: 1), ATP, ΑΤΡ-γ-³³ρ and a buffer containing Mn ++ and / or Mg ++, DTT, BSA, and Tris buffer. Reactions were incubated for 60 minutes at 27 ° C and stopped by adding cold trichloroacetic acid (TFA) to a final concentration of 4%. TCA sediments were collected on plates

- 28 UniFilter GF / C filtration filters (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester (Packard Instrument Co., Meriden, CT) and filter radiation was counted in a 96-well liquid scintillation counter (Packard Instrument Co., Meriden, CT). Dose-response curves were developed to determine the concentration required to inhibit 50% of kinase activity (IC50). Compounds were dissolved in 10 mM in dimethyl sulfoxide (DMSO) and estimated at six concentrations, each in four copies. The final DMSO concentration in the test is 1%. IC50 values ​​were obtained using nonlinear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

[0081] Preferred compounds of the invention inhibit Met kinase with IC 50 values ​​between 0.01 to 100 μΜ. The most preferred compounds have IC values₅₀ less than 0.5 μΜ.

[0082] Another object of the invention are pharmaceutical preparations intended for use in the conditions as described above, including the treatment of cancer, inflammation and arthritis, which contain at least one compound of formula II as defined in the appended claim I or at least one of its pharmacologically acceptable acid addition salts and the use of a compound of formula II as defined in the appended claim 1 for the preparation of a pharmaceutical preparation having activity in the treatment of the proliferative diseases described above including cancer, inflammation and / or arthritis.

[0083] In the following examples and preparative examples, the described method and process for making and using the invention are intended to illustrate rather than limit it. It is understood that there may be other practical implementations falling within the scope of the invention as defined in the appended claims.

EXAMPLES [0084] The disclosure is further described by the following working examples. Examples 48 to 58, 62, 66 to 71, 98, 101, 114, 115, 120 to 125, 129, 130, 132, 134, 137, 140, 146 and 147 are examples of the invention and are preferred embodiments of the invention; other examples do not meet the definition of a substituent of the appended claim 1. All reactions were conducted with steady agitator under dry nitrogen or argon atmosphere. All evaporation and concentration operations were carried out on a rotary evaporator under reduced pressure. Commercial reagents were used as received without further purification. The solvents were anhydrous with commercial purity and used without further drying or purification. Flash chromatography was performed using silica gel (EMerck Kieselgel 60, 0.040-0.060 mm).

[0085] Reverse phase analytical HPLC (RP) was performed using a column

Phenomenex Luna C18 S5 4.6 mm χ 50 mm or YMC S5 ODS 4.6 x 50 mm column. In each case, a 4 min linear gradient was used (from 100% A:% 0 B to 0% A: 100%

B) with the following mobile phase system: A = 90% H₂O / MeOH + 0.2% H₃AFTER₄; B = 90%

MeOH / H₂O + 0.2% H₃AFTER₄ at flow rate = 4 ml / min and detection at 220 nm.

[0086] Reverse phase preparative HPLC (RP) was performed using a linear elution gradient using 10% methanol, 90% water, 0.1% TFA (solvent A) and 90% methanol, 10% water, 0.1% TFA (solvent B) and detection at 220 nm on one of the following columns: A-Shimadzu S5 ODS-VP 20 χ 100 mm column with a flow rate of 20 ml / min; B-YMC S5 ODS 30 χ 100 mm column with a flow rate of 20 ml / min; C-Phenomonex 30 χ 250 mm column with a flow rate of 10 ml / min; D-YMC S5 ODS 20 χ 250 mm column with a flow rate of 10 ml / min; E-YMC S10 ODS 50 χ 500 mm column with a flow rate of 50 ml / min; or F-YMC S10 ODS 30 χ 500 mm column with a flow rate of 20 ml / min.

[0087] All end products were characterized by ¹H NMR, RP HPLC, mass spectroscopy: electrospray ionization (ESI MS) or atmospheric pressure ionization (API MS). spectrum¹H NMR was obtained on either 500 MHz JEOL or 400 MHz Bruker instruments. spectrum¹³C NMR recorded at 100 or 125 MHz. Field strength is expressed in units of δ (parts per million, ppm) relative to solvent signals, and signal multiplets are designated as: s, singlet; d, doublet; dd, doublet of doublets; dm, doublet of multiplets; t, triplet; q, quartet; br s, broad singlet; m, multiplet.

[0088] The following abbreviations have been used for commonly used reagents: Boc or BOC: t-butyl carbamate; Fmoc: 9H-fluorenylmethyl carbamate; TEA: triethylamine; NMM: N-methylmorpholine; Ms: methanesulfonyl; DIEA or DIPEA: diisopropylethylamine or Hunig's base; NMP: N-methylpyrrolidinone; BOP reagent: benzotriazol-1-yloxytris (trimethylamino) phosphonium hexafluorophosphate; DCC: 1,3-dicyclohexylcarbodiimide; EDCI: 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; RT or rt: room temperature; tR: retention time; h: hour (hours); min: minute (minutes); PyBroP: bromotripyrrolidinophosphonium hexafluorophosphate; TBTU: O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate; DMAP: 4-N, N-dimethylaminopyridine; HOBt or HOBT: hydroxybenzotriazole; Na (OAc) 3BH: sodium triacetoxyborohydride; HOAc: acetic acid; TFA: trifluoroacetic acid; LiHMDS: lithium bis (trimethylsilyl) amide; DMSO: dimethyl sulfoxide; MeCN: acetonitrile; MeOH: methanol; EtOAc: ethyl acetate; DMF: dimethylformamide; THF: tetrahydrofuran; DCE: 1,2-dichloroethane; Et2O: diethyl ether; DCM: dichloromethane or methylene chloride; m-CPBA: 4-chloroperbenzoic acid.

Example 1

<img file="PL1737451T3_D0025.tif" />

N- (4-Fluorophenyl) -N- (4- (pyridin-4-yloxy) phenyl) -malonamide

<img file="PL1737451T3_D0026.tif" />

A) 4- (4-Aminophenoxy) pyridine [0091] A solution of 4-chloropyridine hydrochloride (Aldrich, 3.0 g, 20.0 mmol) in dimethyl sulfoxide (40 ml) was treated with 4-aminophenol (Aldrich, 2.1 g, 20.0 mmol) and granules of sodium hydroxide (2.0 g, 50.0 mmol) and the mixture was heated at 100 ° C for 18 h. The mixture was cooled to room temperature, poured into a mixture of ice water (300 g) and extracted with Et2O (3 x 150 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give 4- (4-aminophenoxy) aniline as a pale yellow solid (3.5 g, 94%). ¹H NMR (DMSO-d6) δ 8.38 (dd, 2H, J = 5.5, 1.5 Hz), 6.83-6.79 (m, 4H), 6.63-6.59 (m , 2H), 5.13 (br s, 2H); MS (ESI⁺) m / z 187.2 (M + H)⁺.

<img file="PL1737451T3_D0027.tif" />

B) 3- (4-Fluoro-phenylamino) -3-oxo-propanoic acid [0092] To a solution of 3-chloro-3-oxo-propionate ethyl (Aldrich, 5.0 mL, 40 mmol) in methylene chloride (100 mL) at 0 ° C was added diisopropylethylamine (8.4 mL, 48 mmol) then 4-fluoroaniline (Aldrich, 3.6 mL, 38 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of 100 mL saturated NaHCO3 solution. The aqueous layer was extracted with chloroform (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil which solidifies on standing (10 g). ¹H NMR (CDCl3) δ 9.30 (br s, 1H), 7.55 (m, 2H), 7.05 (t, 2H, J = 8.8 Hz), 4.28 (q, 2H, J = 7.2 Hz),

3.49 (s, 2H), 1.35 (t, 3H, J = 7.1 Hz); MS (ESI⁺) m / z 226.11 (M + H)⁺.

[0093] The above ester was dissolved in 100 mL of ethanol and cooled to 0 ° C. A 1 N aqueous NaOH solution (100 ml) was added and the reaction stirred at 0 ° C for 1 h. The reaction was concentrated in vacuo to remove ethanol. The aqueous solution was extracted with EtOAc (50 mL) and then acidified with 1N aqueous HCl. The aqueous solution was extracted with EtOAc (5 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow solid (6.31 g, 84%) which was used without further purification. ¹H NMR (DMSO-d6) δ 12.9 (br s, 1H), 10.3 (br s, 1H), 7.59 (m, 2H), 7.16 (t, 2H, J = 8.9 Hz), 3.34 (s, 2H); MS (ESI⁺) m / z 198.43 (M + H)⁺.

- 31 C) N- (4-Fluoro-phenyl) -N- (4- (pyridin-4-yloxy) -phenyl) malonamide [0094] A solution of 4- (4-aminophenoxy) pyridine (93 mg, 0.50 mmol) in DMF treated

3- (4-Fluoro-phenylamino) -3-oxopropanoic acid (99 mg, 0.50 mmol), DIPEA (113 μΐ, 0.65 mmol) and TBTU (209 mg, 0.65 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove DMF and the residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The EtOAc layer was washed with saturated sodium bicarbonate solution, brine, dried (MgSO 4 and concentrated to give the title compound as an off-white foam (140 mg, 76%).¹H NMR (DMSO-d6) δ 10.30 (s, 1H), 10.24 (s, 1H), 8.43 (dd, 2H, J = 5.5, 1.5 Hz), 7.70 ( d, 2H, J = 9.1 Hz), 7.63-7.60 (m, 2H), 7.17-7.14 (m, 4H), 6.89 (dd, 2H, J = 5, 5, 1.5 Hz), 3.46 (s, 2H); MS (ESI⁺) m / z 365.9 (M + H)⁺.

Example 2

<img file="PL1737451T3_D0028.tif" />

1- (4- (6-Chloropyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea

<img file="PL1737451T3_D0029.tif" />

A) 4-Chloro-6- (2-fluoro-4-nitrophenose) pyrimidine [0097] A mixture of 4,6-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Aldrich, 0 , 79 g, 5.0 mmol) and DMF (10 mL) were treated with potassium carbonate (0.72 g, 5.2 mmol) and heated at 80 ° C for 3h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and concentrated to give the crude product as a yellow solid. The crude product was triturated with isopropyl ether to give 4-chloro-6- (2-fluoro-4-nitrophenoxy) pyrimidine as a yellow solid (1.3 g, 94%). ¹H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.51 (dd, 1H, J = 8.6,

2.5 Hz), 8.31 (d, 1H, J = 9.1 Hz), 7.87 (d, 1H, J = 9.1 Hz), 7.84 (s, 1H).

<img file="PL1737451T3_D0030.tif" />

B) 4-Chloro-6- (2-amino-2-fluorophenoxy) pyrimidine [0098] A solution of 4-chloro-6- (2-fluoro-4-nitrophenoxy) pyrimidine (1.3 g, 4.8 mmol) in methanol (120 ml) was treated with Raney nickel (1.5 g, aqueous suspension) and the reaction mixture was stirred under a hydrogen atmosphere (from a latex balloon) at RT for 3h. The catalyst was filtered off, the filtrate was concentrated, and the residue was partitioned between CH2Cl2 and water. The methylene chloride layer was separated, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography on silica gel using 1-2% MeOH in CH2Cl2 as the eluent to give 4-chloro-6- (2-amino-2-fluorophenoxy) pyrimidine as a white solid (600 mg, 52%). ¹H NMR (DMSO-d6) 88.64 (s, 1H), 7.39 (s, 1H), 6.97 (dd, 1H, J =

8.8, 8.8 Hz), 6.46 (dd, 1H, J = 13.1, 2.5 Hz), 6.38 (dd, 1H, J = 8.6, 2.5 Hz), 5.44 (br s, 2H);

MS (ESI⁺) m / z 240.04 (M + H)⁺.

C) 1- (4- (6-Chloropyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea [0099] 4-Fluoro-phenylacetyl chloride (Lancaster, 0.52 g, 3.0 mmol) was added to a mixture of NaSCN (0.27 g, 3.3 mmol) and EtOAc (12 mL) and the resulting mixture was stirred at room temperature for 30 min. This mixture was added to a solution of 4-chloro-6- (2 amino-2-fluorophenoxy) pyrimidine in 1: 1 EtOAc / CH 2 Cl 2 (5 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue partitioned between EtOAc / H2O. The EtOAc layer was separated, washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using 10-35% EtOAc / hexanes as the eluent to give the title compound as a yellow crystalline solid (0.85 g, 65%).¹H NMR (DMSO-d6) δ 12.40 (s, 1H), 11.81 (s, 1H),

8.67 (s, 1H), 7.90 (dd, 1H, J = 12.1, 2.0 Hz), 7.62 (s, 1H), 7.47-7.41 (m, 2H) , 7.38-7.35 (m, 2H), 7.17 (t, 2H, J = 8.8 Hz), 3.81 (s, 2H); MS (ESI⁺) m / z 434.98 (M + H)⁺.

Example 3

<img file="PL1737451T3_D0031.tif" />

1- (2- (4-Fluorophenyl) acetyl) -3- (4- (pyridin-4-yloxy) phenyl) thiourea

[0101] The title compound was prepared using 4- (4-aminophenoxy) pyridine (Compound A from example 1) and a similar procedure was described for the preparation of compound C from example 2. Yield: 10%. ¹H NMR (CDCl3) δ 12.3 (s, 1H), 8.63 (s, 1H), 8.49, (d, 2H, J = 6.2 Hz), 7.71 (d, 2H, J = 8.9 Hz), 7.31-7.27 (m, 2H), 7.14-7.09 (m, 4H), 6.90 (dd, 2H, J = 4.8, 1.4 Hz),

3.73 (s, 2H); MS (ESI⁺) m / z 382.2 (M + H)⁺.

Example 4

<img file="PL1737451T3_D0032.tif" />

N - (4- (6-Chloropyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0103] Solution of 4-chloro-6- (2-amino-2-fluorophenoxy) pyrimidine (29 mg, 0.12 mmol,

Compound B of Example 2), 3- (4-fluorophenylamino) -3-oxopropanoic acid (26 mg, 0.13 mmol, Compound B of Example 1) in DMF (1.5 mL) was treated with DIPEA (24 μΐ, 0 , 14 mmol) and TBTU (46 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL), and the organic layer was washed with brine (3 x 20 mL), dried (MgSO 4 and concentrated. The product was purified by flash chromatography using 1-3% MeOH in CH 2 Cl 2 as the eluent to afford the title compound as a white solid (35 mg, 78%). ¹H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.25 (s, 1H), 8.65 (s, 1H), 7.78 (d, 1H, J = 12.1 Hz) , 7.63-7.57 (m, 3H), 7.40-7.34 (m, 2H), 7.16 (t, 2H, J = 8.8 Hz), 3.48 (s, 2H ); MS (ESI⁺) m / z 419.21 (M + H)⁺.

Example 5

<img file="PL1737451T3_D0033.tif" />

N - (3-Fluoro-4- (6- (methylamino) pyrimidin-4-yloxy) phenyl) -N- (4-fluorophenyl) malonamide [0105] N - (4- (6-chloropyrimidin-4-yloxy) solution -3-fluorophenyl) -N- (4-fluorophenyl) malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 ml) was treated with 2 M methylamine / THF (0.2 ml) and heated in capped vial, at 80 ° C for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC using a MeOH-H2O gradient containing 0.1% TFA. The product containing fraction was freeze-dried

To give the title compound as a pale yellow solid (60 mg, 34%). ¹H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, 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 414.16 (M + H)⁺.

Example 6

<img file="PL1737451T3_D0034.tif" />

tert-Butyl 6- (2-fluoro-4- (3- (4-fluorophenylamino) -3-oxopropanoamido) phenoxy) pyrimidin-4-ylcarbamate

<img file="PL1737451T3_D0035.tif" />

A) N- (2,4,6-Trimethoxybenzyl) -6-chloropyrimidine-4-amine A mixture of 4,6-dichloropyrimidine (Aldrich, 1.48 g, 10.0 mmol), hydrochloride 2,4,6 -trimethoxybenzylamine (2.33 g, 10.0 mmol), DIPEA (4.8 mL, 27.7 mmol), and fz-BuOH (50 mL) was heated at 100 ° C for 2 h. The mixture was cooled, diluted with water (200 ml) and the precipitated product were collected by filtration on a Buchner funnel. The product was washed with cold water, ether, and dried in vacuo to give an off-white solid (2.8 g, 90%).¹H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.38 (s, 1H), 6.49 (s, 1H), 6.25 (s, 2H), 4.34 (s, 2H), 3.77 (s, 9H).

<img file="PL1737451T3_D0036.tif" />

B) 6- (2-Fluoro-4-nitrophenoxy) pyrimidine-4-amine A mixture of N- (2,4,6-trimethoxybenzyl) -6-chloropyrimidin-4-amine (2.2 g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and 2-methoxyethyl ether (50 mL) was heated at 160 ° C for 60 h. The reaction mixture was cooled to RT and poured into H2O ( 200 ml). The solid was collected, washed with 2 M aqueous Na2CO3 and H2O, and then vacuum

- dried on a Buchner funnel. The crude product was treated with TFA (20 mL) in dioxane (40 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was separated, dried (MgSO4), concentrated and the crude product was purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-amine (440 mg, 31 %).¹H NMR (DMSO-d6) δ 8.31 (dd, 1H, J = 10.4, 2.5 Hz), 8.14 (dd, 1H, J = 9.8, 2.0 Hz), 8, 04 (s, 1H), 7.61 (dd, 1H, J = 8.3, 8.3 Hz), 7.07 (s, 2H), 6.02 (s, 1H); MS (ESI⁺) m / z 251.15 (M + H)⁺.

<img file="PL1737451T3_D0037.tif" />

C) tert-Butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-ylcarbamate [0110] A mixture of 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-amine (439 mg, 1.2 mmol) , BOC2O (261 mg, 1.2 mmol), DMAP (10 mg), and THF (10 mL) were stirred at room temperature for 1 h, then concentrated in vacuo to give the crude product. The product was purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give tert-butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-ylcarbamate as a white solid (110 mg, 26%). ¹H NMR (DMSO-d6) δ 10.59 (s, 1H), 8.39 (dd, 1H, J =

8,8,1,1 Hz), 8,32 (dd, 1H, J = 10,3, 2,4 Hz), 8.15 (ddd, 1H, J = 9,1,2,5,1, 0 Hz), 7.67 (dd, 1H, J = 8.8, 8.8 Hz), 7.45 (s, 1H), 1.44 (s, 9H); MS (ESI^-) m / z 349.08 (MH).

<img file="PL1737451T3_D0038.tif" />

D) tert-Butyl 6- (4-amino-2-fluorophenoxy) pyrimidin-4-ylcarbamate [0111] Solution of tert-butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-ylcarbamate (11 mg, 0.031 mmol ) in MeOH (2 ml) was treated with PtO2 and the reaction mixture was stirred under a hydrogen atmosphere (from a latex balloon) for 2 h. The catalyst was filtered off and the filtrate was concentrated to give tert-butyl 6- (4-amino-2-fluorophenoxy) pyrimidin-4-ylcarbamate ( 8 mg, 81%). ¹H NMR (DMSO-d6) δ 10.62 (s, 1H), 8.43 (d, 1H, J = 2.5 Hz),

8.36 (dd, 1H, J = 9,8,2,5 Hz), 8.36 (dd, 1H, J = 9.8, 2.5 Hz), 8.20-8.17 (m, 1H), 7.71 (dd, 1H, J = 8.8, 8.8 Hz), 7.49 (s, 1H), 1.48 (s, 9H).

E) tert-Butyl 6- (2-fluoro-4- (3- (4-fluorophenylamino) -3-oxopropanamido) phenoxy) pyrimidin-4-ylcarbamate

[0112] The title compound was obtained from tert-butyl 6- (4-amino-2-fluorophenoxy) pyrimidin-4-ylcarbamate (8 mg, 0.025 mmol) and (4-fluorophenylamino) -3-oxo-propanoic acid (6 mg, 0.031 mmol , Compound B of Example 1), TBTU (11 mg,

0.034 mmol), and DIPEA (6 μΐ, 0.030 mmol) using a similar procedure described for the preparation of compound C, Example 1. Flash chromatography using 1-1.5% MeOH in CH2Cl2 as the eluent provided the title compound as a white solid (10 mg , 80%). ¹H NMR (DMSO-d6) δ 10.48 (s, 1H), 10.46 (s, 1H), 10.25 (s, 1H), 8.39 (s, 1H), 7.74-7, 77 (m, 1H),

7.62 (d, 1H, J = 5.5 Hz), 7.61 (d, 1H, J = 4.9 Hz), 7.36-7.30 (m, 2H), 7.17-7 , 13 (m, 2H), 3.48 (s, 2H), 1.46 (s, 9H); MS (ESI⁺) m / z 500.12 (M + H)⁺.

Example 7

<img file="PL1737451T3_D0039.tif" />

tert-Butyl 6- (2-fluoro-4- (3- (4-fluorophenylamino) -3-oxopropanoamido) phenoxy) pyrimidin-4-yl (methyl) carbamate

<img file="PL1737451T3_D0040.tif" />

A) tert-Butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-yl (methyl) carbamate [0115] Solution of tert-butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-ylcarbamate (Compound C from Example 6, 44 mg, 0.13 mmol) in anhydrous DMF (1 mL) was cooled in an ice bath and treated with 60% NaH (44 mg, 0.16 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was treated with iodomethane (10 μΐ, 0.15 mmol) and stirred at 0-5 ° C for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were dried (MgSO 4 and concentrated in vacuo to give the product (35 mg, 74%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 8.57 (d, 1H, J = 1.1 Hz), 8.37 (dd, 1H, J = 9.8, 3.0 Hz), 8.19 (ddd, 1H, J = 9,1,2,5,1,0 Hz), 7.71 (dd, 1H, J = 8.8, 8.8 Hz), 7.66 (s, 1H), 3.38 (s, 3H), 1.51 (s, 9H).

<img file="PL1737451T3_D0041.tif" />

B) tert-Butyl 6- (4-amino-2-fluorophenoxy) pyrimidin-4-yl (methyl) carbamate [0116] A mixture of tert-butyl 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-yl (methyl ) carbamate in 1: 1 EtOH / MeOH (2 mL) was treated with PtO2 (10 mg) and the reaction mixture was stirred under H2 (latex balloon) for 2 h. The reaction mixture was filtered and concentrated to give the desired product (30 mg, 75% ) as a light brown solid. MS (ESI⁺) m / z 365.13 (M + H)⁺.

C) tert-Butyl 6- (2-fluoro-4- (3- (4-fluorophenylamino) -3-oxopropanamido) phenoxy) pyrimidin-4-yl (methyl) carbamate [0117] The title compound was obtained from tert-butyl 6- (4-amino-2-fluorophenoxy) pyrimidin-4-yl (methyl) carbamate (30 mg, 0.068 mmol), 4-fluorophenylacetyl chloride (Lancaster, 15 mg, 0.088 mmol) and NaSCN (9 mg, 0.11 mmol) in EtOAc / CH2Cl2 using a similar procedure described for the preparation of compound C from example 2. Flash chromatography on SiO2 using 1-40% EtOAc in hexanes as the eluent provided the title compound (30 mg, 83%) as a white solid. ¹H NMR (DMSO-d6) δ

12.40 (s, 1H), 11.79 (s, 1H), 8.55 (s, 1H), 7.86 (dd, 1H, J = 12.1, 2.5 Hz), 7.54 (d, 1H, J = 1.1 Hz), 7.45-7.35 (m, 4H), 7.20-7.14 (ddd, 2H, J = 8.8, 8.8, 2, 1 Hz), 3.81 (s, 2H), 3.36 (s, 3H),

1.49 (s, 9H); MS (ESI⁺) m / z 530.09 (M + H)⁺.

Example 8

<img file="PL1737451T3_D0042.tif" />

1- (3-Fluoro-4- (6- (methylamino) pyrimidin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea [0119] tert-Butyl 6- (2-fluoro- 4- (3- (4-fluorophenylamino) -3-oxopropanoamido) phenoxy) pyrimidin-4-yl (methyl) carbamate (Example 7, 25 mg, 0.047 mmol) was treated with 4M HCl in 1,4-dioxane (3 mL) , stirred at room temperature for 4 h and concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 solution and

EtOAc. The EtOAc layer was separated, dried (MgSO4 and concentrated in vacuo.

- Flash chromatography on SiO2 using 1% MeOH in CH2Cl2 as the eluent afforded the title compound (10 mg, 50%) as a white solid. ¹H NMR (DMSO-d6) δ 12.37 (s, 1H), 11.77 (s, 1H), 8.09 (s, 1H), 7.82 (d, 1H, J = 11.6 Hz) , 7.41-7.35 (m, 5H), 7.32-7.28 (m, 1H),

7.19-7.14 (m, 2H), 3.81 (s, 2H), 2.78 (s, 3H); MS (ESI⁺) m / z 430.07 (M + H)⁺.

Example 9

<img file="PL1737451T3_D0043.tif" />

1- (4- (6-Amino-pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4- fluorophenyl) acetyl) thiourea

<img file="PL1737451T3_D0044.tif" />

A) 6- (N, N-di-tert-Butyloxycarbonyl) amino-4- (2-fluoro-4-nitrophenoxy) pyrimidine [0122] A mixture of 6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-amine ( Compound B of Example 6, 150 mg, 0.60 mmol), BOC2O (275 mg, 1.26 mmol), DMAP (5 mg), and THF (20 mL) were stirred at room temperature for 2.5 h. The reaction mixture concentrated in vacuo to give the crude product. Flash chromatography on SiO2 using 5-15% EtOAc in hexanes as the eluent provided the title compound (180 mg, 67%) as a white solid. ¹H NMR (DMSO-d6) δ 8.62 (d, 1H, J = 1.0 Hz), 8.42-8.39 (m, 1H), 8.21 (ddd, 1H, J = 9.1 , 2.5, 1.0 Hz), 7.77 (dd, 1H, J = 8.8, 8.8 Hz), 7.49 (d, 1H, J = 1.1 Hz), 1.49 (s, 18H); MS (Est) m / z

451.12 (M + H)⁺.

<img file="PL1737451T3_D0045.tif" />

B) 6- (N, N-di-tert-Butyloxycarbonyl) amino-4- (4-amino-2-fluorophenoxy) pyrimidine

[0123] A mixture of 6- (N, N-di-tert-butyloxycarbonyl) amino-4- (2-fluoro-4-nitrophenoxy) pyrimidine (175 mg, 0.38 mmol) in toluene (5 mL) and MeOH (3 mL) was treated with PtO2 (35 mg) and the reaction mixture was stirred under H2 (latex balloon) for 15 h. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 using 1-10% MeOH in CH2Cl2 as the eluent to give the product (110 mg, 68%) as a white solid. ¹H NMR (DMSO-d6) δ 8.56 (s, 1H), 7.17 (s, 1H), 6.97 (dd, 1H, J = 8.8, 8.8 Hz), 6.46 ( dd, 1H, J = 12.6, 2.5 Hz), 6.38 (dd, 1H, J =

<img file="PL1737451T3_D0046.tif" />

C) 1- (4- (N, N-di-tert-Butyloxycarbonyl-6-aminopyrimidin-4-yloxy) -3-fluorophenyl) 3- (2- (4-fluorophenyl) acetyl) thiourea [0124] The title compound was obtained with 6- (N, N-di-tert-butyloxycarbonyl) amino-4- (4-amino2-fluorophenoxy) pyrimidine (20 mg, 0.048 mmol), 4-fluorophenylacetyl chloride (Lancaster, 10 mg, 0.062 mmol), and NaSCN (95 mg, 0.062 mmol) in EtOAc / CH2Cl2 using a similar procedure described for the preparation of compound C from example 2. Flash chromatography on SiO2 using 10-20% EtOAc in hexanes as the eluent provided the title compound (23 mg, 77%) as a white solid. ¹H NMR (DMSO-d6) δ 12.40 (s, 1H), 11.79 (s, 1H), 8.59 (s, 1H), 7.88 (dd, 1H, J = 12.5, 1 , 8 Hz), 7.46-7.41 (m, 2H), 7.38-7.35 (m, 3H), 7.17 (dd, 2H, J = 8.8,

8.8 Hz), 3.81 (s, 2H), 1.47 (s, 18H); MS (ESI⁺) m / z 616.12 (M + H)⁺.

D) 1- (4- (6-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea [0125] A mixture of 1- (4- (N, N-di -tert-butylcarbonyl-6-aminopyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea (18 mg, 0.029 mmol) and 4 M HCl in dioxane (1.5 mL) was stirred at room temperature for 18 h and then concentrated to give the crude product. The crude product was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was separated, dried (MgSO4) concentrated in vacuo and the residue purified by flash chromatography on SiO2 using 1-2% MeOH in CH2Cl2 to give the title compound (12 mg, 99%) as a white solid. ¹H NMR (DMSO-d6) δ 12.38 (s, 1H), 11.77 (s, 1H), 8.05 (s, 1H), 7.83 (dd, 1H, J = 12.1 , 8 Hz), 7.441.35 (m, 3H), 7.31 (dd, 2H, J = 8.8, 8.8 Hz), 7.17 (t, 1H, J = 8.8 Hz), 7.02 (s, 2H), 5.89 (s, 1H), 3.81 (s, 2H); MS (ES⁺) m / z 416.06 (M + H)⁺.

Example 10 [0126]

<img file="PL1737451T3_D0047.tif" />

N -1- (4- (6-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0048.tif" />

A) N - (4- (N, N-di-tert-Butylcarbonyl-6-aminopyrimidin-4-yloxy) -3-fluorophenyl) -N (4-fluorophenyl) malonamide [0128] The title compound was obtained from a mixture of 6- ( N, N-di-tert-butyloxycarbonyl) amino-4- (4-amino-2-fluorophenoxy) pyrimidine (Compound B from Example 9, 20 mg, 0.048 mmol), 3- (4-fluorophenylamino) -3-oxopropane (Compound B with Example 1, 14 mg, 0.072 mmol),

DIPEA (12 μΐ, 0.069 mmol) in DMF using a similar procedure described for the preparation of compound C from example 1. Flash chromatography on SiO2 using 15-50% EtOAc in hexanes as the eluent provided the title compound (23 mg, 80%) as a white body Constant. ¹H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.24 (s, 1H), 8.58 (d, 1H, J = 1Hz), 7.77 (dd, 1H, J = 12 , 9, 1.8 Hz), 7.63-7.60 (m, 2H), 7.37-7.36 (m, 2H), 7.32 (s, 1H), 7.15 (t, 2H, J = 8.8 Hz),

1.47 (s, 18H); MS (ESI⁺) m / z 600.17 (M + H)⁺.

₃

B) 1- (4- (6-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0129] The title compound was obtained from N-1- (4- (N, N-di -tert-butylcarbonyl-6-aminopyrimidin-4-yloxy) -3-fluorophenyl) -N-3- (4-fluorophenyl) malonamide (20 mg, 0.032 mmol) using a similar procedure to prepare Compound D from Example 9 to give the title compound (13 mg, 98%) as a white solid. ¹H NMR (DMSO-d6) δ 10.42 (s, 1H),

10.24 (s, 1H), 8.03 (s, 1H), 7.73 (d, 1H, J = 11.0 Hz), 7.61 (dd, 2H, J = 9.2.4, 9 Hz), 7.33-7.30 (m, 1H), 7.28-7.23 (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 11 [0130]

<img file="PL1737451T3_D0049.tif" />

1- (4- (6- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4- fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0050.tif" />

A) N- (4-Methoxybenzyl) -6-chloropyrimidin-4-amine A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol), 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 mL, 28.8 mmol), and n-BuOH was refluxed for 3h. The mixture was concentrated and the residue treated with H2O (150 mL) and EtOAc (175 mL). The EtOAc layer was separated, washed with saturated aqueous NaHCO3 solution and brine, dried (MgSO4), and concentrated to give the title compound (4.5 g) which was used without further purification. ¹H NMR (DMSO-d6) δ 8.29 (s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J = 8.2 Hz), 6.90 (d, 2H , J = 8.2 Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).

<img file="PL1737451T3_D0051.tif" />

B) N- (4-Methoxybenzyl) -6- (2-fluoro-4-nitrophenoxy) pyrimidin-4-amine [0133] A mixture of N- (4-methoxybenzyl) -6-chloropyrimidin-4-amine (2.3 g , 9.2 mmol), 2-fluoro-4-nitrophenol (1.45 g, 9.2 mmol), DIPEA (15 ml), and 2-methoxyethyl ether (75 ml) was heated at 160 ° C in a sealed pressure bottle for 50 h. The mixture was cooled, poured onto crashed ice (200 g), treated with EtOAc (200 ml). The mixture was stirred vigorously for 10 minutes and then insoluble material was filtered off. The EtOAc layer was washed with saturated aqueous Na2CO3 (100 mL), brine (3 x 100 mL), dried (MgSO4) and concentrated in vacuo. The obtained sticky solid was triturated with isopropyl ether to give the title compound (1.75 g, 76%) as a brown solid.

- 42 ¹H NMR (DMSO-d6) δ 8.32 (dd, 1H, J = 10,22.0 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), 6.91 (d, 2H, J = 8.5 Hz), 6.14 (br

<img file="PL1737451T3_D0052.tif" />

C) N- (4-Methoxybenzyl) -6- (4-amino-2-fluorophenoxy) pyrimidin-4-amine [0134] Solution N- (4-methoxybenzyl) -6- (2-fluoro-4-nitrophenoxy) pyrimidine -4-amines (150 mg, 0.41 mmol) in 1: 1 MeOH / THF (20 ml) were treated with ammonium chloride (0.22 g, 4.1 mmol), and zinc dust (&lt;20 microns, 0, 27 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 1 h. An additional portion of zinc dust (150 mg) was added to the mixture and the reaction mixture was stirred at room temperature for 1 h and heated at 70 ° C for 20 min. The mixture was filtered to remove inorganic solids, concentrated in vacuo, and the residue partitioned between EtOAc and brine. The EtOAc layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (145 mg, 99%).¹H NMR (DMSO-d6) δ 8.10 (br s, 1H), 7.76 (br s, 1H), 7.21 (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, 1H), 4.41 (br s, 2H), 3.73 (s, 3H); MS (ESI⁺) m / z 341.18 (M

<img file="PL1737451T3_D0053.tif" />

D) 2- (4-Fluoro-phenyl) -acetyl isocyanate [0135] Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq) was added to the 4-fluorophenylacetyl chloride solution (Lancaster, 0.794 mL, 5.79 mmol, 1.0 eq.) in toluene (16 mL) at room temperature. The reaction mixture was shielded from light and heated to reflux. After 60 minutes, the mixture was cooled to room temperature and filtered (Acrodisc, PTFE 0.2μΜ) to give a 0.36 M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene, which was used without further purification.

E) 1- (4- (6- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0136] Solution N- (4- methoxybenzyl) -6- (4-amino-2-fluorophenoxy) pyrimidin-4-amine (88 mg, 0.26 mmol) in THF (2 ml) was treated with 0.36 M 2- (4-fluorophenyl) acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the resulting solid

Triturated with isopropyl ether to give the title compound (125 mg, 93%) as an off-white solid. ¹H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H), 7.85 (br s, 0.5H), 7, 66 (d, 1H, J = 12.6 Hz), 7.36-7.15 (m, 9.5 H), 6.88 (d, 1H, J = 8.1 Hz), 5.91 ( s, 1H),

4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s, 3H); MS (ESI⁺) m / z 520.14 (M + H)⁺.

Example 12

<img file="PL1737451T3_D0054.tif" />

N - (4- (6- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0138] The title compound was obtained from N- (4-Methoxybenzyl) -6- (4 -amino-2-fluorophenoxy) pyrimidin-4-amine (Compound C of Example 11.200 mg, 0.59 mmol), acid

3- (4-Fluoro-phenylamino) -3-oxopropane (Compound B of Example 1, 128 mg, 0.65 mmol), TBTU (228 mg, 0.71 mmol), and DIPEA (123 μΐ, 0.71 mmol) in DMF using similar procedure described for the preparation of compound C from example 1. The crude product was purified by trituration with isopropyl ether to give the title compound (250 mg, 82%) as an off-white solid. ¹H NMR (DMSO-d6) δ 10.43 (s, 1H), 10.25 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.72 (dd, 1H, J = 9.1, 5.0 Hz), 7.62 (dd, 2H, J = 8.8, 5.0 Hz), 7.31-7.21 (m, 4H), 7.15 (dd, 2H, J = 8.8, 8.8 Hz), 6.88 (m, 2H), 5.90 (s, 1H), 4.42 (br s, 2H), 3.71 (s , 3H), 3.46 (s, 2H); MS (ESI⁺) m / z 520.14 (M + H)⁺.

Example 13

<img file="PL1737451T3_D0055.tif" />

1- (4- (6-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0140]

<img file="PL1737451T3_D0056.tif" />

A) N- (3-Fluoro-4-hydroxyphenyl) acetamide [0141] The title compound was obtained from commercially available 2-fluoro-4-nitrophenol according to the procedure of Burckhalter, JH et al. (J. Am. Chem. Soc. 1948, 70 , 1363). Nitrophenol (5.73 g, 36.5 mmol) and acetic anhydride (3.72 g, 36.5 mmol) were dissolved in acetic acid (20 mL) and then PtO2 (150 mg) was added. The reaction mixture was shaken under H2 (50 psi) at room temperature for 24 h. The resulting precipitate was filtered off with suction and the filter paper was washed with acetic acid (25 ml). The combined filtrate and washing solutions were concentrated in vacuo to afford the title compound (2.0 g). The solid remaining on the filter paper was treated with MeOH to dissolve the product and filtered off with Pt2O. The filtrate was concentrated in vacuo and the resulting solid was triturated with 1: 1 EtOAc / hexanes (200 mL) to afford the drug projection of the title compound (1.8 g, 62% overall).¹H NMR (DMSO-d6) δ 9.83 (s, 1H), 9.51 (s, 1H), 7.50 (dd, 1H, J = 13.6, 2.5 Hz), 7.03 ( d, 1H, J = 8.5 Hz), 6.84 (dd, 1H, J = 9.3, 9.3 Hz), 1.98 (s, 3H); MS (ESI⁺) m / z 170.23 (M + H)⁺.

<img file="PL1737451T3_D0057.tif" />

B) N- (4- (6-Chloropyrimidin-4-yloxy) -3-fluorophenyl) acetamide [0142] A mixture of 4,6-dichloropyrimidine (1.50 g, 10.0 mmol), N- (3-fluoro- 4-hydroxyphenyl) acetamide (1.70 g, 10.0 mmol), K2CO3 (1.8 g, 13.0 mmol), and DMF (15 ml) were heated at 70 ° C for 1.5 h. The mixture was concentrated to half of the original volumes and cooled in an ice bath. The mixture was treated with H2O (100 mL) to precipitate the product, which was filtered off with suction. The product was washed with H2O and vacuum dried on the funnel overnight to give the title compound (2.0 g, 71%) as a gray solid. ¹H NMR (DMSO-d6) δ 10, 26 (s, 1H), 8.67 (s, 1H), 7.78 (dd, 1H, J = 12,6,2,0 Hz), 7.56 ( s, 1H), 7,377.30 (m, 2H), 2.08 (s, 3H); MS (ESI⁺) m / z 282.10 (M + H)⁺.

<img file="PL1737451T3_D0058.tif" />

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

[0143] A mixture of N- (4- (6-aminopyrimidin-4-yloxy) -3-fluorophenyl) acetamide (1.0 g, 3.5 mmol) and about 7 M NH3 in MeOH (5 mL) was heated to 100 ° C in a sealed pressure bottle for 2 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, washed with brine, dried (MgSO4 and concentrated. Flash chromatography on SiO2 using first 50% EtOAc in hexanes, then 5% MeOH in CH2Cl2 as the eluents provided the title compound (175 mg, 20%) as a brown solid. ¹H NMR (DMSO-d6) δ 10.17 (s, 1H), 8.02 (s, 1H), 7.70 (dd, 1H, J = 13.2, 2.2 Hz), 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 263.15 (M + H)⁺.

<img file="PL1737451T3_D0059.tif" />

D) 6- (4-Amino-2-fluorophenoxy) pyrimidine-4-amine A mixture of N- (4- (6-aminopyrimidin-4-yloxy) -3-fluorophenyl) acetamide (175 mg, 0.67 mmol ), 1 M HCl (6 mL), and MeOH (2 mL) was refluxed for 3h. The reaction mixture was cooled, basified (pH 8) with aqueous Na2CO3 solution and extracted with EtOAc (2 x 25 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (140 mg, 96%) as a brown solid.¹H NMR (DMSO-d6) δ 8.02 (s, 1H), 6.89 (dd, 1H, J = 9.0, 9.0 Hz), 6.80 (br s, 2H), 6.43 (dd, 1H, J = 12,7,2,8 Hz), 6,35 (dd, 1H, J = 8,8,2,2 Hz), 5.67 (s, 1H), 5.34 ( br s, 2H).

E) 1- (4- (6-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0145] The title compound was obtained from 6- (4-amino-2 -fluorophenoxy) pyrimidin-4-amine (92 mg, 0.42 mmol) and 0.36 M 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 1.3 mL, 0.45 mmol) in THF as described above for example 11. The crude product was purified by trituration using 1: 1 EtOH / H2O, then absolute EtOH. The product was vacuum dried to give the title compound (100 mg, 60%). Drugs, slightly less pure crop of product (45 mg, 27%) were obtained by extraction of the combined filtrates and washing solutions with EtOAc.¹H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.50 (s, 1H), 8.01 (s, 1H), 7.65 (dd, 1H, J = 12.2.2 , 1 Hz), 7.33 (dd, 2H, J = 8.1, 6.0 Hz), 7.28 (dd, 1H, J = 8.6, 2.0 Hz), 7.22 (dd , 1H, J = 8.8, 8.8 Hz), 7.17-7.12 (m, 2H), 6.89 (br s, 2H), 5.80 (s, 1H), 3.71 (s, 2H); MS (ESI⁺) m / z 400.09 (M + H)⁺.

Example 14 [0146]

<img file="PL1737451T3_D0060.tif" />

N - (4- (2- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0061.tif" />

A) 2-Chloro-4- (2-fluoro-4-nitrophenoxy) pyrimidine [0148] A mixture of 2,4-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Avacado, 0 , 79 g, 5.0 mmol), K2CO3 (0.76 g, 5.5 mmol), and DMF (50 mL) was heated at 100 ° C for 2 h. The mixture was cooled and diluted with saturated NaHCO3 solution (100 mL) and extracted with EtOAc. The EtOAc extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give a mixture of 2-phenoxy- and 4-phenoxypyrimidine regioisomers as a yellow solid. Regioisomers were separated by flash chromatography using 10-40% EtOAc in hexanes as the eluent to give the title compound (0.71 g, 53%) as a white solid.¹H NMR (DMSO-d6) δ 8.76 (dd, 1H, J = 6.0, 1.6 Hz), 8.43 (dt, 1H, J = 9.8, 2.2 Hz), 8, 23 (dd, 1H, J = 8,8,1,6 Hz), 7.80 (dt, 1H, J =

9.8, 2.2 Hz), 7.48 (dd, 1H, J = 6.0, 2.2 Hz).

<img file="PL1737451T3_D0062.tif" />

B) N- (4-Methoxybenzyl) -4- (2-fluoro-4-nitrophenoxy) pyrimidin-2-amine A mixture of 2-chloro-4- (2-fluoro-4-nitrophenoxy) pyrimidine (0.66 g, 2.44 mmol), 4-methoxybenzylamine (0.34 g, 3.45 mmol), K2CO3 (0.37 g, 2.66 mmol), and DMF (15 mL) was heated at 100 ° C for 1h. The mixture was cooled, diluted with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed twice, each with

- saturated NaHCO3 solution and brine. The organic layers were dried (MgSO4) and concentrated to give a crude product. Flash chromatography on SiO2 using 1-3% MeOH in CH2Cl2 as the eluent afforded the title compound (275 mg, 29%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 8.40-8.21 (m, 2H), 8.16 (dd, 1H, J = 8.8, 1.7.7 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), 6.37 (s, 1H) , 4.43 (br s,

<img file="PL1737451T3_D0063.tif" />

C) N- (4-Methoxybenzyl) -4- (4-amino-2-fluorophenoxy) pyrimidin-2-amine [0150] The title compound was obtained by reduction of N- (4-methoxybenzyl) -4- (2-fluoro-4 -nitrophenoxy) pyrimidin-2-amine (270 mg, 0.73 mmol) with zinc dust (475 mg, 7.3 mmol) and NH4Cl (3387 mg, 7.3 mmol) in 1: 1 THF / MeOH (20 ml ) using a similar procedure described for Compound C of example 11. Flash chromatography on SiO2 using 1-3% MeOH in CH2Cl2 as the eluent afforded the title compound (235 mg, 95%) as a brown film. ¹H NMR (DMSO-d6) δ 8.01 (s, 1H), 7.65 (br s, 0.5 H), 7.49 (br s, 0.5H), 7.08 (br s, 1H ), 6.83 (br s, 2H), 6.81 (m, 1H), 6.69 (br s, 2H), 6.39 (br s, 0.5H), 6.31 (br s, 0.5H), 6.01 (m, 1H), 5.26 (br s, 2H), 4.24 (br s, 1H), 3.95 (br s, 1H), 3.61 (s, 3H); MS (ESI⁺) m / z 341.16 (M + H)⁺.

₃

D) N1- (4- (2- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0151] The title compound was obtained from N- (4-Methoxybenzyl) - 4- (4-amino-2-fluorophenoxy) pyrimidin-2-amine (34 mg, 0.10 mmol), 3- (4-fluorophenylamino) -3-oxopropanoic acid (Compound B from Example 1, 22 mg, 0, 11 mmol), TBTU (39 mg, 0.12 mmol) and DIPEA (23 mL, 0.17 mmol) using a similar procedure described for the preparation of compound C from example 1. The crude product was triturated with 3: 1 isopropyl ether / EtOAc to give the title compound (35 mg, 61%) as an off-white solid. ¹H NMR (DMSO-d6) δ 10.47 (br s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.77 (m, 3H), 7.61 (m , 2H), 7.35-7.25 (m, 2H), 7.15 (dd, 2H, J =

8.8, 8.8 Hz), 6.81-6.73 (m, 2H), 6.24 (s, 1H), 4.32 (br s, 1H), 3.96 (br s, 1H ), 3.68 (s, 1H),

3.48 (s, 2H); MS (ESI⁺) m / z 520.14 (M + H)⁺.

Example 15 [0152]

<img file="PL1737451T3_D0064.tif" />

1- (4- (2- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0153] N- (4-Methoxybenzyl) -4 solution - (4-amino-2-fluorophenoxy) pyrimidin-2-amine (Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 mL) was treated with 0.36 M 2 (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.31 mL, 0.11 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the resulting solid was triturated first with 3: 1 isopropyl ether / EtOAc and then CH2Cl2 to give the title compound (32 mg, 62%) as an off-white solid. ¹H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J = 12.6 Hz) , 7.61 (dd, 3H, J = 9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s, 3H ), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s, 2H); MS (ESI⁺) m / z 520.14 (M + H)⁺.

Example 16

<img file="PL1737451T3_D0065.tif" />

[0155] Mixture N¹- (4- (2- (4-Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) N³- (4-fluorophenyl) malonamide (Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1 mL) was heated at 85 ° C for 6 h. TFA was removed in vacuo and the residue was separated between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated in vacuo. Flash chromatography on SiO2 using EtOAc, then 1-2% MeOH in CH2Cl2 as the eluents provided the title compound (12 mg, 63%) as an off-white solid.¹H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H), 7.66 (dd, 1H, J = 12.6, 2 , 0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (t, 2H, J = 8.6 Hz), 7.16 (t, 2H, J = 9.1 Hz), 6.91 (s, 2H), 3.73 (s, 2H); MS (ESI⁺) m / z

400.11 (M + H)⁺.

Example 17 [0156]

<img file="PL1737451T3_D0066.tif" />

1- (4- (2-Aminopyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0157] The title compound was obtained from 1- (4- (2- (4 -Methoxybenzylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Example 15, 20 mg, 0.039 mmol) using a similar procedure described for example 16. Flash chromatography on SiO2 using EtOAc, then 1-2% MeOH in CH2Cl2 as the eluents provided the title compound (10 mg, 62%) as an off-white solid. ¹H NMR (DMSO-d6) δ 11.01 (s, 1H), 10.52 (s, 1H), 8.20 (d, 1H, J = 6.0 Hz), 7.70 (dd, 1H, J = 12.1, 2.0 Hz), 7.36-7.30 (m, 6H), 7.16 (dd, 2H, J = 8.8, 8.8 Hz), 6.45 (d , 1H, J = 6.1 Hz), 3.73 (s, 2H); MS (ESI⁺) m / z 400.09 (M + H)⁺.

Example 18

<img file="PL1737451T3_D0067.tif" />

N - (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy) phenyl) -N- (4-fluorophenyl) malonamide, hydrochloride salt

<img file="PL1737451T3_D0068.tif" />

A) N- (4- (2-Chloropyridin-4-yloxy) -3-fluorophenyl) acetamide [0160] A mixture of N- (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), Kz2O3 (1.6 g, 11.8 mmol), and DMF (25 mL) was heated at 100 ° C for 9 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated NaHCO3 solution. layer

EtOAc was washed with brine, dried (MgSO4), and concentrated. Flash chromatography

Using 30-80% EtOAc in hexanes as the eluent to provide the title compound (1.6 g, 73%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 10.24 (s, 1H), 8.65 (s, 1H), 7.89-7.64 (m, 1H), 7.56 (s, 1H), 7, 46-7.19 (m, 2H), 2.06 (s, 3H); MS (ESI⁺) m / z 281.16 (M + H)⁺.

<img file="PL1737451T3_D0069.tif" />

B) N-4- (2-Chloropyridin-4-yloxy-1-oxide) -3-fluorophenyl) acetamide [0161] A mixture of N- (4- (2-chloropyridin-4-yloxy) -3-fluorophenyl) acetamide ( 0.98 g, 3.5 mmol), m-chloroperbenzoic acid (&gt; 90%, 1.3 g, 7.6 mmol), and CHCl 3 (50 mL) was stirred at room temperature for 60 h. The mixture was concentrated and the residue triturated with Et2O (2 x 100 mL) to afford the title compound (0.89 g, 87%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 10.25 (s, 1H), 8.34 (d, 1H, J = 7.1 Hz), 7.80 (d, 1H, J = 13.2 Hz), 7 , 49 (d, 1H, J = 3.3 Hz), 7.33 (d, 2H, J = 4.9 Hz), 7.02 (dd, 1H, J = 7.1, 3.3 Hz) , 2.06 (s, 3H); MS (ESI) m / z 295.04 (MH).

<img file="PL1737451T3_D0070.tif" />

C) N- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy-1-oxide) phenyl) acetamide [0162] A mixture of N- (4- (2-chloropyridin-4-yloxy- 1-oxide) -3-fluorophenyl) acetamide (205 mg, 0.62 mmol), 4- (2-aminoethyl) morpholine (Aldrich, 169 mg, 1.30 mmol), and absolute EtOH was heated at reflux for 16 h. The mixture reaction mixture was concentrated in vacuo, the residue treated with H2O (3 mL) and applied to a 10g Varian C-18 cartridge. The cartridge was eluted first with H2O, then with 30% MeOH in H2O. Fractions containing the desired product were collected, concentrated to 5 mL volume, and extracted 3 times with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (100 mg, 40%).¹H NMR (DMSO-d6) δ 10.22 (s, 1H), 7.84 (d, 1H, J = 6.1 Hz), 7.77 (dd, 1H, J = 13.2,

2.2 Hz), 7.31 (dd, 1H, J = 8.8, 2.2.2 Hz), 7.24 (t, 1H, J = 8.8 Hz), 6.41 (m, 1H) , 6.13 (dd, 1H, J =

5.5, 2.2 Hz), 5.81 (d, 1H, J = 2.2 Hz), 3.60-3.52 (m, 4H), 3.31-3.28 (m, 2H ), 2.38 (t, 2H, J =

7.1 Hz), 2.34 (m, 4H), 2.06 (s, 3H); MS (ESI⁺) m / z 405.22 (M + H)⁺.

<img file="PL1737451T3_D0071.tif" />

D) N- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-ylacy) phenyl) acetamide, trifluoroacetic acid salt [0163] A mixture of N- (3-fluoro-4- (2- ( 2-morpholinoethylamino) pyridin-4-yloxy-1oxide) phenyl) acetamide (100 mg, 0.26 mmol), and triphenylphosphine deposited on a polymer (1.42,0 mmol / g) on ​​polystyrene (500 mg) and DMF (2 ml) was stirred at 135 ° C for 15 h. The mixture was filtered to remove the resin and the resin was washed with DMF and EtOAc. The filtrate and washing solutions were combined and concentrated. The crude product was purified by preparative HPLC (Shimadzu S5 VP-ODS 20 x 100 mm) to give the title compound (45 mg, 46%) as a white solid. ¹H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.02 (d, 1H, J = 6.6 Hz) 7.84 (dd, 1H, J = 13.2, 2.0 Hz ), 7.39-7.31 (m, 2H), 6.52 (s, 1H), 6.10 (s, 1H), 3.83 (br s, 4H), 3.64 (m, 2H) ), 3.28 (m, 6H), 2.08 (s, 3H); MS (ES⁺) m / z 375.12 (M + H)⁺.

<img file="PL1737451T3_D0072.tif" />

E) 4- (4-Amino-2-fluorophenoxy) -N- (2-morpholinoethyl) pyridine-2-amine, hydrochloride salt [0164] Mixture of N- (3 -fluoro-4- (2- (2-morpholinoethylamino ) trifluoroacetate pyridin-4-yloxy) phenyl) acetamide (40 mg), MeOH (1 ml), and 6 M HCl (0.2 ml) was refluxed for 3h. The reaction mixture was concentrated on a rotary evaporator and the residue was freeze-dried to give the title compound (30 mg, 76%) as a white solid.¹H NMR (DMSO-d6) δ

11.12 (br s, 1H), 8.85 (br s, 1H), 7.95 (d, 1H, J = 7.2 Hz), 7.08 (dd, 1H, J = 8.8, 8.8 Hz), 6.656.63 (m, 2H), 6.54 (d, 1H, J = 8.3 Hz), 6.31 (br s, 1H), 3.85 (m, 6H), 3.33 (m, 6H); MS (ESI^-) m / z 373.14 (MH).

F) N - (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy) phenyl) -N- (4-fluorophenyl) malonamide [0165] The title compound was obtained from a mixture of 4- (4-amino -2-fluorophenoxy) -N- (2-morpholinoethyl) pyridin-2-amine, hydrochloride salt (15 mg, 0.043 mmol), 3- (4-fluorophenylamino) -3-oxopropanoic acid (Compound B from Example 1, 10 mg, 0.052 mmol) .

TBTU (17 mg, 0.052 mmol), DIPEA (30 μ! -), and DMF (1 ml) using a similar procedure

- described for the preparation of compound C from example 1. The crude product was purified by preparative HPLC (Shimadzu S5 VP-ODS 20 x 100 mm). The product obtained from HPLC purification was treated with 1 M HCl and lyophilized to afford the title compound (10 mg, 40%) as a white solid.¹H NMR (DMSO-d6) δ 10.37 (s, 1H), 10.05 (s, 1H), 9.90 (br s, 1H), 7.90 (d, 1H, J = 6.1 Hz ), 7.75 (d, 1H, J = 13.2 Hz), 7.58-7.55 (m, 2H), 7.53-7.50 (m, 1H), 7.40 (d, 1H, J = 8.8 Hz), 7.24 (t, 1H, J = 8.8 Hz), 7.08-7.03 (m, 3H), 6.39 (d, 1H, J =

6.1 Hz), 6.11 (s, 1H), 3.80-3.81 (m, 4H), 3.67-3.65 (m, 2H), 3.47 (br s, 2H) , 3.20 (br s, 4H); MS (ESI⁺) m / z 512.12 (M + H)⁺.

Example 19

<img file="PL1737451T3_D0073.tif" />

Τ

N - (3-Fluoro-4- (pyridin-4-yloxy) phenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0074.tif" />

Τ

A) N - (3-Fluoro-4-hydroxyphenyl) -N - (4-fluorophenyl) malonamide [0168] To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 ml tetrahydrofuran and 6 ml methanol at 0 ° C, zinc dust (2.08 g, 31.8 mmol, &lt;10 microns) was added, followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a small pad of Celite^® with methanol and the filtrate concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81%).

[0169] 3- (4-Fluoro-phenylamino) -3-oxopropanoic acid (Compound B from Example 1, 197 mg,

1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 μ! 1.00 mmol) was added and the solution was cooled to 0 ° C. 4-Amino-2-fluorophenol (Step A from Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and then stirred at room temperature for 3h.

The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water provided the title compound (211 mg, 69%) as

- 53 white solid. ¹H NMR (CD3OD δ 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J = 13, 2.5 Hz), 7.086.99 (m, 3H), 6.88 (t , 1H, J = 9.4 Hz), 3.51 (s, 2H); MS (ESI⁺) m / z 307.44 (M + H)⁺.

B) N - (3-Fluoro-4- (pyridin-4-yloxy) phenyl) -N- (4-fluorophenyl) malonamide.

[0170] N¹- (3-Fluoro-4-hydroxyphenyl) -N³- (4-fluorophenyl) malonamide (31 mg, 0.10 mmol), copper (II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μΐ, 0.20 mmol) was placed in a pressure tube in that order. The tube was filled with methylene chloride (0.5 ml) and sealed. The reaction was stirred at 120 ° C for 5 h. The reaction mixture was filtered through silica gel using 5% methanol / ethyl acetate. After concentration, the crude product was purified by prep. HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was basified with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3 x 10ml) and the combined organic extracts dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water provided the title compound (8 mg, 21%) as a yellow solid.¹H NMR (CD3OD) δ

8.31 (d, 2H, J = 6.1 Hz), 7.72 (dd, 1H, J = 12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7 , 27-7.25 (m, 1H), 7.15 (t, 1H, 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 384.21 (M + H)⁺.

Example 20

<img file="PL1737451T3_D0075.tif" />

τ

N - (4- (2-Chloropyridin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0076.tif" />

A) 2-Fluoro-4-aminophenol [0173] A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) was stirred under H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to give the title compound (1.00 g, 100%) as a solid which was used without further purification.¹H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H),

6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI⁺) m / z 128 (M + H)⁺.

<img file="PL1737451T3_D0077.tif" />

B) 4- (2-Chloropyridin-4-yloxy) -3-fluorobenzeneamine Sodium hydride (60%, 0.104 g, 2.60 mmol, 1.1 eq) was added to the solution of 2-fluoro-4aminophenol (0 , 30 g, 2.36 mmol, 1.0 eq) in DMF (6.5 mL) at room temperature 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 heated to 90 ° C for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaCl solution and extracted with ethyl acetate (3 x 70 mL). The combined organic extracts were washed with 10% aqueous LiCl (3 x 70 mL), dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound (0.430 g, 76%) which was used without further purification.¹H NMR (DMSO-d6) δ 8.27 (d, 1H, J = 5.7 Hz), 6.90-7.04 (m, 3H), 6.42-6.54 (m, 2H), 5.54 (s, 2H); MS (ESI⁺) m / z 239 (M + H)⁺; HRMS (ESI⁺) calculated: 239.0387, found: 239.0391.

C) N - (4- (2-Chloropyridin-4-yloxy) -3-fluoro-phenyl) -N- (4-fluorophenyl-malonamide) [0175] Diisopropylethylamine (0.091 mL, 0.525 mmol, 2.5 eq) was added to the 4- solution (2-chloropyridin-4-yloxy) -3-fluorobenzenamine (0.050 g, 0.21 mmol, 1.0 eq), 3- (4-fluoro-phenylamino) -3-oxopropanoic acid (Compound B from Example 1, 0.041 g, 0.21 mmol, 1.0 eq), and PyBroP (0.117 g, 0.252 mmol, 1.2 eq) in CH 2 Cl 2 (1.0 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched by adding a saturated aqueous NaCl solution to the reaction mixture, and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Merck, 40-63 μΜ, 230-240 mesh, eluting with 3/1 ethyl acetate / hexane) to give the title compound (0.0.56 g, 64%) as a solid.¹H NMR (DMSO-d6) δ

10.61 (s, 1H), 10.34 (s, 1H), 8.36-8.38 (m, 1H), 7.91-7.93 (m, 1H), 7.67-7, 71 (m, 2H), 7.466.48 (m, 2H), 7.04-7.26 (m, 4H), 3.56 (s, 2H); MS (ESI⁺) m / z 418 (M + H)⁺; HRMS (ESI⁺) calculated: 418.0770, found: 418.0767.

Example 21 [0176]

<img file="PL1737451T3_D0078.tif" />

1- (4- (2-Chloropyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea [0177] 4-Fluoro-phenylacetyl chloride (Aldrich, 0.072 ml, 0.525 mmol, 2, 5 eq) was added to a solution of sodium thiocyanate (0.056 g, 0.695 mmol, 3.3 eq) in ethyl acetate (2.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to give a solution of 2- (4-fluoro-phenyl) ethanoyl isothiocyanate (0.263 M). A solution of 4- (2-chloropyridin-4-yloxy) -3-fluorobenzeneamine (0.050 g, 0.21 mmol, 1.0 eq) in CH2Cl2 (1.0 mL) was added dropwise to a solution of 2- (4-fluorophenyl) ethanoyl isothiocyanate and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the obtained residue was purified by silica gel flash chromatography (Merck, 40-63 μΜ, 230-240 mesh, eluting with 3/1 hexane / ethyl acetate) to give the title compound (0.058 g, 64%) as solid. ¹H NMR (DMSO-d6) δ 12.46 (s, 1H), 11.84 (s, 1H),

8.35-8.33 (m, 1H), 8.02-8.33 (m, 1H), 6.99-7.52 (m, 8H), 3.84 (s, 2H); MS (ESI⁺) m / z 434 (M + H)⁺; HRMS (ESI⁺) calculated: 434.054, found: 434.0547.

Example 22

<img file="PL1737451T3_D0079.tif" />

N - (4- (2- (Benzylamino) pyridin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0080.tif" />

A) tert-Butyl 4- (2-chloropyridin-4-yloxy) -3-fluorophenylcarbamate

[0180] Di-tert-butyl-dicarbonate (0.920 g, 4.22 mmol, 4.5 eq) was added to the solution of 4- (2-chloropyridin-4-yloxy) -3-fluorobenzeneamine (Compound B from Example 20, 0.224 g, 0.939 mmol, 1.0 eq) and triethylamine (0.391 mL, 3.00 mmol, 3.0 eq) in THF (10 mL) and the reaction mixture was heated at 55 ° C for 14 h. The reaction mixture was cooled to room temperature and quenched with 1N HCl. The solution was extracted with CH2Cl2 (3 x 70 mL), the combined organic extracts were washed with 1N NaOH (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Merck, 40-63 μΜ, 230-240 mesh, eluting with 4: 1 hexane / ethyl acetate) to give the title compound (0.270 g, 85%).¹H NMR (DMSO-d6) δ 8.35-8.36 (m, 1H), 7.55-7.57 (m, 1H), 7.45-7.46 (m, 1H), 7.21 -7.24 (m, 1H), 6.96-6.97 (m, 2H), 1.40 (s, 9H); MS (ESI⁺) m / z 339 (M + H)⁺; HRMS (ESI⁺) calculated: 339.0912, found: 339.0915.

<img file="PL1737451T3_D0081.tif" />

B) tert-Butyl-4- (2- (Benzylamino) pyridin-4-yloxy) -3-fluorophenylcarbamate [0181] tert-Butyl 4- (2-chloropyridin-4-yloxy) -3-fluorophenylcarbamate (0.100 g, 0.295 mmol, 1.0 eq) was added to the degassed solution of dppf.PdCl2 (Matrix Scientific, 0.011 g, 0.0148 mmol, 0.05 eq), dppf (0.012 g, 0.022 mmol, 0.075 eq), and NaOt- Bu (0.040 g, 0.414 mmol, 1.4 eq) in toluene at room temperature. Benzylamine (0.045 mL, 0.414 mmol, 1.4 eq.) Was added to the reaction mixture and the resulting solution was stirred at 80 ° C for 4 h. The reaction mixture was cooled to room temperature, quenched with 1N HCl and the solution extracted with CHCl 3 (3 x 50 ml). The combined organic extracts were washed with 1 N NaOH (70 mL), dried (Na 2 SO 4) filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Merck, 40-63 μΜ, 230-240 mesh, eluting with 2: 1 hexane / ethyl acetate) to give the title compound (0.020 g, 17%). ¹H NMR (CDCl3) δ 7.80-7.90 (m, 1H), 7.35-7.45 (m, 1H), 7.19-7.24 (m, 3H), 6.91-6 , 93 (m, 2H), 6.59 (br m, 1H), 6.10-6.20 (m, 1H), 5.75 (br m, 1H), 5.30-5.40 (m , 1H), 4.34 (s, 2H), 1.46 (s, 9H); MS (ESI⁺) m / z 410 (M + H)⁺; HRMS (ESI⁺) calculated: 410.1880, found: 410.1884.

<img file="PL1737451T3_D0082.tif" />

C) 4- (4-Amino-2-fluoro-phenoxy) -N-benzyl-pyridine-2-amine, hydrochloride salt

[0182] Anhydrous HCl in dioxane (4N, 2.00 mL, 8.00 mmol, 165 eq) was added to tert-butyl 4- (2- (benzylamino) pyridin-4-yloxy) -3-fluorophenylcarbamate (0.020 g , 0.0489 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo to give the title compound (0.017 g, 100%) as a solid which was used without further purification. MS (ESI +) m / z 310 (M + H)⁺; HRMS (ESI⁺) calculated: 310.1356, found: 310.1364.

D) N - (4- (2- (Benzylamino) pyridin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0183] Diisopropylethylamine (0.014 mL, 0.081 mmol, 3.5 eq) to the solution 4- (4 amino-2-fluoro-phenoxy) -N-benzyl-pyridin-2-amine, hydrochloride salt (0.008 g, 0.023 mmol, 1.0 eq), 3- (4-fluorophenylamino) -3-oxopropanoic acid ( Compound B of Example 1, 0.005 g, 0.023 mmol, 1.0 eq), and PyBroP (0.013 g, 0.028 mmol, 1.2 eq) in CH 2 Cl 2 (1.0 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (YMC-ODS-A, C-18, S10, 30x500 mm, eluting with 20-90% aqueous MeOH with 0.1% TFA, 30 min gradient). The appropriate fractions were concentrated in vacuo, neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3 x 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.0025 g, 45%) as a solid. MS (ESI⁺) m / z 489 (M + H)⁺; FIRMS (ESI⁺) calculated: 489.1738, found: 489.1743.

Example 23

<img file="PL1737451T3_D0083.tif" />

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

<img file="PL1737451T3_D0084.tif" />

A) 3-Fluoro-4- (pyridin-4-yloxy) benzenamine

[0186] Potassium hydride (30%, 0.520 g, 3.90 mmol, 3.0 eq) was added to the 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) at room temperature and the reaction mixture was stirred for 15 minutes. 4-chloro-pyridine (Aldrich, 0.200 g, 1.30 mmol, 1.0 equiv) was added and the reaction mixture was heated to 150 ° C for 2 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH and the solution extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with 1N aqueous NaOH (2 x 30 mL), then 10% aqueous LiCl (3 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a solid.¹H NMR (DMSO-d6) δ

8.44-8.46 (m, 2H), 6.89-7.03 (m, 1H), 6.87-6.88 (m, 2H), 6.44-6.56 (m, 2H) ), 5.51 (s, 2H); MS (ESI⁺) m / z 205 (M + H)⁺; HRMS (ESI⁺) calculated, 205.0777, found: 205.0775.

B) 1- (3-Fluoro-4- (pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0187] Silver cyanate (0.912 g, 6.08 mmol, 1 , 05 eq.) Was added to a solution of 4-fluoro-phenylacetyl chloride (Aldrich, 0.794 mL, 5.79 mmol, 1.0 eq) in toluene (16 mL) at room temperature, shielded from light. The reaction mixture was heated to reflux for 60 minutes and then cooled to room temperature. The reaction mixture was filtered (Acrodisc, PTFE 0.2μΜ) and the resulting solution of 2- (4-fluorophenyl) acetyl isocyanate (0.36 M, 0.75 mL, 0.27 mmol, 1.1 eq) was added to the solution 3- fluoro-4- (pyridin-4-yloxy) benzenamine (0.050 g, 0.245 mmol, 1.0 eq) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, quenched by the addition of saturated aqueous NaCl solution, and the mixture was extracted with CH 2 Cl 2 (3 x 30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Merck, 40-63 μΜ, 230-240 mesh, eluting with 0-5% MeOH in CHCl₃) to give the title compound (0.043 g, 46%) as a solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.60 (s, 1H), 8.47 (s, 2H), 7.77-7.80 (m, 1H), 6, 92-7.48 (m, 8H), 3.75 (s, 2H); MS (ESI⁺) m / z 384 (M + H)⁺; HRMS (ESI⁺) obl,: 384.1160, found: 384.1147.

Example 24

<img file="PL1737451T3_D0085.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0189]

<img file="PL1737451T3_D0086.tif" />

A) 4- (4-Amino-2-fluoro-phenoxy) -N-benzyl-pyridine-2-amine [0190] Benzylamine (9.1 ml, 83.8 mmol, 20 eq) was added to 4- (2-chloropyridin-4-yloxy) ) -3-fluorobenzenamine (Compound B of Example 20, 1.0 g, 4.19 mmol, 1.0 eq), copper powder (0.266 g, 4.19 mmol, 1.0 eq) and K2CO3 (0.578 g, 4.19 mmol, 1.0 eq.) in a sealed tube and the reaction mixture was heated to 160 ° C for 12 h. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous NaCl solution. The solution was extracted with ethyl acetate (3 x 100 mL), the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC C-18 ODSA S10 50 x 500 mm, eluting with 10-90% aqueous MeOH with 0.1% TFA, 30 minutes gradient) and the appropriate fractions concentrated in vacuo. The concentrated residue was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.675 g, 52%) as a solid.¹H NMR (CD3OD) δ 7.78-7.80 (m, 1H), 7.28-7.30 (m, 5H), 6.80-6.90 (m, 1H), 6.52-6 , 55 (m, 2H), 6.18-6.20 (m, 1H), 5.87-5.88 (m, 1H), 4.40 (s, 2H); MS (ESI⁺) m / z 310 (M + H)⁺; HRMS (ESI⁺) calculated: 310.1356, found: 310.1360.

<img file="PL1737451T3_D0087.tif" />

B) 4- (4-Amino-2-fluorophenoxy) pyridine-2-amine [0191] Palladium hydroxide on carbon (10%, 0.050 g) was added to a solution of 4- (4-amino-2-fluoro-phenoxy) -N-benzyl-pyridine-2 -amines (0.245 g, 0.790 mmol, 1.0 eq) in 5% HCO2HMeOH (10 mL) in a hydrogen atmosphere (from a balloon) at room temperature. The reaction mixture was stirred at room temperature for 12 h, filtered through Celite^® and the filtrate was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30 x 500 mm, 10-90% aqueous MeOH with 0.1% TFA, 30 minutes gradient) and the appropriate fractions concentrated in vacuo. The concentrated residue was neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3 x 35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.045 g, 26%) as a solid.¹H NMR (CD3OD δ

- 60 7.62-7.63 (m, 1H), 6.77-6.82 (m, 1H), 6.3 8-6.47 (m, 2H), 6.09-6.11 ( m, 1H), 5.83-5.84 (m, 1H); MS (ESI⁺) m / z 220 (M + H)⁺; HRMS (ESI⁺) calculated: 220.08, found: 220.0877.

C) 1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0192] 2- (4-Fluoro-phenyl) -acetyl isocyanate (Compound D from Example 11, 0.362 M, 0.351 mL, 0.127 mmol, 1.3 eq) was added to a solution of 4- (4-amino, -2-fluorophenoxy) pyridin-2-amine (0.022 g, 0.100 mmol, 1.0 eq.) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred for 13 h at room temperature and then concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck gel 40-63μM, 230-240 mesh, 1: 1 ethyl acetate / hexane) to give the title compound (0.025 g, 64%) as a solid. ¹H NMR (CD3OD) δ 7.62-7.67 (m, 2H), 7.23-7.29 (m, 2H),

7.07-7.12 (m, 2H), 6.95-6.99 (m, 2H), 6.12-6.14 (m, 1H), 5.86-5.87 (m, 1H ), 3.61 (s, 2H); MS (ESI⁺) m / z 399 (M + H)⁺; HRMS (ESI⁺) calculated: 399.1269, found: 399.1269.

[0193] Alternatively, Example 24 was prepared as follows:

<img file="PL1737451T3_D0088.tif" />

A ') 4-Chloropicolinamide [0194] A heterogeneous mixture of 4-chloropicolinic acid (TCI America, 5.4 g, 34.2 mmol, 1.0 eq) and thionyl chloride (30 mL) was heated at 80 ° C for 2h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with a solution of ammonia in MeOH (7N, 45 ml) in an ice bath and the reaction mixture was stirred for 15 minutes. The ice bath was then removed and the reaction warmed to room temperature and then stirred for 3h. The reaction mixture was concentrated in vacuo and the residue purified by crystallization from EtOAc to give the product (5., 14 g, 96%) as a solid. ¹H NMR (DMSO-d6) δ 8.61-8.63 (m, 1H), 8.21 (m, 1H), 8.03-8.04 (m, 1H), 7.76-7.83 (m, 2H); MS (ESI⁺) m / z 157 (M + H)⁺.

<img file="PL1737451T3_D0089.tif" />

B ') 4- (4-Amino-2-fluorophenoxy) picolinamide [0195] Solution of 4-amino-2-fluorophenol (Compound A from Example 20, 0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 equiv.) At room temperature and the reaction mixture was stirred for 1h. 4-chloropicolinamide (1.0 g, 6.4 mmol, 1.0 equiv) was added and the reaction mixture was heated to 110 ° C for 8h. The reaction was cooled to room temperature and the reaction was quenched by adding to

- 61 reaction mixture with water. The resulting heterogeneous solution was filtered and the solid washed with water. The solid was triturated with a small amount of MeOH, then Et2O. The solid was filtered and dried in vacuo to give the product (1.3 g, 82%) as a solid.¹H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m , 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H ); MS (ESI⁺) m / z 248 (M

<img file="PL1737451T3_D0090.tif" />

C ') 1- (4- (2-Carbamoylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0196] Solution of 2- (4-fluorophenyl) acetyl isocyanate ( Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 equiv) was added to 4- (4-amino-2-fluoro-phenoxy) picolinamide (1.86 g, 7.53 mmol, 1.0 eq.) in 10/3 DCM / DMF (65 ml) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with a saturated aqueous NaCl solution, the organic fraction was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1/3 hexane / EtOAc, then eluting the product with 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid.¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J = 5.60 Hz), 8.16-8.19 ( m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS (ESI⁺) m / z 427 (M + H)⁺, HRMS (ESI⁺) calculated: 427.1218, found: 427.1214.

D ') 1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0197] Bis- (trifluoroacetoxy) iiodenzene (Aldrich, 3.09 g, 7.20 mmol, 1 .4 eq.) 1- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4 -fluorophenyl) acetyl) urea (2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) and pyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was treated with 1 N HCl and the aqueous solution was extracted with Et2O, discarding the organic layer. The aqueous layer was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with 10% aqueous LiCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (50 mL), cooled to 0 ° C and treated with anhydrous HCl (4N, 10 mL, 40 mmol, 7.8

- 62 equivalents). The reaction mixture was allowed to warm to room temperature and stirred for 2h to give a heterogeneous solution. The solution was filtered and the solid washed with Et2O and dried in vacuo to give the title compound (1.38 g, 63%) as a solid.¹H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.65 (s, 1H), 7.97-8.00 (m, 1H), 7.83-7.90 (m, 3H ), 7.35-7.48 (m, 4H), 7.15-7.21 (m, 2H), 6.70-6.72 (m, 1H), 6.16-6.17 (m , 1H), 3.77 (s, 2H); MS (ESI⁺) m / z 399 (M + H)⁺, HRMS (ESI⁺) calculated: 399.1269; Found: 399.1258. Elemental analysis for C20H16N4O3F2 1.0 HCl. 0.22 H2O

Obl.:C; 54.75, H; 4.01, N; 12.77, Cl; 8.08, Found: C; 54.75, H; 4.35, N; 4.35, Cl; 8.06.

Example 25

<img file="PL1737451T3_D0091.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2-fluoro-5-methylbenzamide Diisopropylethylamine (0.035 mL, 0.200 mmol, 2.0 eq) was added to the 4- ( 4-amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 0.022 g, 0.100 mmol, 1.0 eq), 2-fluoro-5-methyl-benzoic acid (Aldrich, 0.015 g, 0.100 mmol, 1.0 eq), EDCI (0.021 g, 0.11 mmol, 1.1 eq) and HOBT (0.014 g, 0.100 mmol, 1.0 eq) in DMF (0.700 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h, quenched by the addition of saturated aqueous NaHCO3 solution and extracted with CHCl3 (3 x 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30 x 500 mm, 30-90% aqueous MeOH with 0.1% TFA, 30 minutes gradient) and the appropriate fractions concentrated in vacuo. The concentrated residue was neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.014 g, 40%) as a solid.¹H NMR (CD3OD) δ 7.67-7.80 (m, 2H), 7.36-7.45 (m, 3H), 7.03-7.14 (m, 2H), 6.14-6 , 16 (m, 1H), 5.89-5.90 (m, 1H), 2.29 (s, 3H); MS (ESI⁺) m / z 356 (M + H)⁺; HRMS (ESI⁺) calculated: 356.1211, found: 356.1203.

Example 26 [0200]

<img file="PL1737451T3_D0092.tif" />

N - (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenylmalonamide) Diisopropylethylamine (0.105 ml, 0.604 mmol, 3.3 eq) was added to solution 4- (4amino -2-fluorophenoxy) pyridin-2-amine (Compound B from example 24, 0.040 g, 0.183 mmol, 1.0 eq), 3- (4-fluorophenylamino) -3-oxopropanoic acid (Compound B from example 1, 0.054 g, 0.274 mmol, 1.5 eq), and PyBroP (0.139 g, 0.298 mmol, 1.6 eq) in CH2Cl2 (2.0 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was treated with saturated aqueous NaHCO3 solution and the solution was extracted with CHCl3 (3 x 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Merck 40-63μΜ, 230-240 mesh, eluting with 0-6% MeOH in CHCl3 to give the title compound (0.056 g, 77%) as a solid.¹H NMR (CD3OD δ 7.677.68 (m, 2H), 7.48-7.52 (m, 2H), 7.13-7.25 (m, 1H), 7.10-7.12 (m, 1H), 6.94-6.99 (m, 2H), 6.16-6.17 (m, 1H), 5.88-5.89 (m, 1H), 3.30 (s, 2H) MS (ESI) m / z 399 (MH⁺); HRMS (ESI⁺) calc: 399.1269, found: 399.1261.

Example 27

<img file="PL1737451T3_D0093.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) thiourea [0203] 4-Fluoro-phenylacetyl chloride (Aldrich, 0.017 mL, 0.126 mmol, 2 , 5 eq) was added to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq) in ethyl acetate (1.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to give a solution of 2- (4-fluoro-phenyl) ) ethanoyl isothiocyanate (0.126 M). 4- (4-Amino-2-fluorophenoxy) pyridine-2amine (Compound B of Example 24, 0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.0 mL) and 2- (4-fluorophenyl) was added. ) ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol,

1.3 eq.) And the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the obtained residue was purified by flash chromatography on silica gel (Merck, 40-63 μΜ, 230-240 mesh, eluting 0- 6% MeOH in CHCl3) to give the title compound (0.008 g, 38%) as a body

- 64 fixed. ¹H NMR (CD3OD δ 7.85-7.95 (m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7, 00 (m, 2H), 6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS (ESI⁺) m / z 415 (M + H)⁺; HRMS (ESI⁺) calculated: 415.1040, found: 415.1041.

Example 28

<img file="PL1737451T3_D0094.tif" />

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

<img file="PL1737451T3_D0095.tif" />

A) N- (3-Fluoro-4- (2- (4-fluorophenylamino) pyridin-4-yloxy-1-oxide) phenyl) acetamide [0206] A mixture of N- (4- (2-chloropyridin-4-yloxy- 1-oxide) -3-fluorophenyl) acetamide (Compound B of Example 18, 62 mg, 0.21 mmol), 4-fluoroaniline (47 mg, 0.42 mmol), and 2-methoxyethyl ether (91 mL) was heated at 140 ° C for 15 min. The mixture was cooled to RT, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine (several times), dried (MgSO4) and concentrated in vacuo to give a 4: 1 mixture of the title compound and parent pyridine as a light brown oil (45 mg, 58%). The product was used in the next step without further purification. MS (ESI⁺) m / z 372.1 (M + H)⁺.

<img file="PL1737451T3_D0096.tif" />

B) N- (3-Fluoro-4- (2- (4-fluorophenylamino) pyridin-4-yloxy) phenyl) acetamide [0207] A mixture of N- (3-fluoro-4- (2- (4-fluorophenylamino) pyridine -4-yloxy-1-oxide) phenyl) acetamide (45 mg), triphenylphosphine polymer supported (~ 3 mmol / g) on ​​polystyrene

- 65 (200 mg, Fluka) and DMF (3 ml) were heated at 135 ° C for 48 h. The resin was filtered off, washed with DMF and EtOAc. The filtrate and washing solutions were combined and concentrated in vacuo. The crude product was purified by flash chromatography using 30-80% EtOAc in hexanes as the eluent to afford the title compound (22 mg, 51%) as a pink solid.¹H NMR (DMSO-d6) δ 10.24 (s, 1H), 8.99 (s, 1H), 8.03 (d, 1H, J = 6.3 Hz), 7.80 (dd, 1H, J = 13.0, 2.1 Hz), 7.63-7.60 (m, 2H), 7.36-7.29 (m, 2H), 7.05 (dd, 1H, J = 9, 1, 8.6 Hz), 6.44 (dd, 1H, J = 5.5, 2.2 Hz), 6.09 (d, 1H, J = 2 Hz), 2.07 (s, 3H) ; MS (ESI⁺) m / z 356.7 (M + H)⁺.

<img file="PL1737451T3_D0097.tif" />

C) 4- (4-Amino-2-fluorophenoxy) -N- (4-fluorophenyl) pyridin-2-amine [0208] A mixture of N- (3-fluoro-4- (2- (4-fluorophenylamino) pyridin-4 -yloxy) phenyl) acetamide (18 mg, 0.051 mmol), 6 M HCl (0.1 mL, 0.60 mmol) and MeOH (1.5 mL) were refluxed for 2 h. The mixture was concentrated in vacuo and the residue basified with saturated aqueous NaHCO3 solution, the solution was then extracted with EtOAc. The extract was dried (MgSO4) and concentrated in vacuo to give the title compound (14 mg, 88%) as a red gum. ¹H NMR (DMSO-d6) δ 8.97 (s, 1H), 7.98 (d, 1H, J = 5.8 Hz), 7.64-7.60 (m, 2H), 7.05 ( dd, 2H, J = 9.1, 8.8 Hz), 6.97 (dd, 1H, J = 9.4, 8.8 Hz), 6.51 (dd, 1H, J = 13.3, 2.6 Hz), 6.40 (ddd, 2H, J = 9.0, 6.2, 2.1 Hz), 6.08 (d, 1H, J = 2.0 Hz), 5.44 ( br s, 2H); MS (ESI⁺) m / z 314.17 (M + H)⁺.

D) 1- (3-Fluoro-4- (2- (4-fluorophenylamino) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0209] Solution 4- (4 -amino-2-fluorophenoxy) -N- (4-fluorophenyl) pyridin-2-amine (11 mg, 0.035 mmol) in THF (1 ml) was cooled in an ice bath and treated with a solution of 2- (4-fluorophenyl) isocyanate acetyl in toluene (Compound D from Example 11, 250 μΐ, 0.070 mmol) and stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was triturated with isopropyl ether to give the title compound (11 mg, 65%) as a white solid. ¹H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.56 (s, 1H), 9.01 (s, 1H), 8.03 (d, 1H, J = 5.6 Hz) , 7.77 (dd, 1H, J = 13,3,2,0 Hz), 7.63-7.60 (m, 2H), 7.41-7.3 (m, 5H), 7.197.14 (m, 2H), 7.05 (dd, 1H, J = 9.1, 8.5 Hz), 6.43 (dd, 1H, J = 6.2, 2.1 Hz), 6.10 ( d, 1H, J =

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

Example 29 [0210]

<img file="PL1737451T3_D0098.tif" />

N - (4- (6- (4- (Benzyloxy) phenylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide

<img file="PL1737451T3_D0099.tif" />

A) N- (4- (6- (4- (Benzyloxy) phenylamino) pyrimidin-4-yloxy) -3-fluorophenyl) acetamide [0212] A mixture of N- (4- (6-chloropyrimidin-4-yloxy) -3 -fluorophenyl) acetamide (Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated at 160 ° C for 45 min . The cooled mixture was treated with H2O (50 mL) and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (3 x 25 mL), dried (MgSO 4) and concentrated in vacuo to give the title compound (200 mg, 22%) as a purple solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 ​​(s, 1H), 7.72 (dd, 1H, J = 12, 5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J = 8.0, 6.9 Hz), 7.33-7.23 (m , 3H), 6.98 (d, 2H, J = 9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H), 2.05 (s, 3H); MS (ESI⁺) m / z 445.13 (M + H)⁺.

<img file="PL1737451T3_D0100.tif" />

B) 6- (4-Amino-2-fluorophenoxy) -N- (4- (benzylose) phenyl) pyrimidine-4-amine [0213] A mixture of N- (4- (6- (4- (benzyloxy) phenylamino) pyrimidine -4-yloxy) -3-fluorophenyl) acetamide (150 mg, 0.34 mmol), 6 M HCl (0.5 mL) and MeOH (3 mL) was refluxed for 2 h. The mixture was concentrated to remove MeOH and the residue was treated with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried (MgSO 4 and concentrated in vacuo to give the title compound (123 mg, 90%) as a pink solid. ¹H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.24 (s, 1H), 7.46-7.31 (m, 7H), 6.99-6.92

- 67 (m, 3H), 6.48 (dd, 1H, J = 12.5, 2.7 Hz), 6.39 (dd, 1H, J = 8.6, 2.7 Hz), 5, 97 (s, 1H), 5.39 (br s, 2H), 5.08 (s, 2H); MS (ESI⁺) m / z 403.09 (M + H)⁺.

C) N - (4- (6- (4- (Benzyloxy) phenylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -N- (4-fluorophenyl) malonamide [0214] The title compound was obtained from a mixture of 6- (4 -amino-2-fluorophenoxy) -N- (4- (benzyloxy) phenyl) pyrimidin-4-amine (45 mg, 0.11 mmol), 3- (4-fluorophenylamino) -3-oxopropanoic acid (Compound B from example 1.24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described for the preparation of compound C from Example 1. The crude product was triturated with isopropyl ether to give the title compound (56 mg, 88%) as a pink solid. ¹H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J = 12.7, 2.0 Hz), 7.65-7.62 (m, 2H), 7.46 (d, 4H, J = 7.3 Hz), 7.40 (dd, 2H , J = 7.6, 7.3 Hz),

7.37-7.29 (m, 3H), 7.17 (dd, 2H, J = 9.0, 8.3 Hz), 7.00 (d, 2H, J = 9.0 Hz) 6, 09 (s, 1H), 5.09 (s, 2H) 3.49 (s, 2H); MS (ESI⁺) m / z 582.3 (M + H)⁺.

Example 30

<img file="PL1737451T3_D0101.tif" />

1- (4- (6- (4- (Benzyloxy) phenylamino) pyrimidin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0216] The title compound was obtained from 6 - (4-amino-2-fluorophenoxy) -N- (4- (benzyloxy) phenyl) pyrimidin-4-amine (Compound B from Example 29, 45 mg, 0.11 mmol) and a solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.13 mmol) in THF using a similar procedure described for the preparation of Compound E from Example 11. The crude product was triturated with isopropyl ether to give the title compound (58 mg, 90%) as a pink solid. ¹H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.54 (s, 1H), 9.46 (s, 1H), 8.24 (s, 1H), 7.70 (dd, 1H, J = 12.7, 2.4 Hz), 7.46-7.26 (m, 9H), 7.18 (dd, 2H, J = 9.6,

8.3 Hz), 7.00 (d, 2H, J = 9.6 Hz), 6.11 (s, 1H), 5.09 (s, 2H), 3.75 (s, 2H); MS (ESI⁺) m / z 582.3 (M + H)⁺.

Example 31 [0217]

<img file="PL1737451T3_D0102.tif" />

1- (3-Fluoro-4- (2- (4-fluorophenylamino) pyrimidin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0103.tif" />

A) N- (4- (2-Chloropyrimidin-4-yloxy) -3-fluorophenyl) acetamide [0219] Mixture of 2,4-dichloropyrimidine (Aldrich, 1.5 g, 10.0 mmol), N- (3- fluoro-4-hydroxyphenyl) acetamide (0.85 g, 5.0 mmol), K2CO3 (0.76 g, 5.5 mmol), and CH3CN (100 mL) was refluxed for 2 h. The mixture was concentrated and the residue partitioned between EtOAc and saturated NaHCO3 solution. EtOAc layer with saturated NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient from 30% EtOAc in hexanes to 100% EtOAc to give the title compound (1.1 g, 78%) as a white solid. ¹H NMR (DMSO-d6) δ 10.22 (s, 1H), 8.63 (d, 1H, J = 5.6 Hz), 7.74 (dd, 1H, J = 12.6, 2.4 Hz), 7.34-7.26 (m, 3H),

<img file="PL1737451T3_D0104.tif" />

B) N- (3-Fluoro-4- (2- (4-fluorophenylamino) pyrimidin-4-yloxy) phenyl) acetamide [0220] A mixture of N- (4- (2-chloropyrimidin-4-yloxy) -3-fluorophenyl ) acetamide (100 mg, 0.36 mmol), 4-fluoroaniline (Aldrich, 40 mg, 0.36 mmol), and 1,4-dioxane (3 mL) was heated at reflux for 2 h. The mixture was concentrated in vacuo and the residue triturated with ether to give a gray solid. The product was dissolved in MeOH, treated with silica gel (150 mg) and the mixture concentrated to dryness. The compound was concentrated on gel

- silica gel and applied to a silica gel column and eluted first with EtOAc then with 100: 1 MeOH / NH4OH in CH2Cl2 to give the title compound (40 mg, 31%) as a white solid. ¹H NMR (DMSO-d6) δ 10.19 (s, 1H), 9.61 (s, 1H), 8.33 (d, 1H, J = 5.6 Hz), 7.71 (d, 1H, J = 12.7 Hz), 7.40 (s, 2H), 7.30-7.26 (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 357.13 (M + H)⁺.

<img file="PL1737451T3_D0105.tif" />

C) 4- (4-Amino-2-fluorophenoxy) -N- (4-fluorophenyl) pyrimidin-2-amine [0221] A mixture of N- (3-fluoro-4- (2- (4-fluorophenylamino) pyrimidin-4 -yloxy) phenyl) acetamide (32 mg, 0.09 mmol), 6M HCl (0.2 mL) and MeOH (2 mL) was refluxed for 2 h. The mixture was cooled, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using 30-40% EtOAc in hexanes containing 1% Et3N provided the title compound (15 mg, 46%) as a white solid. ¹H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.25 (d, 1H, J = 5.5 Hz), 7.43 (br s, 2H), 6.92-6.85 (m, 3H), 6.45 (dd, 1H, J = 13.5, 2.1 Hz), 6.38-6.35 (m, 2H), 5.35 (br s, 2H), MS (ESI⁺) m / z 315.17 (M + H)⁺.

D) 1- (3-Fluoro-4- (2- (4-fluorophenylamino) pyrimidin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0222] Solution 4- (4 -amino-2-fluorophenoxy) -N- (4-fluorophenyl) pyrimidin-2-amine (10 mg, 0.032 mmol) in THF (1 ml) was cooled in an ice bath and treated with a solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 228 μ ^ 0.064 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with isopropyl ether to give the title compound (15 mg, 93%) as a white solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H), 8.39 (d, 1H, J = 5.7 Hz) , 7.76 (dd, 1H, J = 13.5, 2.1 Hz), 7.43 (br s, 2H), 7.46-7.35 (m, 6H), 7.18 (dd, 2H, J = 8.8, 8.8 Hz), 6.57 (d, 1H, J = 5.4 Hz), 3.76 (s, 2H); MS (ESI⁺) m / z 492.0 (M + H)⁺.

Example 32

<img file="PL1737451T3_D0106.tif" />

1- (2- (4-Fluorophenyl) acetyl) -3- (4 - ((2- (pyridin-2-ylamino) -thiazol-5-yl) methylamino) phenyl) thiourea

<img file="PL1737451T3_D0107.tif" />

A) N.¹- ((2- (Pyridin-2-ylamino) thiazol-5-yl) methyl) benzene-1,4-diamine [0225] Solution of 2- (pyridin-2-ylamino) -thiazole-5-carbaldehyde (0.10 g, 0.49 mmol, WO2004 / 001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) and triethylsilane (0.19 mL, 1.2 mmol) in CH2Cl2-TFA (3: 1, 4 ml) was stirred at ambient temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product that contained the title compound along with the starting aldehyde and benzene-1,4-diamine was used directly for the next step.

B) 1- (2- (4-Fluorophenyl) acetyl) -3- (4 - ((2- (pyridin-2-ylamino) thiazol-5-yl) methylamino) phenyl) thiourea [0226] 4-Fluoro-phenylacetyl chloride ( 7.4 μΐ, 0.053 mmol) was added to a suspension of NaSCN (4.5 mg, 0.055 mmol) in EtOAc (0.5 mL) and the resulting mixture was stirred at room temperature for 30 min. The mixture was then added to a solution of the above mixture obtained in A (14.5 mg) in CH2Cl2 (0.5 mL) and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 using a 2-5% MeOH-CHCl3 elution gradient to give the title compound (2 mg) as an orange film. MS (ESI⁺) m / z 493.2 (M + H)⁺.

Example 33

<img file="PL1737451T3_D0108.tif" />

1- (4- (3-Ethylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0228]

<img file="PL1737451T3_D0109.tif" />

A) 4- (2-Fluoro-4-nitrophenoxy) -3-iodopyridine [0229] A mixture of 4-chloro-3-iodopyridine (1.50 g, 6.30 mmol, obtained according to Tabanella, S. et al. Org. Biomol Chem. 2003, 1, 4254-4261.), 2-fluoronitrophenol (Lancaster, 2.0 g, 12.7 mmol), DIPEA (5 ml), and NMP (10 ml) were heated at 150 ° C. After 12 h, more 2-fluoro-nitrophenol (0.50 g, 3.18 mmol) was added to the reaction mixture and heating was continued for 4 h. Most of the volatiles were removed in vacuo at 75 ° C, the residue was treated with saturated aqueous NaHCO3 (150 mL) and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine, dried (MgSO4 and concentrated in vacuo to give the crude product. Purification by silica gel flash chromatography using 0-100% CH2Cl2 / hexanes, then 2% MeOH / CH2Cl2 provided the title compound (1.0 g , 43%) as a yellow solid.¹H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.47 (d, 2H, J = 5.5 Hz), 8.44 (dd, 1H, J = 2.7, 9.2 Hz), 7.49 (dd, 1H, J = 8.8, 8.2 Hz), 7.07 (d, 1H, J = 5.5 Hz); MS (ESI⁺): m / z 361.05 (M

<img file="PL1737451T3_D0110.tif" />

B) 4- (2-Fluoro-4-nitrophenoxy) -3-vinylpyridine [0230] Solution of 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine (200 mg, 0.56 mmol), tributylvinyl tin (212 mg , 0.67 mmol) in DMF (1 ml) was treated with CsF (169 mg,

1.12 mmol), then (Ph3P) 4Pd (36 mg, 0.031 mmol) and CuI (10 mg, 0.056 mmol) and the mixture was heated at 45 ° C for 1 h. The mixture was cooled, diluted with CH2Cl2 (15 mL) and H2O (10 ml), shaken vigorously and then filtered through Celite^®. The filter cake was washed with 1: 1 CH2Cl2 / EtOAc and the washing solutions combined with the filtrate. The solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on SiO2 using 0-2% MeOH / CH2Cl2 to give a semi-pure product. The product was treated with 2 M HCl / Et2O (10 mL) and the precipitated hydrochloride derivative was filtered and washed with Et2O and EtOAc to give a yellow solid (145 mg, 87%).¹H NMR (DMSO-d6) δ 9.11 (s, 1H),

8.64 (s, 1H), 8.51-8.48 (m, 1H), 8.24 (d, 1H, J = 7.7 Hz), 7.83-7.79 (m, 1H) , 7.28 (d, 1H, J = 6.0 Hz), 7.02-6.95 (m, 1H), 6.24 (d, 1H, J = 17.6 Hz), 5.68 ( d, 1H, 11.5 Hz); MS (ESI⁺): m / z 261.18 (M + H)⁺.

[0231] The above hydrochloride salt was converted to the free base as follows: Pyridine hydrochloride (230 mg) was mixed with NaHCO3 (25 mL) and EtOAc (20 mL) until homogeneous and the EtOAc layer was separated, washed with brine, dried (MgSO4) and concentrated. The title compound (190 mg) was obtained as a yellow oil.

<img file="PL1737451T3_D0111.tif" />

C) 4- (3-Ethylpyridin-4-yloxy) -3-fluorobenzenamine [0232] Solution of 4- (2-fluoro-4-nitrophenoxy) -3-vinylpyridine (80 mg, 0.30 mmol) in 1: 1 EtOAc / MeOH (2 mL) was hydrogenated with 10% palladium on carbon (30 mg) for 1 h using H2 from a latex balloon. To the mixture, Pt2O (10 mg) was added and the reaction continued for 1 h. The mixture was filtered through Celite^® and concentrated in vacuo to give the title compound (50 mg, 63%) as a yellow oil. ¹H NMR (DMSO-d6) δ 8.33 (s, 1H), 8.22 (d, 1H, J = 5.6 Hz), 6.96 (dd, 1H, J = 8.7, 9.1 Hz), 6.50 (dd, 1H, J = 2.0, 13.7 Hz), 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, J = 7.6 Hz).

D) 1- (4- (3-Ethylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0233] Solution 4- (3-ethylpyridinyl) 4-yloxy) -3-fluorobenzenamine (23 mg, 0.10 mmol) in CH2Cl2 (1 mL) was treated with a solution of 0.3 M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0 , 33 ml, 0.11 mmol) and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated in vacuo and the residue was triturated with 1: 1 isopropyl ether / EtOAc to give a yellow solid. The product was treated with absolute MeOH (1 mL) and 2 M HCl / Et 2 O (1 mL), stirred at room temperature for 5 min and concentrated in vacuo to give the title compound (15 mg, 36%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.57 (s, 1H), 8.41 (s, 1H), 8.26 (d, 1H, J = 5.6 Hz) , 7.76 (dd, 1H, J = 2.0, 12.7 Hz), 7.40-7.28 (m, 4H),

7.19-7.14 (m, 3H), 6.54 (d, 1H, J = 5.6 Hz), 3.73 (s, 2H), 2.72 (q, 2H, J = 7, 6 Hz), 1.23 (t, 3H, J = 7.6 Hz); MS (ESI⁺): m / z 412.20 (M + H)⁺.

Example 34 [0234]

<img file="PL1737451T3_D0112.tif" />

1- (4- (2-Amino-3-ethylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt

<img file="PL1737451T3_D0113.tif" />

A) (4-Chloro-3-iodopyridin-2-yl) -carbamic acid tert-butyl ester [0236] Solution of (4-chloro-pyridin-2-yl) -carbamic acid tert-butyl ester (CB Research and Development Inc ., 5.0 g, 22.0 mmol), TMEDA (8 mL) in anhydrous THF (100 mL) was placed under nitrogen and cooled to -70 ° C and 2.5 M n-BuLi in hexane was added dropwise (22, 0 ml, 54.8 mmol) during 30 min. The mixture was stirred at -70 ° C for 1 h, then a solution of I2 (14 g, 110 mmol) in anhydrous THF (16 mL) at -70 ° C was added dropwise. After the addition was complete, the reaction was stirred at -70 ° C for 30 min, then allowed to warm to room temperature. The mixture was treated with a solution of sodium bisulfate (16 g) in H2O (100 mL) and stirred for 30 min, then extracted with EtOAc. The extract was washed with brine, dried (MgSO 4) and concentrated in vacuo. The product was purified by flash chromatography on SiO2 eluting with 05% MeOH / CH2Cl2 to give the title compound (5.8 g, 78%) as a white solid.¹H NMR (DMSO-d6) δ 9.46 (s, 1H), 8.29 (d, 1H, J = 5.6 Hz), 7.46 (d, 1H, J = 5.0 Hz), 1 , 44 (s, 9H); MS (ESI^-): m / z 352.99 (MH)^-.

<img file="PL1737451T3_D0114.tif" />

B) 4-Chloro-3-iodopyridin-2-amine [0237] Suspension of (4-chloro-3-iodo-pyridin-2-yl) carbamic acid tert-butyl ester (5.6 g, 15.8 mmol) in 48% hydrobromic acid was heated at 100 ° C for 10 minutes to give a clear solution. The mixture was cooled, treated with crushed ice and basified with 6M NaOH. The precipitated product was filtered off with suction, washed with H2O and sucked partly on a funnel to give a white solid. The product was dissolved in THF and the solution was dried over MgSO 4 and concentrated in vacuo to give

- title compound (3.7 g, 93%) as a white solid. ¹H NMR (DMSO-d6) δ 7.84 (d, 1H, J =

5.1 Hz), 6.73 (d, 1H, J = 5.6 Hz), 6.51 (br s, 2H); MS (ESI⁺): m / z 254.97 (M + H)⁺.

<img file="PL1737451T3_D0115.tif" />

C) 4- (2-Fluoro-4-nitrophenoxy) -3-iodopyridin-2-amine A mixture of 4-chloro-3-iodopyridin-2-amine (3.6 g, 14.2 mmol) and 2- fluoro-4-nitrophenol (Lancaster, 4.5 g, 28.4 mmol), DIPEA (3.6 mL, 20.7 mmol) and NMP (8 mL) were placed in a glass pressure vessel and heated quickly to 170 ° C and heating continued for 18 h. Volatiles were distilled off under reduced pressure and the viscous residue was poured into ice water (150 ml). The mixture was sonicated for 15 minutes to break the sticky solid and the pH of the mixture was adjusted to value

7.5 with saturated aqueous NaHCO3 solution. The solid was filtered off with suction, washed with H2O, partly aspirated on the funnel. Partially dried solid was suspended in toluene (150 ml) and the mixture concentrated in vacuo and the process repeated 3 times to give a brown solid. The product was dissolved in MeOH (150 ml), treated with 4M HCl / 1,4-dioxane (8 ml) and stirred at room temperature for 5 minutes and then the mixture was concentrated in vacuo. The hydrochloride salt thus obtained was washed and triturated with EtOAc and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was separated, washed with brine and then dried (MgSO4). The EtOAc solution was treated with activated charcoal, stirred at room temperature for 10 minutes and the carbon filtered off. The solution was concentrated in vacuo to give the title compound (3.9 g, 74%) as a yellow solid.¹H NMR (DMSO-d6) δ 8.39 (dd, 1H, J = 2.5, 10.7 Hz), 8.12 (dd, 1H, J = 1.5, 9.2 Hz), 7, 86 (d, 1H, J = 5.6 Hz), 7.32 (dd, 1H, J = 8.6, 8.6 Hz),

6.40 (br s, 2H), 6.18 (d, 1H, J = 5.6 Hz).

<img file="PL1737451T3_D0116.tif" />

D) 4- (2-Fluoro-4-nitrophenoxy) -3-vinylpyridin-2-amine [0239] The title compound was obtained from 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridin-2-amine and tributylvinyltin on by a Stillego coupling reaction in the same manner as described in

Stage B from Example 33. ¹H NMR (DMSO-d6) δ 8.35 (dd, 1H, J = 10.7, 3.1 Hz), 8.09 (d, 1H,

J = 9.2 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.31-7.15 (m, 1H), 6.54 (dd, 1H, J = 17.8 , 11.7 Hz), 6.24

- 75 (br s, 2H), 6.20 (d, 1H, J = 5.6 Hz), 5.71 (d, 1H, J = 17.8 Hz), 5.46 (d, 1H, J = 11.7 Hz); MS (ESI⁺): m / z 276.17 (M + H)⁺.

<img file="PL1737451T3_D0117.tif" />

E) tert-Butyl 4- (2-fluoro-4-nitrophenoxy) -3-vinylpyridin-2-ylcarbamate [0240] Solution of 4- (2-fluoro-4-nitrophenoxy) -3-vinylpyridin-2-amine (60 mg , 0.22 mmol) in 1,4-dioxane (0.5 ml) and tert-butyl alcohol (1.5 ml) was treated with Boc2O (140 mg, 0.64 mmol) and heated at 65 ° C for 5 h The mixture was cooled, partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 to afford the title compound (50 mg, 60%) as a yellow solid. ¹H NMR (DMSO-d6) δ 9.37 (s, 1H), 8.41 (dd, 1H, J = 10.7, 2.5 Hz), 8.22 (d, 1H, J = 5.6 Hz), 8.15 (d, 1H, J = 8.6 Hz), 7.42 (t, 1H, J = 8.6 Hz), 6.86 (d, 1H, J = 5.6 Hz) , 6.58 (dd, 1H, J = 17.8, 11.7 Hz), 5.82 (d, 1H, J = 16.3 Hz), 5.52 (d, 1H, J = 11.7 Hz), 1.42 (s, 9H); MS (ESI⁺): m / z 376.18 (M + H)⁺.

<img file="PL1737451T3_D0118.tif" />

F) tert-Butyl 4- (4-amino-2-fluorophenoxy) -3-ethylpyridin-2-ylcarbamate [0241] Solution of tert-butyl 4- (2-fluoro-4-nitrophenoxy) -3-vinylpyridin-2-ylcarbamate (48 mg, 0.13 mmol) was hydrogenated on 10% palladium on carbon (10 mg) and Pt2O (5 mg) for 1.5 h using H2 from a rubber balloon. The mixture was filtered through Celite^® and the filtrate was concentrated in vacuo to give the title compound (40 mg, 89%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 9.04 (s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 6.95 (dd, 1H, J = 8.6,

8.6 Hz), 6.50 (dd, 1H, J = 2.5, 13.2 Hz), 6.41 (dd, 1H, J = 2.5, 9.4 Hz), 6.3 6 (d, 1H, J = 5.6 Hz), 5.44 (s, 2H), 2.67-2.62 (m, 2H), 1.43 (s, 9H), 1.11 (t, 3H, J = 7.1 Hz); MS (ESI⁺): m / z 348.22 (M + H)⁺.

<img file="PL1737451T3_D0119.tif" />

G) tert-Butyl 3-ethyl-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-2-ylcarbamate [0242] The title compound was obtained from tert-butyl 4- (4-amino-2-fluorophenoxy) -3-ethylpyridin-2-ylcarbamate (20 mg, 0.058 mmol) and 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (232 p, 0.070 mmol) in THF same method as step D from example 33. MS (ESI⁺): m / z 527.31 (M + H)⁺.

H) 1- (4- (2-Amino-3-ethylpyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, salt with trifluoroacetic acid [0243] Solution tert- butyl 3-ethyl-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-2-ylcarbamate (16 mg, 0.03 mmol) was dissolved in anhydrous THF ( 0.5 ml) and treated with 4 M HCl / 1,4-dioxane (1.5 ml) and stirred at room temperature for 3h. The mixture was concentrated in vacuo and the product was purified by preparative HPLC, method A to give the title compound (5 mg, 36%) as a white solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.6 (s, 1H), 7.80-7.79 (m, 4H), 7.43-7.33 (m, 4H ), 7.16 (dd, 2H, J = 8.9, 8.9 Hz), 6.19 (d, 1H, J = 7.1 Hz), 3.73 (s, 2H), 2.71 -2.66 (m, 2H), 1.10 (t, 3H, J = 7.1 Hz); MS (ESI⁺): m / z 427.18 (M + H)⁺.

Example 35

<img file="PL1737451T3_D0120.tif" />

1- (4- (3- (2- (4-Aminocyclohex-1-enyl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea [0245]

<img file="PL1737451T3_D0121.tif" />

A) 4- (tert-Butoxycarbonyl) cyclohex-1-enyl-trifluoromethanesulfonate [0246] A solution of N-Boc-4-aminocyclohexanone (Astatech Inc., 213 mg, 1.0 mmol) in THF (7 mL) was cooled to -70 ° C and treated with a solution of 0.5 M KHMDS in toluene (2.4 mL, 1.2 mmol). The mixture was stirred at -70 ° C for 20 min, a solution of phenyltrifluoromethanesulfonimide (392 mg, 1.1 mmol) in THF (4 mL) was added dropwise and stirred at -70 ° C for 25 min. The mixture was quenched by the addition of a saturated aqueous NH4Cl solution, diluted with EtOAc, washed with 10% Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 eluting with 10-25% EtOAc / hexanes to afford the title compound (180 mg, 52%) as a white solid.¹H NMR (DMSO-d6) δ 5.68 (s, 1H), 4.50 (s, 1H), 3.82 (s, 1H), 2.68-2.25 (m, 3H), 2, 22-1.89 (m, 2H), 1.87-1.63 (m, 1H), 1.43 (s, 9H).

<img file="PL1737451T3_D0122.tif" />

B) tert-Butyl 4- (2- (trimethylsilyl) ethynyl) cyclohex-3-enylcarbamate [0247] A mixture of 4- (tert-butoxycarbonyl) cyclohex-1-enyl trifluoromethanesulfonate (170 mg, 0.49 mmol), trimethylsilylacetylene (138) μζ 0.98 mmol), Et₃N (0.68 mL) and THF (8 mL) in the reaction flask were purged with argon and treated successively with CuI (14 mg, 0.072 mmol) and (Ph3P) 4Pd (27 mg, 0.024 mmol). The reaction mixture was stirred at room temperature for 25 min, and then diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 eluting with 0-25% EtOAc / hexanes to afford the title compound (116 mg, 81%) as a yellow solid. ¹H NMR (DMSO-d6) δ 6.06 (s, 1H), 4.50 (s, 1H), 3.76 (s, 1H), 2.46 (d, 1H, J = 18.8 Hz) , 2.36-2.14 (m, 2H), 2.00-1.78 (m, 2H), 1.66-1.50 (m, 1H), 1.43 (s, 9H), 0 , 27-0.05 (m, 9H).

<img file="PL1737451T3_D0123.tif" />

C) tert-Butyl 4-ethynylcyclohex-3-enylcarbamate treated with 1.0 M tetrabutylammonium fluoride in THF (Aldrich, 440 μζ 0.44 mmol) and the mixture was stirred at -15 ° C. for 40 min The mixture was treated with 5% Na2CO3 (25 mL) and extracted with ether. The ether extract was washed with 5% Na2CO3 and brine, dried (MgSO4 and concentrated in vacuo to afford the title compound (83 mg, 99%) as a brown oil. ¹H NMR (DMSO-d6) δ 6.09 (s, 1H), 4.51 (s, 1H), 3.77 (s, 1H), 2.82 (s, 1H), 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).

<img file="PL1737451T3_D0124.tif" />

D) tert-Butyl 4- (2- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) cyclohex-3enylcarbamate [0249] Solution 4- (2-fluoro-4-nitrophenoxy) -3 iodopyridine (Compound A of Example 33, 130 mg, 0.36 mmol) and N-Boc-4-ethynylcyclohex-3-enamine (80 mg, 0.36 mmol) in anhydrous THF (2 mL) was treated with Et3N (2 ml) and degassed using vacuum / argon purge. The solution was treated with tetrakistriphenylphosphine palladium (20 mg, 0.0018 mmol) and CuI (10 mg, 0.054 mmol) and then heated at reflux for 2 h. The mixture was cooled and partitioned between saturated aqueous NaHCO3 and EtOAc. The EtOAc layer was separated, washed with brine, dried (MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 0-40% EtOAc / hexanes to give the title compound (124 mg, 76%) as a yellow solid. ¹H NMR (DMSO-d6) δ 8.68 (s, 1H), 8.51 (d, 1H, J = 5.6 Hz), 8.43 (dd, 1H, J = 2.5, 10, 7 Hz), 8.15 (d, 1H, J = 9.2 Hz), 7.49 (dd, 1H, J = 8.6, 8.6 Hz), 7.14 (d, 1H, J = 5 , 6 Hz), 6.85 (d, 1H, J = 7.1 Hz), 6.04-6.00 (m, 1H), 3.48-3.35 (m, 1H), 2.36 -2.25 (m, 1H), 2.172.04 (m, 2H), 2.03-1.89 (m, 1H), 1.78-1.69 (m, 1H), 1.46-1 , 35 (m, 1H), 1.36 (s, 9H); MS (ESI⁺): m / z 454.27 (M + H)⁺.

<img file="PL1737451T3_D0125.tif" />

E) tert-Butyl 4- (2- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) ethynyl) cyclohex-3enylcarbamate [0250] A mixture of tert-butyl 4- (2- (4- (2 -fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) cyclohex-3-enylcarbamate (110 mg, 0.24 mmol), iron powder, ~ 325 mesh (150 mg, 2.7 mmol), NH4Cl (280 mg , 5.3 mmol), DMF (1 ml), H2O (1 ml) and EtOH (1 ml) _® heated at 100 ° C for 30 minutes. The mixture was filtered through a pad of Celite using DMF to wash the filter cake and the filtrate was basified to pH 8 with saturated aqueous NaHCO3. The mixture was extracted twice with EtOAc and dried (MgSO 4) and concentrated in vacuo to give the title compound (105 mg) which was used without further purification. MS (ESI⁺): m / z 424.27 (M + H)⁺.

<img file="PL1737451T3_D0126.tif" />

F) tert-Butyl 4- (2- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) ethynyl) cyclohex-3-enylcarbamate [0251] A solution of tert-butyl 4- (2- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) ethynyl) cyclohex-3-enylcarbamate (50 mg, 0.12 mmol) in dry CH2Cl2 ( 2 ml) was treated with a 0.3 M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.8 ml, 0.24 mmol) and the mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and the residue was purified by silica gel flash chromatography eluting with 10-60% EtOAc / hexanes to give the title compound (50 mg, 69%) as a white solid. ¹H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.57 (s, 1H), 8.57 (s, 1H), 8.36 (d, 1H, J = 5.7 Hz) , 7.78 (dd, 1H, J = 1.8, 13.1 Hz), 7.41-7.29 (m, 3H), 7.16 (dd, 3H, J = 8.6, 8, 6 Hz), 6.85 (d, 1H, J = 8.3 Hz), 6.70 (d, 1H, J = 5.7 Hz), 6.13-6.08 (m, 1H), 3 , 73 (s, 2H), 3.51-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.27-2.20 (m, 2H), 1.82 -1.72 (m, 1H), 1.54-1.28 (m, 2H), 1.37 (s, 9H); ESI MS): m / z 603.24 (M + H)⁺.

G) 1- (4- (3- (2- (4-Aminocyclohex-1-enyl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3 (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0252] 4- (2- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) ethynyl) cyclohex tert-butyl solution -3-enylcarbamate (40 mg, 0.066 mol) in anhydrous 1,4-dioxane (2 mL) was cooled to -10 ° C and treated with 4M HCl / 1,4-dioxane (4 mL). The mixture was stirred at -5 ° C for 2.5 h, then at room temperature for 1 h. The mixture was concentrated in vacuo without any heating to give the title compound (32 mg, 84%) as a yellow solid. ¹H NMR (DMSO-d6) δ 11.05 (s, 1H),

10.61 (s, 1H), 8.69 (s, 1H), 8.44 (d, 1H, J = 6.1 Hz), 8.06 (d, 1H, J = 2.0 Hz), 7.80 (dd, 1H, J = 12.7, 2.0 Hz), 7.46-7.38 (m, 1H), 7.35 (dd, 1H, J = 8.6, 5.6 Hz), 7.19-7.13 (m, 1H), 6.82 (d, 1H, J = 5.6 Hz), 6.17 (s, 1H), 3.74 (s, 2H), 3.73-3.62 (m, 2H), 3.62-3.54 (m, 1H), 3.34-3.22 (m, 1H), 2.31 (s, 1H), 1, 99-1.96 (m, 1H), 1.71-1.66 (m, 1H); MS (ESI⁺): m / z 503.12 (M + H)⁺.

Example 36 [0253]

<img file="PL1737451T3_D0127.tif" />

1- (4- (3- (3- (3- (Aminomethyl) azetidin-1-yl) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl ) acetyl) urea, trihydrochloride salt

<img file="PL1737451T3_D0128.tif" />

A) 3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol [0255] Solution of 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine (Compound A of Example 33, 300 mg, 0.83 mmol), propargyl alcohol (Aldrich, 145 μ ^ 2.50 mmol), Et₃N (2 ml) and anhydrous

THF (2 mL) was degassed using vacuum / argon purge and treated

Pd (Ph3P) 4 (31 mg, 0.027 mmol) and CuI (10 mg, 0.054 mmol). The mixture was refluxed under nitrogen for 10 min, cooled to rt and diluted with EtOAc (25 mL) and H2O (20 mL). The EtOAc layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography using 0-3% MeOH / CH2Cl2 to give the desired product (185 mg, 77%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 8.69 (s, 1H), 8.49 (d, 1H, J = 5.6 Hz), 8.43 (dd, 1H, J = 10.7, 2.5 Hz), 8.17 (d, 1H, J = 9.2 Hz), 7.57 (t, 1H, J = 8.6 Hz), 7.04 (d, 1H, J =

5.6 Hz), 5.40 (t, 1H, J = 6.1), 4.28 (d, 2H, J = 6.1 Hz); MS (ESI⁺): m / z 289.13 (M + H)⁺.

<img file="PL1737451T3_D0129.tif" />

B) tert-Butyl (1- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) azetidin-3-yl) methylcarbamate [0256] Solution 3- (4 - (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol (43 mg, 0.15 mmol) and DIPEA (45 μ ^ 0.26 mmol) in anhydrous THF (1 , 5 ml) cooled to 0 ° C and

- 81 were treated with methanesulfonyl chloride in portions (15 mg, 0.11 mmol). After stirring at 0 ° C for 1 h, the mixture was concentrated under reduced pressure. The residue was treated with DMF (1.0 mL), DIPEA (45 µL, 0.26 mmol) and azetidin-3-ylmethyl-carbamic acid tert-butyl ester (Beta Pharma Inc., 145 mg, 0.78 mmol) and stirred at room for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the EtOAc layer was separated, washed with brine, dried (MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with 1-5% MeOH / CH2Cl2 to give the title compound (33 mg , 48%) as a colorless oil. ¹H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.51 (d, 1H, J = 5.6 Hz), 8.41 (dd, 1H, J = 10.7, 2.5 Hz), 8.15 (d, 1H, J = 9.2 Hz), 7.53 (t, 1H, J = 8.6 Hz), 7.09 (d, 1H, J = 6.1 Hz) , 6.86 (t, 1H, J = 5.6 Hz), 3.39 (s, 2H), 3.24-3.14 (m, 2H), 3.072.98 (m, 2H), 2, 94-2.87 (m, 2H), 2.37-2.26 (m, 1H), 1.33 (s, 9H); MS (ESI⁺): m / z 401.20 (100), [(M-C4H9)]⁺; m / z 457.20 (25), (M + H)⁺.

<img file="PL1737451T3_D0130.tif" />

C) tert-Butyl (1- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) azetidin-3-yl) methylcarbamate [0257] The title compound was obtained by reduction tert-butyl (1- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) azetidin-3-yl) methylcarbamate (30 mg, 0.66 mmol) in the same the method as in Step E of Example 35 using Fe powder (50 mg, 0.091 mmol) and NH4Cl (96 mg, 1.82 mmol). The product was used in the next reactions without further purification. MS (ESI⁺): m / z 371.24 (100), [(M-C4H9)]⁺; m / z 427.27 (25), (M +

<img file="PL1737451T3_D0131.tif" />

D) tert-Butyl (1- (3- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) prop-2-ynyl) azetidin-3-yl) methylcarbamate [0258] The title compound was obtained from tert-butyl (1- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) azetidin-3 -yl) methylcarbamate (25 mg, 0.059 mmol) and

- 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.37 mL, 0.11 mmol) in the same manner as Step D from Example 33 to give the title compound as white solid (20 mg, 57%). ¹H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.58 (s,

<img file="PL1737451T3_D0132.tif" />

9H); MS (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) acetyl) urea, trihydrochloride salt [0259] tert-Butyl (1- (3- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridine -3-yl) prop-2-ynyl) azetidin-3-yl) methylcarbamate (20 mg, 0.033 mmol) was dissolved in CH2Cl2 (2 mL) and treated with TFA (0.5 mL) and the mixture was stirred at room temperature for 1 , 5 h The mixture was concentrated in vacuo and purified by preparative HPLC (Column A) to give the TFA salt. The TFA salt was dissolved in absolute MeOH and treated with 1.0M HCl / ether, stirred for 5 min and concentrated in vacuo to give the title compound (9 mg, 45%) as a white solid.¹H NMR (DMSO-

<img file="PL1737451T3_D0133.tif" />

MS (ESI⁺): m / z 506.18 (M + H)⁺.

[0260] Examples 37-40 were obtained in a similar manner as described in Example 36.

Example 37 [0261]

NH

1- (4- (3- (3- (3-aminoazetidin-1-yl) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) - urea, trihydrochloride salt [0262] MS (ESI⁺): m / z 492.17 (M + H)⁺

Example 38 [0263]

<img file="PL1737451T3_D0134.tif" />

1- (3-Fluoro-4- (3- (3- (piperazin-1-yl) prop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- (4- fluorophenyl) acetyl) urea, trihydrochloride salt [0264] ¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.63 (s, 1H), 9.44 (s, 1H), 8.91 (s, 1H), 8.50 (d, 1H, J = 6.2 Hz), 7.84-7.78 (m, 1H), 7.45-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7 , 16 (t, 2H, J = 8.8 Hz), 6.85 (d, 1H, J = 6.2 Hz), 4.26 (s, 2H), 3.75 (s, 2H), 3 , 34 (br s, 4H), 2.49 (br s, 4H); MS (ESI⁺): m / z 506.23 (M + H)⁺.

Example 39

<img file="PL1737451T3_D0135.tif" />

1- (4- (3- (3- (4-Amino-piperidin-1-yl) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) - urea, trihydrochloride salt [0266] ¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.81 (s, 1H), 8.48 (d, 1H, J = 6.1 Hz) , 8.31 (s, 2H), 7.80 (dd, 1H, J = 2.2, 12.7 Hz), 7.44-7.33 (m, 4H), 7.19-7.13 (m, 2H), 6.78 (d, 1H, J = 5.7 Hz), 4.40 (s, 2H), 3.74 (s, 2H), 3.64-3.60 (m, 2H), 3.34-3.22 (m, 1H), 3.193.13 (m, 2H), 2.16-2.13 (m, 2H), 1.99-1.88 (m, 2H) ; MS (ESI⁺): m / z 506.23 (M + H)⁺.

Example 40

<img file="PL1737451T3_D0136.tif" />

- 84 (±) -1- (4- (3- (3- (3-Aminopyrrolidin-1-yl) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) 3- (2- (4 -fluorophenyl) acetyl) urea, trihydrochloride salt [0268] ¹H NMR (DMSO-d6) δ 11.08 (s, 1H), 10.65 (s, 1H), 8.96 (s, 1H), 8.54 (d, 1H, J = 6.1 Hz) , 7.83 (d, 1H, J = 12.7 Hz), 7.43 (s, 2H), 7.37-7.33 (m, 2H), 7.16-7.14 (m, 2H ), 6.90 (d, 1H, J = 5.6 Hz), 4.62 (s, 2H), 4.06-3.87 (m, 1H), 3.75 (s, 2H), 3 , 70-3.55 (m, 3H), 3.49-3.44 (m, 2H), 2.25-2.08 (m, 1H); MS (ESI⁺): m / z 506.22 (M + H)⁺.

Example 41

<img file="PL1737451T3_D0137.tif" />

1- (3-Fluoro-4- (3- (3 - ((3R, 4R) -3-hydroxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl) prop-1-ynyl) pyridin-4-yloxy ) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trihydrochloride salt

<img file="PL1737451T3_D0138.tif" />

A) (3R, 4R) -1- (3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol [0271] Solution of 3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol (Compound A of Example 36, 43 mg, 0.15 mmol) and DIPEA (45 µL, 0.26 mmol) in anhydrous THF (1.5 mL) was cooled to 0 ° C and treated with methanesulfonyl chloride (15 mg, 0.11 mmol) in portions. After stirring at 0 ° C for 1 h, the mixture was concentrated under reduced pressure. The residue was treated with DMF (1.0 mL), DIPEA (45 µL, 0.26 mmol) and (3R, 4R) -4 (pyrrolidin-1-yl) pyrrolidin-3-ol (Lexicon Pharmaceutical Corp., 94 mg, 0.6 mmol) and stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the EtOAc layer was separated, washed with

- brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 eluting with 0-1.5% MeOH / CH2Cl2 to give the title compound (38 mg, 59%) as a brown oil.¹H NMR (DMSO-d6) δ 8.72 (s, 1H), 8.54 (d, 1H, J = 5.6 Hz), 8.40 (dd, 1H, J = 10.7, 2.5 Hz), 8.14 (d, 1H, J = 9.2 Hz), 7.43 (t, 1H, J =

8.6 Hz), 7.15 (d, 1H, J = 5.6 Hz), 4.99-4.81 (m, 1H), 4.11-4.10 (m, 0.5H), 3.92-3.84 (m, 1H), 3.54 (s, 2H), 3.59-3.50 (m, 0.5H), 3.16-3.15 (m, 1H), 2.79-2.75 (m, 1H), 2.60-2.32 (m, 4H), 1.70-1.59 (m, 4H); MS (ESI⁺): m / z 427.24 (M + H)⁺.

<img file="PL1737451T3_D0139.tif" />

B) (3R, 4R) -1- (3- (4- (4-Amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol [0272] A mixture of (3R, 4R) -1- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -4 (pyrrolidin-1-yl) pyrrolidin- 3-ol (35 mg, 0.082 mmol), DMF (1 ml), EtOH (1 ml) and H2O (1 ml) were treated with Fe powder (67 mg, 1.2 mmol, 2.4 mmol) and heated to 100 ° C for 45 min. The mixture was filtered through Celite^®, basified with NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give crude aniline (16 mg, 50%), which was used directly in the next step without further purification. MS (ESI⁺): m / z 397.28 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (3 - ((3R, 4R) -3-hydroxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl) prop-1-ynyl) pyridine -4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trihydrochloride salt [0273] The title compound was obtained from (3R, 4R) -1- (3- (4- (4-amino) -2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol (16 mg, 0.04 mmol) and 0.3M solution 2 (4-fluorophenyl) acetyl isocyanate in toluene (Compound D of Example 11, 0.13 mL, 0.04 mmol) in a similar manner to that of Step D of Example 33. The product was purified by preparative HPLC (Column A) and converted into the hydrochloride salt in the same manner as in Step E of Example 36 to give the title compound (9 mg, 33%) as a white solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.62 (s, 1H), 8.86 (s, 1H), 8.45 (d, 1H, J =

6.1 Hz), 7.81 (d, 1H, J = 12.2 Hz), 7.45-7.40 (m, 4H), 7.33-7.28 (m, 4H), 7, 16 (dd, 2H, J =

9.2, 8.6 Hz), 6.80 (d, 1H, J = 6.1 Hz), 4.64 (s, 1H), 4.34 (s, 2H), 3.84-3, 70 (m, 4H), 2.70-3.55 (m, 2H), 3.55-2.98 (m, 3H), 2.08-1.92 (m, 2H), 1.92- 1.75 (m, 2H); MS (ESI⁺): m / z 576.25 (M + H)⁺.

Example 42

<img file="PL1737451T3_D0140.tif" />

1- (3-Fluoro-4- (3- (3- (2- (pyrrolidin-1-yl) acetamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- (4- fluorophenyl) acetyl) urea, dihydrochloride salt [0275]

<img file="PL1737451T3_D0141.tif" />

A) N-Boc-propargylamine [0276] Di-tert-butyl-dicarbonate (21.8 mg, 100.0 mmol) was dissolved in THF (25 mL) and the solution was cooled to 0 ° C and a solution of propargylamine (Aldrich, 5 was added dropwise) , 0 g, 90.0 mmol) keeping the temperature below 15 ° C. The mixture was stirred at room temperature for

1.5 h then concentrated in vacuo. The residue was dissolved in hexanes and filtered through a silica gel column using 0-100% CH 2 Cl 2 / hexanes to elute the product. The product containing eluent was concentrated in vacuo to give a colorless oil which was dissolved in hexanes (150 ml) and cooled to 0 ° C to give white crystals. The crystals were filtered off and dried in vacuo to give the title compound (10.5 g, 75%).¹H NMR (CDCl3) δ 4.75 (s, 1H), 3.95 (s, 2H), 2.25-2.24 (m, 1H), 1.48 (s, 9H).

<img file="PL1737451T3_D0142.tif" />

B) tert-Butyl 3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynylcarbamate [0277] The title compound was obtained from N-Boc-propargylamine (98 mg, 0.63 mmol ) and 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine (Compound A of Example 33, 150 mg, 0.42 mmol) in Sonagashira cross-coupling reaction using Pd (Ph3P) 4 (9 mg, 0.008 mmol) and CuI (1.5 mg, 0.008 mmol) in 1: 1 Et3N / THF (3 mL) according to step C of Example 35. The title compound (124 mg, 76%) was obtained as a red oil. ¹H NMR (DMSO-d6) δ 8.66 (s, 1H), 8.50 (d, 1H, J = 5.6 Hz), 8.40 (dd, 1H, J = 2.5, 10.7 Hz), 8.15 (d, 1H, J = 9.2 Hz), 7.52 (dd, 1H, J = 8.1, 8.6 Hz), 7.33-7.30 (m, 1H ), 7.07 (d, 1H, J = 5.6 Hz), 3.95 (d, 2H, J = 5.6 Hz), 1.35 (s, 9H); MS (ESI⁺): m / z 388.21 (M + H)⁺.

<img file="PL1737451T3_D0143.tif" />

C) 3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yno-1-amine [0278] 3- (4- (2-fluoro-4- tert-butyl solution) nitrophenoxy) pyridin-3-yl) prop-2-ynylcarbamate (300 mg, 0.78 mmol) in CH 2 Cl 2 (10 mL) was treated with TFA (2 mL) and stirred at room temperature for 45 min. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (180 mg, 80%) as a red oil. ¹H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.47 (d, 1H, J = 5.6 Hz), 8.43 (dd, 1H, J = 10.7, 2.5 Hz), 8.17 (d, 1H, J = 8 , 6 Hz), 7.54 (t, 1H, J = 8.6 Hz), 7.04 (d, 1H, J = 5.6 Hz), 3.49 (s, 2H); MS (ESI⁺): m / z 288.17 (M +

<img file="PL1737451T3_D0144.tif" />

D) N- (3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-yl) acetamide [0279] Solution 3- (4 - (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yno-1-amine (80 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (2.5 mL) was cooled to 0 ° C and treated with chloride chloroacetyl (40 mg, 0.37 mmol) the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to remove solvent and excess reagent and the residue was redissolved in CH3CN (1.5 mL), treated with pyrrolidone (55 mg, 0.78 mmol) and stirred at room temperature for 4 h. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the organic layer were separated, washed with brine, dried (MgSO4) and concentrated to give the crude product. The residue was purified by silica gel flash chromatography eluting with 010% MeOH / CH2Cl2 to give the title compound (40 mg, 39%) as a brown oil. ¹H NMR (DMSO-d6) δ 8.66 (s, 1H), 8.50 (d, 1H, J = 6.1 Hz), 8.41 (dd, 1H, J = 2.8, 10.4 Hz), 8.18-8.15 (m, 2H), 7.51 (dd, 1H, J = 8.3, 8.8 Hz), 7.06 (d, 1H, J = 5.5 Hz ) 4.10 (d, 2H, J = 5.5 Hz), 3.01 (s, 2H), 2.47-2.43 (m, 4H), 1.67-1.63 (m, 4H ); MS (ESI⁺): m / z 399.27 (M + H)⁺.

<img file="PL1737451T3_D0145.tif" />

E) N- (3- (4- (4-Amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-yl) acetamide [0280] The title compound was obtained by reduction N- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-yl) acetamide (35 mg, 0.088 mmol) in a similar manner to that of step E from example 35 using Fe powder (67 mg, 1.21 mmol) and NH4Cl (128 mg, 2.42 mmol). The product was used in the next reactions without further purification. Yellow oil (30 mg, 93%). MS (ESI⁺): m / z 319.24 (M + H)⁺.

F) 1- (3-Fluoro-4- (3- (3- (2- (pyrrolidin-1-yl) acetamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- ( 4-fluorophenyl) acetyl) urea, dihydrochloride salt [0281] The title compound was obtained from N- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidine -1-yl) acetamide (32 mg, 0.088 mmol) and 0.3 M solution of 2- (4-fluoro-phenyl) -acetyl-isocyanate in toluene (Compound D from Example 11, 0.40 mL, 0.12 mmol) using THF (0 , 5 ml) in a similar manner to that of step D of example 33. The product was purified by preparative HPLC (Column B). The product containing fraction was treated with excess 1M hydrochloric acid, concentrated in vacuo and lyophilized to afford the title compound (30 mg, 63%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 10.09 (s, 1H), 9.17-9.14 (m, 1H), 8, 65 (s, 1H), 8.43 (d, 1H, J =

5.6 Hz), 7.81 (dd, 1H, J = 2.5, 12.7 Hz), 7.44-7.33 (m, 4H), 7.19-7.12 (m, 2H ), 4.31 (d, 2H, J = 5.6 Hz), 4.05 (d, 2H, J = 5.6 Hz), 3.74 (s, 2H), 3.56-3.51 (m, 2H), 3.05-2.99 (m, 2H), 1.961.90 (m, 2H), 1.88-1.79 (m, 2H); MS (ESI⁺): m / z 548.26 (M + H)⁺.

Example 43

<img file="PL1737451T3_D0146.tif" />

1- (3-Fluoro-4- (3- (3- (2- (4-hydroxy-piperidin-1-yl) acetamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- (4- fluorophenyl) acetyl) urea, dihydrochloride salt [0283]

<img file="PL1737451T3_D0147.tif" />

A) N- (3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (4-hydroxypiperidin-1-yl) acetamide [0284] The title compound was obtained from 3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-y-1-amine (Compound A of Example 36, 80 mg, 0.26 mmol), 4-hydroxypiperidine (79 mmol , 0.78 mmol) and chloroacetyl chloride (40 mg, 0.36 mmol) in the same manner as for Step D of Example 42. The residue was purified by flash chromatography on silica gel eluting with 1-3% MeOH / CH2Cl2 to give a white foam (40 mg, 36%). ¹H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.49 (d, 1H, J = 5.5 Hz), 8.41 (dd, 1H, J = 10.4,

2.7 Hz), 8.18-8.12 (m, 2H), 7.55-7.50 (m, 1H), 7.05 (d, 1H, J = 6.0 Hz), 4, 54 (d, 1H, J = 3.8 Hz), 4.11 (d, 2H, J = 6.0 Hz), 3.43-3.36 (m, 1H), 2.86 (s, 2H ), 2.64-2.58 (m, 2H), 2.12-2.05

<img file="PL1737451T3_D0148.tif" />

B) N- (3- (4- (4-Amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (4-hydroxypiperidin-1-yl) acetamide [0285] The title compound was obtained by reduction of N- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (4-hydroxypiperidin-1-yl) acetamide (33 mg, 0.077 mmol) in a method similar to that of step E of example 35 using Fe (powder, 67 mg, 1.21 mmol), NH4Cl (128 mg, 2.42 mmol). The product (30 mg, 100%) was obtained as a yellow oil which was used directly in the next step. MS (ESI⁺): m / z 399.27 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (3- (2- (4-hydroxypiperidin-1-yl) acetamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- ( 4-fluorophenyl) acetyl) urea, dihydrochloride salt [0286] The title compound was obtained from N- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (4 -hydroxypiperidin-1-yl) acetamide (25 mg, 0.063 mmol) and 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.40 ml, 0.12 mmol) using THF (0.5 mL) in a similar manner to that of Step D of Example 33. The product was purified by preparative HPLC (Column B). The product containing fraction was treated with excess 1N hydrochloric acid, concentrated and lyophilized to give

- title compound (10 mg, 30%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 11.08 (s, 1H), 10.64 (s, 1H), 9.83-9.72 (m, 1H), 9.25-9.20 (m, 1H ), 8.66 (s, 1H), 8.45 (d, 1H, J = 6.1 Hz), 7.83 (dd, 1H, J = 2.0, 13.2 Hz), 7.46 -7.35 (m, 3H), 7.21-7.11 (m, 2H), 6.77 (d, 1H, J =

6.1 Hz), 4.33-4.31 (m, 2H), 3.99-3.94 (m, 2H), 3.92-3.89 (m, 1H), 3.76 (s , 2H), 3.46-3.40 (m, 2H), 3.29-3.21 (m, 2H), 3.10-3.00 (m, 1H), 1.98-1.87 (m, 2H), 1.72-1.62 (m, 2H); MS (ESI⁺): m / z 528.25 (M + H)⁺.

Example 44

<img file="PL1737451T3_D0149.tif" />

(S) -1- (3-Fluoro-4- (3- (3- (2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carboxamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) - 3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt

<img file="PL1737451T3_D0150.tif" />

A) (S) -N- (3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carboxamide 3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yno-1-amine (Compound A of Example 36, 55 mg, 0.19 mmol) was dissolved in CH2Cl2 (5 ml), treated with 4-nitrophenyl chloroformate (0.38 mg, 0.19 mmol) and pyridine (15 μ! 0.19 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was treated with Et3N (30 mL, 0.20 mmol) and (S) - (+) - 1- (2-pyrrolidinylmethyl) pyrrolidone (Aldrich, 32 mg, 0.21 mmol) and stirred at room temperature for 15 h. The mixture was then diluted with CH 2 Cl 2 (50 mL), washed with 1 M NaOH and brine, dried (MgSO 4) and concentrated in vacuo to give the crude product. The residue was purified by flash silica gel chromatography eluting with 0-10% MeOH / CH2Cl2 to give the title compound (53 mg, 60%) as a yellow oil. ¹H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.49 (d, 1H, J = 6.1 Hz), 8.41 (dd, 1H, J = 2.8 Hz, 10, 5 Hz), 8.16 (d, 1H, J = 7.7 Hz),

- 91 7.52 (dd, 1H, J = 8.3, 8.8 Hz), 7.05 (d, 1H, J = 6.1 Hz), 4.11-4.06 (m, 2H) , 3.99-3.95 (m, 2H), 3.76 (s, 2H), 3.16-3.11 (m, 2H), 2.57-2.48 (m, 2H), 2 , 43-2.41 (m, 2H), 3.36-2.34 (m, 2H), 1.90-1.86 (m, 2H), 1.76-1.62 (m, 3H) ; MS (ESI⁺): m / z 468.27 (M + H)⁺.

<img file="PL1737451T3_D0151.tif" />

B) (S) -N- (3- (4- (4-Amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carboxamide [0290 ] The title compound was obtained by reduction of (S) -N- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynyl) -2- (pyrrolidin-1-ylmethyl) pyrrolidine -1-carboxamide (50 mg, 0.11 mmol) in a similar manner to that of Step E of Example 35 using Fe (powder, 67 mg, 1.21 mmol), NH4Cl (128 mg, 2.42 mmol). The product (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) (S) -1- (3-Fluoro-4- (3- (3- (2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carboxamido) prop-1-ynyl) pyridin-4-yloxy) phenyl) - 3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0291] The title compound was obtained from (S) -N- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop -2-ynyl) -2- (pyrrolidin-1-ylmethyl) pyrrolidine-1-carboxamide (36 mg, 0.057 mmol) and 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11 , 0.37 ml, 0.11 mmol) in the same manner as in Step D of Example 33. The product was purified by preparative HPLC (Column B) and converted to its hydrochloride according to step C of Example 43 to afford the title compound (10 mg, 25%) as an oil in amber color. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.60 (s, 1H), 9.56 (s, 1H), 8.58 (s, 1H), 8.38 (d, 1H, J = 5.6 Hz), 7.80 (dd, 1H, J = 2.6, 12.7 Hz), 7.42 (dm, 1H, J = 10.6 Hz), 7.38- 7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.20-7.10 (m, 2H), 6.69 (d, 1H, J = 6.1 Hz) , 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), 2.03-1.76 (m, 5H), 1.71-1.61 (m, 1H) ; MS (ESI⁺): m / z 617.20 (M +

H)⁺.

Example 45 [0292]

<img file="PL1737451T3_D0152.tif" />

(E) -1- (4- (3- (3- (4-Amino-piperidin-1-yl) -3-oxoprop-1-enyl) -pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4 -fluorophenyl) acetyl) urea, salt with trifluoroacetic acid

<img file="PL1737451T3_D0153.tif" />

A) (E) -tert-Butyl 3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylate [0294] A mixture of 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine ( Compound A of Example 33, 150 mg, 0.42 mmol), tert-butylacrylate (Aldrich, 107 mg, 0.84 mmol), tri-n-butylamine (0.21 mL, 0.92 mmol) and DMF (2 ml) was degassed using vacuum / argon purge and then treated with Pd (OAc) 2 (17 mg, 0.078 mmol). The mixture was heated at 100 130 ° C under argon for 45 min, then the mixture was cooled to rt, partitioned between EtOAc and saturated aqueous NaHCO3 solution. The layers were separated and the EtOAc extracts were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 eluting with 0-20% EtOAc / CH2Cl2 to give the title compound (118 mg, 78%) as a pale yellow oil which solidifies at room temperature. ¹H NMR (DMSO-d6) δ 9.02 (s, 1H), 8.49 (d, 1H, J = 5.5 Hz), 8.46 (dd, 1H, J = 2.5, 11.7 Hz), 8.21 (dm, 1H, J = 9.2 Hz), 7.74 (d, 1H, J = 16.3 Hz), 7.65 (dd, 1H, J = 8.1, 8 , 6 Hz), 6.95 (d, 1H, J = 6.1 Hz), 6.77 (d, 1H, J = 16.3 Hz), 1.47 (s, 9H); MS (ESI⁺): m / z 361.15 (M + H)⁺.

<img file="PL1737451T3_D0154.tif" />

B) (E) -3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylic acid [0295] (E) -tert-Butyl 3- (4- (2-fluoro-4- nitrophenoxy) pyridin-3-yl) acrylate (115 mg, 0.32 mmol) was treated with 1: 1 TFA / CH 2 Cl 2 (6 mL) and stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo and the residue treated with MeOH (5 ml) and

93 2 M HCl / Et2O (15 mL) and concentrated in vacuo. Partitioning a second time with MeOH (5 mL) and 2 M HCl / Et 2 O (15 mL) and re-concentration provided the title compound (120 mg).¹H NMR (DMSO-d6) δ 9.17 (s, 1H), 8.62 (d, 1H, J = 6.6 Hz), 8.50 (dd, 1H, J = 2.6, 10.1 Hz), 8.25 (d, 1H, J = 9.1 Hz), 7.78 (d, 1H, J = 16.3 Hz), 7.74 (dd, 1H, J = 8.1, 8 , 6 Hz), 7.17 (d, 1H, J = 6.1 Hz), 6.87 (d, 1H, J = 16.3 Hz); MS (ESI⁺): m / z 305.11 (M + H)⁺.

<img file="PL1737451T3_D0155.tif" />

C) (E) -tert-Butyl 1- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) acryloyl) piperidin-4-ylcarbamate [0296] Acid solution (E) -3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylic (143 mg, 0.42 mmol), 4-N-Boc-aminopiperidine (Aldrich, 84 mg, 0.42 mmol) in DMF ( 1.5 ml) was treated with DIPEA (160 μ! 0.92 mmol), and TBTU (160 mg, 0.50 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting first with 30-100% EtOAc / hexanes then 5% MeOH / CH2Cl2 to give the title compound (110 mg, 54%) as a light brown solid.¹H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.48 (d, 1H, J = 5.6 Hz), 8.44 (dd, 1H, J = 2.5, 10.5 Hz), 8.18 (d, 1H, J = 9.2 Hz), 7.69 (d, 1H, J = 15.3 Hz), 7.58 (dd, 1H, J = 8.6, 8 , 6 Hz), 7.50 (d, 1H, J = 15.7 Hz), 6.97 (d, 1H, J = 5.6 Hz), 6.89 (d, 1H, J = 7.6 Hz), 4.31-4.16 (m, 2H), 3.55-3.46 (m, 1H),

3.20-3.14 (m, 1H), 2.83-2.81 (m, 1H), 1.82-1.71 (m, 2H), 1.34-1.18 (m, 2H ), 1.37 (s, 9H); MS (ESI⁺): m / z 431.04 (100) [(M-C4H9) ⁺H]⁺; m / z 487.10 (90) (M + H)⁺.

<img file="PL1737451T3_D0156.tif" />

D) (E) -tert-Butyl 1- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) acryloyl) piperidin-4-ylcarbamate [0297] The title compound was obtained by reduction (E) -tert-butyl 1- (3- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) acryloyl) piperidin-4-ylcarbamate (100 mg, 0.21 mmol) in a manner similar to that from step E of Example 35 using Fe powder (55 mg, 2.7 mmol),

- 94 NH4Cl (280 mg, 5.3 mmol). The product (90 mg, 95%) was obtained as a light brown solid which was used directly in the next step. MS (ESI⁺): m / z 457.18 (M + H)⁺.

<img file="PL1737451T3_D0157.tif" />

E) (E) -tert-Butyl 1- (3- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) acryloyl) piperidine -4-ylcarbamate [0298] The title compound was obtained from (E) -tert-butyl 1- (3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) acryloyl) piperidin-4-ylcarbamate (42 mg, 0.092 mmol) and 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.50 mL, 0.15 mmol) in a manner similar to that from Step D of Example 33 . The crude product was adsorbed onto silica gel and purified by flash chromatography eluting with 0-5% MeOH / EtOAc to give the product (20 mg, 33%) as a white solid. ¹H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.59 (s, 1H), 9.03 (s, 1H), 8.37 (d, 1H, J = 5.6 Hz) , 7.82-7.74 (m, 2H), 7.47 (d, 1H, J = 15.8 Hz), 7.42-7.33 (m, 4H), 7.20-7.13 (m, 2H), 6.89 (d,

IH, J = 8.1 Hz), 6.63 (d, 1H, J = 5.6 Hz), 4.31 (d, 1H, J = 13.7 Hz), 4.19 (d, 1H, J = 12.7 Hz),

3.74 (s, 2H), 3.56-3.47 (m, 1H), 3.22-3.13 (m, 1H), 2.84-2.76 (m, 1H), 1, 76 (s, 2H), 1.37 (s, 9H), 1.32-1.20 (m, 2H); MS (ESI⁺): m / z 636.23 (M + H)⁺.

F) (E) -1- (4- (3- (3- (4-Aminopiperidin-1-yl) -3-oxoprop-1-enyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [0299] (E) -tert-Butyl 1- (3- (4- (2-fluoro-4- (3- (2- (4-fluorophenyl)) acetyl) ureido) phenoxy) pyridin-3-yl) acryloyl) piperidin-4-ylcarbamate (15 mg, 0.024 mmol) was dissolved in anhydrous MeOH (0.5 mL), treated with 4 M HCl / 1,4-dioxane ( 1.5 ml) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give a crude product which was purified by preparative HPLC (Column A). The product containing fraction was treated with excess 1M hydrochloric acid, concentrated and lyophilized to afford the title compound (8 mg, 44%) as a pale yellow solid.¹H NMR (DMSO-d6) δ

II, 07 (s, 1H), 10.61 (s, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 7.91 (m, 3H), 7.86-7 , 69 (m, 2H), 7.557.28 (m, 5H), 7.23-7.08 (m, 2H), 6.80-6.72 (m, 1H), 5.61-5.33 (m, 1H), 4.45-4.20 (m, 2H),

3.74 (s, 2H), 3.39-3.07 (m, 2H), 2.82-2.68 (m, 1H), 1.91-1.51 (m, 2H), 1, 50-1.15 (m, 1H); MS (ESI⁺): m / z 536.16 (M + H)⁺.

Example 46 [0300]

<img file="PL1737451T3_D0158.tif" />

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

<img file="PL1737451T3_D0159.tif" />

A) 2- (2- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridine [0302] A mixture of 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine (Compound A from Example 33, 50 mg, 0.14 mmol) and 2-ethynylpyridine (Aldrich, 57 mg, 0.54 mmol), THF (1 mL) and Et3N (1 mL) were degassed using vacuum / argon purging and treated successively with CuI (3 mg, 0.016 mmol) and (Ph3P) 4Pd (10 mg, 0.009 mmol). The mixture was heated at 60 ° C 45 minutes, cooled, partitioned between EtOAc and saturated sodium bicarbonate and the EtOAc layer was dried (MgSO 4) and concentrated in vacuo to give the crude product. Purification of the residue by flash column chromatography on SiO2 eluting with 0-1.5% MeOH / CH2Cl2 provided the title compound (42 mg, 89%) as a brown solid.¹H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.60 (d, 1H, J = 4.5 Hz), 8.45 (dd, 1H, J = 2.6, 10.7 Hz), 8.19 (d, 1H, J = 9.1 Hz), 7.86-7.83 (m, 1H), 7.66 (dd, 1H, J = 8.7, 8.7 Hz ), 7.57 (d, 1H, J = 7.6 Hz), 7.45-7.42 (m, 2H), 7.14 (d, 1H, J = 4.5 Hz); MS (ESI⁺): m / z 336.20 (M + H)⁺.

<img file="PL1737451T3_D0160.tif" />

B) 3-Fluoro-4- (3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) benzeneamine [0303] The title compound was obtained from 2- (2- (4- (2-fluoro- 4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridine (30 mg, 0.090 mmol) in a manner similar to that from step E of example 35 to give the title compound (20 mg) as a brown solid. MS (ESI⁺): m / z 306.20 (M + H)⁺.

96 C) 1- (3-Fluoro-4- (3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) - urea, dihydrochloride salt [0304] The title compound was obtained from 3-fluoro-4- (3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) benzenamine (19 mg, 0.062 mmol) and 0.3M solution 2 - (4-Fluoro-phenyl) -acetylisocyanate in toluene (Compound D from Example 11, 0.50 mL, 0.15 mmol) in a manner similar to that from Step D of Example 33. Purification of the reaction mixture by flash chromatography on SiO2 eluting with 0-100% EtOAc / CH2Cl2 provided a white solid which was converted to the hydrochloride in a similar manner to step D from Example 33 to give the title compound (19 mg, 60%) as a white body Constant. ¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.61 (s, 1H), 8.79 (s, 1H), 8.63 (d, 1H, J = 5.6 Hz) , 8.47 (d, 1H, J = 5.6 Hz), 7.89-7.86 (m, 1H), 7.83 (dd, 1H, J = 1.5, 12.7 Hz), 7.67 (d, 1H, J = 7.6 Hz), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.27 ( m, 1H), 7.20-7.16 (m, 2H), 7.14-7.10 (m, 1H), 6.77 (d, 1H, J = 5.6 Hz), 3.75 (s, 2H); MS (ESI⁺): m / z 485.17 (M + H)⁺.

Example 47

<img file="PL1737451T3_D0161.tif" />

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

<img file="PL1737451T3_D0162.tif" />

A) 3- (2- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridine [0307] A mixture of 4- (2-fluoro-4-nitrophenoxy) -3-iodopyridine (Compound A from Example 33, 50 mg, 0.14 mmol) and 3-ethynylpyridine (57 mg, 0.54 mmol), THF (1 ml) and Et3N (1 ml) were degassed using vacuum / argon purge and treated successively with CuI ( 3 mg, 0.016 mmol), and (Ph3P) 4Pd (10 mg, 0.009 mmol). The mixture was heated at 60 ° C 45 minutes, cooled, partitioned between EtOAc and saturated sodium bicarbonate and the EtOAc layer was dried (MgSO 4) and concentrated in vacuo. Purification of the residue by flash chromatography on SiO2 eluting with 0-1.5% MeOH / CH2Cl2 provided the title compound (33 mg, 77%) as a brown solid.¹H NMR (DMSO-d6) δ 8.86 (s, 1H), 8.65 (s,

- 97 1H), 8.61-8.57 (m, 2H), 8.45 (dd, 1H, J = 2.6, 10.7 Hz), 8.18 (d, 1H, J = 9, 2 Hz), 7.90 (d, 1H, J = 9.2 Hz), 7.62 (dd, 1H, J = 8.7, 8.7 Hz), 7.46 (dd, 1H, J = 4.6, 8.1 Hz), 7.17 (d, 1H, J = 5.6

Hz); MS (ESI⁺): m / z 336.19 (M + H)⁺.

<img file="PL1737451T3_D0163.tif" />

B) 3-Fluoro-4- (3- (2- (pyridin-3-yl) ethynyl) pyridin-4-yloxy) benzenamine [0308] The title compound was obtained from 3- (2- (4- (2-fluoro- 4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridine (30 mg, 0.090 mmol) in a similar manner to Step E of Example 35 to give the title compound as a brown solid (25 mg, 93%). MS (ESI⁺): m / z 306.20 (M +)⁺.

C) 1- (3-Fluoro-4- (3- (2- (pyridin-3-yl) ethynyl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0309] The title compound was obtained from 3-fluoro-4- (3- (2- (pyridin-3-yl) ethynyl) pyridin-4-yloxy) benzenamine (22 mg, 0.072 mmol) and 0.3M solution 2- ( 4-fluorophenyl) acetylisocyanate in toluene (Compound D of Example 11, 0.50 mL, 0.15 mmol) in a manner similar to Step D of Example 33. Purification of the reaction mixture by flash column chromatography on SiO2 eluting with 0-100% EtOAc / CH2Cl2 provided a white solid which was converted to the hydrochloride in a similar manner to step D from Example 33 to give the title compound (15 mg, 38%) as white solid. ¹H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.59 (s, 1H), 8.76 (s, 1H), 8.74 (d, 1H, J = 1.1 Hz) , 8.60 (dd, 1H, J = 5,6,1,1 Hz), 8,45 (d, 1H, J = 6,1 Hz), 7.98 (d, 1H, J = 7.7 Hz), 7.80 (d, 1H, J = 12.1 Hz), 7.47-7.45 (m, 1H), 7.41 (s, 2H), 7.36-7.34 (m , 2H), 7.16 (dd, 2H, J = 8.8, 8.9 Hz), 6.78 (d, 1H, J = 5.5 Hz), 3.74 (s, 2H); MS (ESI⁺): 485.13 m / z.

Example 48

<img file="PL1737451T3_D0164.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2-bromoisoonicotinamide, trifluoroacetic acid salt

- 98 [0311]

COCI

<img file="PL1737451T3_D0165.tif" />

A) 2-Bromo-isonicotinacyl chloride [0312] A solution of 2-bromo-isonicotinic acid (Lancaster, 70 mg, 0.34 mmol) in thionyl chloride (1.2 mL) was heated at reflux for 1.5 h. The mixture was concentrated and the crude 2-bromoisonicotinoyl chloride product was used directly in the next step without further purification.

B) N- (4- (2-Aminopyridin-4-yloxy) -3-fluoro-phenyl) -2-bromo-isonicotinamide [0313] To the above residue, a solution of 4- (4-amino-2-fluoro-phenoxy) -pyridine-2-amine (Compound B) was added to the above residue. from Example 24, 70 mg, 0.32 mmol) in CH 2 Cl 2 (3 mL) at room temperature, and the reaction was stirred for 1 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to afford the title compound (75 mg, 45%) as yellow solid (TFA salt). ¹H NMR (DMSO-d6) δ 11.03 (s, 1H), 8.62 (d, 1H, J = 5.0 Hz), 8.17 (s, 1H), 7.89-8.04 (m, 4H), 7.71 (d, 1H, J = 8.8 Hz), 7.51 (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

<img file="PL1737451T3_D0166.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2- (4-fluorophenylamino) isonicotinamide, bis-trifluoroacetic acid salt

<img file="PL1737451T3_D0167.tif" />

A) 2- (4-Fluorophenylamino) isonicotinic acid [0316] To a mixture of 2-fluoro-isonicotinic acid (Aldrich, 423 mg, 3.0 mmol) and 4-fluoroaniline (555 mg, 5.0 mmol) in DMF (18 ml) NaH was added at room temperature

- 99 (500 mg 60% in oil), and the mixture was heated at 85 ° C for 75 min. Acetic acid (0.7 mL) was added to the reaction mixture and concentrated in vacuo. EtOAc (100 mL) and water (20 mL) were added to the residue, stirred for 20 min and the solid filtered, washed with EtOAc and dried to give the desired product (600 mg, 50%) as a beige solid.¹H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.04 (d, 1H, J = 4.9 Hz), 7.69 (dd, 2H, J = 8.8, 4.9 Hz),

7.24 (s, 1H), 7.05 (dd, 2H, J = 8.2, 6.0 Hz); MS (ESI⁺) m / z 233.3 (M + H)⁺.

<img file="PL1737451T3_D0168.tif" />

F

B) 2- (4-Fluoro-phenylamino) isonicotinacyl chloride [0317] A mixture of 2- (4-fluoro-phenylamino) -isonicotinic acid (464 mg, 2.0 mmol) and thionyl chloride (10 ml) was heated at reflux for 2 h. The reaction was concentrated under vacuum, and the crude product was used directly in the next step.

C) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2- (4-fluorophenylamino) isonicotinamide [0318] 4- (4-Amino-2-fluorophenoxy) pyridine solution 2-amine (Compound B of Example 24, 450 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL) was slowly added to the solution of the acyl chloride obtained above in 1,2-dichloroethane (10 mL) at a bath temperature with ice, with stirring. The reaction mixture was left at room temperature overnight. EtOAc (150 mL) and saturated aqueous NaHCO3 (50 mL) were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (69 mg, 6.3%) as a yellow solid (bis-TFA salt).¹H NMR (DMSO-d6) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.27 (d, 1H, J = 5.5 Hz), 7.92-7.07 ( m, 11H), 6.68 (dd, 1H, J = 7.1, 2.2 Hz), 6.10 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z 217.9 (M + H)⁺.

Example 50

<img file="PL1737451T3_D0169.tif" />

N- (4- (2-Aminopyridin-4-yloxyp3-fluorophenyl) -6-oxo-1,6-dihydropyridine-2-carboxamide, trifluoroacetic acid salt

[0320] To a solution of 6-hydroxypicolinic acid (Aldrich, 28 mg, 0.20 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (2 mL) at room temperature was added EDCI.HCl (50 mg, 0.26 mmol), then 4- (4-amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 42 mg, 0.19 mmol), and the reaction mixture was stirred overnight at room temperature. Purification of the reaction mixture by preparative HPLC provided the desired product (24 mg, 25%) as a light brown solid (TFA salt).¹H NMR (CD3OD) δ 8.03 (dd, 1H, J = 12.6, 2.2 Hz), 7.79-7.36 (m, 5H), 6.85 (d, 1H, J = 8 , 8 Hz), 6.67 (dd, 1H, J = 7.2,

4.4 Hz), 6.22 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z 341.3 (M + H)⁺.

Example 51

<img file="PL1737451T3_D0170.tif" />

N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [0322] For 2-hydroxynicotinic acid solution (Aldrich, 42 mg, 0.30 mmol) and HOBt (18 mg) in DMF (2 mL) at room temperature EDCI was added. HCl (80 mg, 0.42 mmol), then 4- (4-amino-2-fluorophenoxy) pyridine -2-amine (Compound B from Example 24, 65 mg, 0.30 mmol), and the reaction mixture was stirred for 20 h at room temperature. Purification of the reaction mixture by preparative HPLC gave the desired product (70 mg, 49%) as a beige solid (TFA salt). ¹H NMR (CD3OD) δ 8.59 (dd, 1H, J = 7.1, 2.2 Hz), 8.03 (dd, 1H, J = 12.6, 2.2 Hz), 7.83 ( d, 1H, J = 7.7 Hz), 7.75 (dd, 1H, J = 6.6,

2.2 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.32 (t, 1H, J = 8.8 Hz), 6.67 (m, 2H), 6.21 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z 341.2 (M + H)⁺.

Example 52

<img file="PL1737451T3_D0171.tif" />

- 101 N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, trifluroacetic acid salt [0324] For 2- hydroxy-6-methylnicotinic (Lancaster, 72 mg, 0.47 mmol) and HOBt (50 mg) in DMF (5 mL) at room temperature EDCI was added. HCl (130 mg, 0.68 mmol), then 4- (4 -amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixture was stirred at room temperature for 72 h. Purification of the reaction mixture by preparative HPLC gave the desired product (125 mg, 55%) as a beige solid (TFA salt). ¹H NMR (CD3OD) δ 8.46 (d, 1H, J = 7.9 Hz), 8.03 (dd, 1H, J = 12.7, 2.8 Hz), 7.83 (d, 1H, J =

7.1 Hz), 7.44 (dd, 1H, J = 8.8, 2.2 Hz), 7.33 (t, 1H, J = 8.8 Hz), 6.67 (dd, 1H, J = 7.7, 2.7 Hz),

6.45 (d, 1H, J = 7.7 Hz), 6.21 (d, 1H, J = 2.8 Hz), 2.40 (s, 3H); MS (ESI⁺) m / z 355.2 (M + H)⁺.

Example 53

<img file="PL1737451T3_D0172.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -5-chloro-2-oxo-1,2-dihydropyridine-3-carboxamide, trifluroacetic acid salt [0326] For 2-hydroxy acid solution 5-chloronicotinic (Avocado, 87 mg, 0.50 mmol) and HOBt (40 mg) in DMF (4 mL) at room temperature added EDCI.HCl (130 mg, 0.68 mmol), then 4- (4-amino -2-fluorophenoxy) pyridin-2-amine (Compound B from Example 24, 110 mg, 0.50 mmol), and the reaction mixture was stirred for 72 h. Purification of the reaction mixture by preparative HPLC gave the desired product (115 mg, 45%) as a beige solid (TFA salt). ¹H NMR (CD3OD) δ 8.50 (d, 1H, J = 3.3 Hz), 8.03 (dd, 1H, J = 12.6, 2.1 Hz), 7.84 (m, 2H) , 7.46 (d, 1H, J = 8.8 Hz), 7.34 (t, 1H, J = 8.8 Hz), 6.67 (dd, 1H, J = 7.2, 2.2 Hz), 6.21 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z 375.1, 377.1 (M + H)⁺.

Example 54 [0327]

- 102 -

<img file="PL1737451T3_D0173.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -5-bromo-2-oxo-1,2-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [0328] For 2-hydroxy acid solution S-bromo-nicotinic (147 mg, 0.67 mmol, Syn. Comm., 1989, 19, 553-559) and HOBt (30 mg) in DMF (4 ml) at room temperature EDCI.HCl (160 mg, 0.83 mmol), then 4- (4-amino-2-fluorophenoxy) pyridine-2amine (Compound B from Example 24, 147 mg, 0.67 mmol), and the reaction mixture was stirred at room temperature overnight. Purification of the reaction mixture by preparative HPLC provided the title compound (120 mg, 33%) as a beige solid (TFA salt). ¹H NMR (DMSO-d6) δ 13.22 (s, 1H), 12.23 (s, 1H), 8.40 (d, 1H, J = 2.8 Hz), 8.14 (d, 1H, J = 2.8 Hz), 8.12-7.46 (m, 5H), 6.68 (dd, 1H, J = 7.2, 2.2 Hz), 6.14 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z 419/421 (M + H)⁺.

Example 55

<img file="PL1737451T3_D0174.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [0330] For 4-hydroxy-6 solution -methyl-nicotinic acid (Wako, 77 mg, 0.50 mmol) and HOBt (50 mg) in DMF (5 mL) at room temperature EDCI.HCl (130 mg, 0.68 mmol) was added, followed by 4- (4 -amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixture was stirred at room temperature overnight, and then heated at 75 ° C for 1.5 h. After cooling the reaction mixture to rt, purification by preparative HPLC provided the title compound (70 mg, 29%) as a white solid (TFA salt). ¹H NMR (DMSO-d6) δ 13.22 (br s, 1H), 12.53 (s, 1H), 8.47

- 103 (d, 1H, J = 5.5 Hz), 8.04 (d, 1H, J = 2.2 Hz), 7.95 (d, 1H, J = 8.2 Hz), 7.82 (s, 2H), 7.46-7.42 (m, 2H), 6.70 (dd, 1H, J = 7.7, 2.7 Hz), 6.39 (s, 1H), 6, 14 (d, 1H, J = 2.2 Hz); MS (ESI⁺) m / z

355.3 (M + H)⁺.

Example 56

<img file="PL1737451T3_D0175.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -5-benzyl-4-oxo-1,4-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [0332]

<img file="PL1737451T3_D0176.tif" />

A) 3-Bromo-5- (hydroxy (phenyl) methyl) pyridin-4-ol [0333] To a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10 mmol, obtained according to the procedure in Synthesis, 2001, 14, 2175-2179) in anhydrous THF (20 mL) at -78 ° C under an Ar atmosphere, a solution of phenyl magnesium bromide (11 mL of a 1M solution in THF, 11 mmol) was added. After mixing for 15 min. a solution of n-BuLi (5.5 mL of a 2 M solution in cyclohexane) was added, and the reaction mixture was stirred for 15 min at -78 ° C under an atmosphere of Ar. To this mixture, benzaldehyde (2.15 mL) was added and the reaction mixture was stirred for 2h at -78 ° C under an atmosphere of Ar. The reaction mixture was treated with HOAc (3 mL) and TFA (3 mL), concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with hexane / EtOAc / MeOH // 750: 250: 50 then hexane / EtOAc / MeOH / Et3N // 460: 460: 50: 10 to give the desired product (2.85 g, 91%) as a white solid.¹H NMR (CD3OD) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS (ESI⁺) m / z 280, 282 (M + H)⁺.

<img file="PL1737451T3_D0177.tif" />

104 B) 3-Benzyl-5-bromopyridin-4-ol [0334] A mixture of 3-bromo-5- (hydroxy (phenyl) methyl) pyridin-4-ol (2.55g, 91 mmol), TFA (16 mL ) and Et3SiH in CH2Cl2 (30 mL) was stirred at room temperature for 10 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane / EtOAc / MeOH // 600: 300: 50 then hexane / EtOAc / MeOH // 400: 400: 50: 10 to give an impure product, which was triturated with a small amount of MeOH and Et2O to give the desired product (255 mg, 10%) as a white solid. ¹H NMR (DMSO-d6) δ 11.75 (br s, 1H),

8.13 (s, 1H), 7.54 (s, 1H), 7.26-7.14 (m, 5H), 2.49 (s, 2H).

<img file="PL1737451T3_D0178.tif" />

C) 5-Benzyl-4-hydroxynicotinic acid [0335] To a solution of 3-benzyl-5-bromopyridin-4-ol (220 mg, 0.83 mmol) in anhydrous THF (8 ml) at -78 ° C under an atmosphere of Ar a solution of MeLi (0.61 ml 1.5 M THF solution, 0.92 mmol) was added. After mixing for 5 min. a solution of n-BuLi (0.5 mL 2 M solution in cyclohexane, 1.0 mmol) was added and the mixture was stirred for 15 min at -78 ° C under an atmosphere of Ar. Carbon dioxide was bubbled through the reaction mixture for 20 min at -78 ° C. The reaction was then quenched by adding HOAc (2 mL) to the reaction mixture, concentrated in vacuo, and the residue purified by preparative HPLC to give the desired product (100 mg, 35%) as a white solid (TFA salt). ¹H NMR (DMF-d7) δ 12.99 (br s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 7.35-7.19 (m, 5H), 3 , 90 (s, 2H); MS (ESI⁺) m / z 230.1 (M + H)⁺.

D) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -5-benzyl-4-oxo-1,4-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [0336] For acid solution 4-hydroxy-5-benzylonicotinic acid (35 mg, 0.15 mmol) and HOBt (30 mg) in DMF (2.5 ml) at room temperature EDCI was added. HCl (80 mg, 0.42 mmol), then 4- (4-amino-2-fluorophenoxy) pyridine-2-amine (Compound B from Example 24, 35 mg, 0.16 mmol), and the reaction mixture was stirred for 40 h at room temperature. Purification of the reaction mixture by preparative HPLC gave the desired product (35 mg, 43%) as a white solid, TFA salt. ¹H NMR (DMSO-d6) δ 13.25 (br s, 1H), 12.44 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.08 (dd, 1H , J = 13.2, 2.2 Hz), 7.97 (d, 1H, J = 7.1 Hz), 7.81 (d, 1H, J = 9.4 Hz), 7.52-7 , 19 (m, 7H), 6.72 (dd, 1H, J = 7.2, 2.2 Hz), 6.15 (d, 1H, J = 2.5 Hz), 3.81 (s, 2H), 3.51 (br s, 2H); MS (ESD m / z 431.2 (M + H)⁺.

Example 57 [0337]

- 105 -

<img file="PL1737451T3_D0179.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, trifluoroacetic acid salt

<img file="PL1737451T3_D0180.tif" />

A) (E) -Dimethyl-2- (3- (phenylamino) allylidene) malonate [0339] To a solution of 2- (3-methoxyallylidene) malonic acid dimethyl ester (Acros Organics, 200 mg, 1.0 mmol) in THF ( 2 ml) aniline (300 mg, 3.2 mmol) was added at room temperature and the reaction mixture was heated at 60 ° C for 8.5 h. Purification of the reaction mixture by preparative HPLC provided the desired product (150 mg, 57%) as yellow solid. ¹H NMR (DMSO-d6) δ 10.16 (d, 1H, J = 12.7 Hz), 8.06 (t, 1H, J =

12.7 Hz), 7.74 (d, 1H, J = 12.7 Hz), 7.30 (t, 2H, J = 8.7 Hz), 7.16 (d, 2H, J = 7, 7 Hz), 6.98 (t, 1H, J = 7.7 Hz), 6.35 (t, 1H, J = 12.1 Hz), 3.69 (s, 3H), 3.65 (s , 3H).

<img file="PL1737451T3_D0181.tif" />

B) Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate [0340] To a solution of the aniline adduct obtained above (130 mg, 0.50 mmol) in methanol (8 mL) at room temperature was added NaH (50 mg 60% NaH in oil, 1.2 mmol) and the mixture was stirred at room temperature for 3h. Acetic acid (0.3 mL) was added to the mixture, concentrated to a volume of ~ 4 mL, and purification of the reaction mixture by preparative HPLC provided the desired product (105 mg, 92%) as a yellow solid.¹H NMR (CD3OD) δ 8.30 (dd, 1H, J = 7.2, 2.2 Hz), 7.87 (dd, 1H, J = 6.6, 1.7 Hz), 7.57- 7.38 (m, 5H), 6.53 (t, 1H, J = 7.0 Hz), 3.84 (s, 3H); MS (ESI⁺) m / z 230.3 (M + H)⁺.

- 106 -

<img file="PL1737451T3_D0182.tif" />

C) 2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid [0341] Mixture of methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (70 mg, 0.31 mmol) and LiOH (40 mg) in methanol (6 ml) and water (1 ml) were stirred at room temperature overnight. EtOAc (50 mL) and 1 N aqueous HCl (15 mL) were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4, and concentrated in vacuo to give the product (55 mg, 83%) as a pale yellow solid.¹H NMR (DMF-d7) δ 11.77 (br s, 1H), 8.57 (dd, 1H, J = 7.4, 2.0 Hz), 8.26 (dd, 1H, J = 6, 6, 1.6 Hz), 7.64-7.55 (m, 5H), 6.88 (t, 1H, J = 7.0 Hz); MS (ESI⁺) m / z 216.2 (M + H)⁺.

D) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [0342] For 2-oxo-1 acid solution -phenyl-1,2-dihydropyridine-3-carboxyl (36 mg, 0.17 mmol) and HOBt (18 mg) in DMF (3 mL) at room temperature EDCI was added. HCl (45 mg, 0.23 mmol) m then 4- (4-amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 36 mg, 0.17 mmol), and the reaction mixture was stirred at room temperature overnight. Purification of the reaction mixture by preparative HPLC provided the title compound (32 mg, 36%) as a beige solid (TFA salt). ¹H NMR (DMSO-d6) δ 13.35 (br s, 1H), 12.11 (s, 1H), 8.52 (dd, 1H, J = 7.3, 2.1 Hz), 8.08 (dd, 1H, J =

6.6, 2.1 Hz), 8.03 (d, 1H, J = 2.3 Hz), 7.89 (d, 1H, J = 7.2 Hz), 7.81 (s, 1H) , 7.54-7.36 (m, 6H), 6.69-6.63 (m, 2H), 6.08 (d, 1H, J = 2.4 Hz), 3.55 (br s, 1H); MS (ESI⁺) m / z 417.2 (M + H)⁺.

Example 58

<img file="PL1737451T3_D0183.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -6- (4-fluorophenyl) pyridyl-N-oxideamide, trifluoroacetic acid salt [0344]

- 107 -

<img file="PL1737451T3_D0184.tif" />

A) 6- (4-Fluoro-phenyl) picolinic acid [0345] A solution of 2-bromo-picolinic acid (Aldrich, 2.02 g, 10 mmol) in DME containing 4 ml of 10% aqueous Na2CO3 was purged with Ar gas. To this mixture was added Pd (PPh3) 4 then 2- (4-fluorophenyl) -5,5-dimethyl-1,3,2-dioxaborinane (Aldrich,

2.40 g, 11.5 mmol) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100 ° C for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd (PPh3) 4 were added, and after purging with gaseous Ar, it was heated at 100 ° C for 4.5 hours. Trifluoroacetic acid (20 ml) was added to the reaction and the mixture concentrated under vacuum. MeOH (150 ml) was added to the residue and insoluble material was filtered off, and the filtrate was concentrated in vacuo. Purification of the obtained residue by flash column chromatography on silica gel eluting with EtOAc / MeOH // 900: 100, then EtOAc / MeOH / HOAc // 700: 1500: 50 afforded the desired product (1.0 g, 40% relative to starting borinate) as a white solid. ¹H NMR (CD3OD) δ 8.01 (d, 1H, J = 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 234 (M + H)⁺.

<img file="PL1737451T3_D0185.tif" />

B) 6- (4-Fluorophenyl) picolinic acid N-oxide [0346] A mixture of the picolinic acid derivative (1.0 g, 4.6 mmol), Na2HPO4 (1.2 g) and mCPBA (1.1 g, -70 % from Aldrich) in CH2ClCH2Cl (30 mL) was stirred at room temperature for 2 h. Additional Na2HPO4 (0.8 g) and m-CPBA (1.0 g) were added to the reaction mixture and stirred for 3h at room temperature. Further Na2HPO4 (0.5 g) and mCPBA (0.5 g) were added to the reaction mixture and stirred at room temperature overnight. CHCl3 (160 mL) and 2 N aqueous HCl (50 mL) were added to the reaction mixture, and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc / MeOH / HOAc // 700: 240: 60 to give the desired product which was impure with m-CPBA. This impure material was purified by preparative HPLC to give the desired product (175 mg, 16%) as a white solid.¹H NMR (DMF-d7) 8.45 (dd, 1H, J = 8.3, 2.2 Hz), 8.15 (d, 1H, J = 2.2 Hz), 8.13-8.00 (m, 4H),

7.45 (t, 2H, J = 8.7 Hz).

C) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -6- (4-fluorophenyl) pyridyl-N-oxideamide, trifluoroacetic acid salt

[0347] To a solution of 6- (4-fluorophenyl) picolinic acid-N-oxide (23 mg, 0.1 mmol) and HOBt (10 mg) in DMF (2 ml) at room temperature was added EDCI.HCl (30 mg, 0.16 mmol), then 4- (4-amino-2-fluorophenoxy) pyridin-2-amine (Compound B of Example 24, 22 mg, 0.1 mmol), and the reaction mixture was stirred at room temperature overnight . Purification of the reaction mixture by preparative HPLC provided the title compound (25 mg, 46%) as a white solid (TFA salt).¹HNMR (DMF-d7) δ 14.00 (s, 1H),

8.43 (dd, 1H, J = 8.0, 2.2 Hz), 8.15 (dd, 1H, J = 12.8, 2.4 Hz), 8.08 (d, 1H, J = 7.1 Hz), 7.997.37 (m, 9H), 6.72 (dd, 1H, J = 7.0, 2.4 Hz), 6.32 (d, 1H, J = 2.3 Hz) , 3.7 (br s, 2H); MS (ESI⁺) m / z 417.2 (M + H)⁺.

Example 59

<img file="PL1737451T3_D0186.tif" />

1- (4- (3- (4- (2-Amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, hydrochloride salt

<img file="PL1737451T3_D0187.tif" />

A) 2- (4- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid [0350] A 25 mL round bottom flask was filled with 4- (2-fluoro-4-nitrophenoxy) - 3-iodopyridine (Compound A of Example 33, 120 mg, 0.33 mmol), 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetic acid (Frontier Scientific, 13 1 mg, 0.50 mmol), tetrakis (triphenylphosphine) palladium (0) (Strem Chemicals, 38 mg, 0.033 mmol), and sodium carbonate (245 mg, 2.3 mmol). The flask was purged with nitrogen and then filled with dioxane and water (1 mL each). After stirring at 80 ° C for 10 h, the mixture was cooled to room temperature and then concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (30% MeOH / EtOAc) to afford the title compound (120 mg, 99%) as a white solid.¹H NMR (CD3OD) δ 8.61 (s, 1H), 8.48 (d, 1H, J = 5.6 Hz), 8.22 (dd, 1H, J = 10.4, 2.8 Hz) , 8.14-8.11 (m, 1H), 7.54 (d, 2H, J = 8.1 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.40 ( m, 1H), 7.05 (d, 1H, J = 5.7 Hz), 3.56 (s, 2H); MS (ESI⁺) m / z 369.16 (M + H)⁺.

- 109 -

<img file="PL1737451T3_D0188.tif" />

B) 2- (4- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide [0351] A 25 mL round bottom flask was charged with 2- (4- (4- (2-fluoro -4-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). The flask was purged with nitrogen and then DMF (1 mL) was added. After stirring at room temperature for 1 h, the solution was cooled to 0 ° C and then filled with ammonium hydroxide (0.5 ml). The reaction was stirred at 0 ° C for 1 h and then diluted with brine (5 mL) and extracted with ethyl acetate (3x5 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% MeOH / EtOAc) to afford the title compound (33 mg, 66%) as a colorless oil.¹H NMR (CD3OD) δ 8.49 (s, 1H), 8.38 (d, 1H, J = 5.6 Hz), 8.10 (dd, 1H, J = 10.4, 2.4 Hz) , 7.99 (m, 1H), 7.45 (d, 2H, J = 8.2 Hz), 7.3 0 (d, 2H, J = 8.2 Hz), 7.28 (m, 1H )

6.93 (d, 1H, J = 5.6 Hz), 3.44 (s, 2H); MS (ESI⁺) m / z 368.18 (M + H)⁺.

C) 1- (4- (3- (4- (2-Amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea [0352 ] A solution of 2- (4- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide (33 mg, 0.09 mmol) in THF (0.8 ml) and methanol (1, 2 ml) was treated with Zn dust (59 mg, 0.9 mmol), then ammonium chloride (48 mg, 0.9 mmol). The mixture was stirred at temperature_® room for 4 h and then filtered through a thin pad of Celite with methanol. The filtrate was concentrated and the residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The EtOAc layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product (25 mg, 82%) as a yellow oil that was sufficiently pure for use in the next step without further purification.¹H NMR (CD3OD) δ 8.33 (s, 1H), 8.19 (d, 1H, J = 5.6 Hz), 7.49 (d, 2H, J = 8.1 Hz), 7.32 (d, 2H, J = 8.2 Hz), 6.82 (t, 1H, J = 8.8 Hz), 6.61 (d, 1H, J = 5.6 Hz), 6.44 (qd , 1H, J = 12.8, 2.8 Hz), 3.48 (s, 2H); MS (ESI⁺) m / z 338.25 (M + H)⁺.

[0353] The above amine was dissolved in THF (1 mL) and then 2- (4-fluoro-phenyl) -acetyl-isocyanate (Compound D from Example 11.250 µL, 0.074 mmol, 0.3 M in toluene) was added. After stirring at room temperature for 1 h, the reaction was purified directly by silica gel flash chromatography (10% MeOH / EtOAc) to give the title compound as a white solid. The solid was dissolved in dioxane (2 mL) and cooled to 0 ° C. Anhydrous HCl (2 mL, 1 N in ether) was added. After stirring at 0 ° C for 5 min, the solution was concentrated in vacuo. The resulting HCl salt was lyophilized from acetonitrile / water to afford the title compound (23 mg, 57%) as a white solid.¹H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.59 (s, 1H), 8.83 (s, 1H), 8.58 (d, 1H, J =

- 110 6.4 Hz), 7.79 (dd, 1H, J = 12.8, 2.4 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.46-7, 34 (m, 4H), 7,317,28 (m, 2H), 7.11 (t, 2H, J = 8.7 Hz), 6.88 (d, 1H, J = 5.6 Hz), 3, 70 (s, 2H), 3.40 (s, 2H); MS (ESI⁺) m / z 517.19 (M + H)⁺.

Example 60

<img file="PL1737451T3_D0189.tif" />

1- (4- (3- (4- (Aminomethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt

<img file="PL1737451T3_D0190.tif" />

A) 4- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) benzaldehyde. [0356] Obtained in a similar manner as in Step A of Example 59, the title compound was obtained (86%) as a colorless oil. ¹H NMR (CD3OD) δ 9.92 (s, 1H), 8.56 (s, 1H), 8.41 (d, 1H, J = 6 Hz), 8.12 (dd, 1H, J = 10, 3, 2.6 Hz), 8.05-8.01 (m, 1H), 7.90 (d, 2H, J = 8.3 Hz), 7.73 (d, 2H, J = 8.2 Hz), 7.35 (t, 1H, J = 8.4 Hz), 6.95 (d, 1H, J = 6 Hz); MS (ESI⁺) m / z 339.19

<img file="PL1737451T3_D0191.tif" />

B) tert-Butyl-4- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) benzylcarbamate 4- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) benzaldehyde (81 mg, 0.24 mmol) in methanol (2 mL) was added ammonium acetate (185 mg, 2.4 mmol), followed by sodium cyanoborohydride (16 mg, 0.24 mmol). The reaction was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in water (5 ml) and extracted with EtOAc (2-5 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous Na2SO4, and concentrated in vacuo. Crude

- the product was dissolved in dichloromethane (2 ml) and then triethylamine (50 µL, 0.36 mmol), DMAP (tip of the shoulder), and di-tert-butyl dicarbonate (Aldrich, 57 mg, 0.26 mmol) were successively added. . The reaction was stirred at room temperature for 2 h and then purified directly by flash column chromatography on silica gel (EtOAc) to afford the title compound (13 mg, 12%) as a colorless oil.¹HNMR (CD3OD) δ 8.50 (s, 1H), 8.37 (d, 1H, J = 5.6 Hz), 8.09 (dd, 1H, J = 6.1, 2.6 Hz), 8.01-7.99 (m, 1H), 7.45 (d, 2H, J = 8 Hz), 7.26 (d, 2H, J = 8.2 Hz), 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- (Aminomethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0358] Obtained in a similar the method as in Step C of Example 59. After formation of the acylurea, 4N HCl in dioxane (5 mL) was added. After stirring at room temperature for 5 min, the reaction was concentrated in vacuo. The residue was suspended in EtOAc, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The raw material was purified by prep. HPLC. The appropriate fractions were concentrated in vacuo to remove methanol. Toluene was added and then concentrated (2-5 mL). The resulting solid was lyophilized from acetonitrile / water to give the TFA salt of the title compound (6 mg, 25%) as a white solid.¹H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.53 (s, 1H), 8.55 (s, 1H), 8.40 (d, 1H, J = 4 Hz), 7 , 73 (dd, 1H, J = 12.4 Hz), 7.67 (d, 2H, J = 8 Hz),

7.51 (d, 2H, J = 8 Hz), 7.34-7.27 (m, 4H), 7.13-7.09 (m, 2H), 6.73 (d, 1H, J = 4 Hz), 4.03 (s, 2H), 3.68 (s, 2H); MS (ESI⁺) m / z 489.18 (M + H)⁺.

Example 61

<img file="PL1737451T3_D0192.tif" />

1- (3-Fluoro-4- (3- (6- (piperazin-1-yl) pyridin-3-yl) pyridin-4-yloxy) phenyl) -3- (2- (4- fluorophenyl) acetyl) urea, hydrochloride salt [0360]

<img file="PL1737451T3_D0193.tif" />

A) tert-Butyl 4- (5- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate [0361] Obtained in a similar manner as step And from example 59, the title compound (87%) was obtained as a colorless oil. ¹H NMR (CD3OD) δ 8.62 (s, 1H), 8.46 (d, 1H, J = 6 Hz), 8.36 (d, 1H, J = 2.4 Hz), 8.24 (dd , 1H, J = 10.4, 2.8 Hz), 8.15-8.11 (m, 1H), 7.84 (dd, 1H, J = 8.8, 2.4 Hz), 7, 41 (t, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 5.6 Hz), 6.92 (d, 1H, J = 8.8 Hz), 3.61- 3.59 (m, 4H), 3.56-3.54 (m, 4H), 1.50 (s, 9H); MS (ESI⁺) m / z 496.23 (M + H)⁺.

<img file="PL1737451T3_D0194.tif" />

B) tert-Butyl 4- (5- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate. [0362] Obtained in a similar manner as step C from Example 59, the title compound (96%) was obtained as a colorless oil. ¹H NMR (CD3OD δ 8.34 (s, 1H), 8.29 (d, 1H, J = 2 Hz), 8.18 (d, 1H, J = 6 Hz), 7.78 (dd, 1H, J = 9.2, 2.8 Hz), 6.87-6.83 (m, 2H), 6.61 (d, 1H, J = 5.6 Hz), 6.48 (dd, 1H, J = 12.8, 2.8 Hz), 6.44-6.41 (m, 1H), 3.50-3.46 (m, 8H), 1.38 (s, 9H); MS (ESI⁺) m / z 466.25 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (6- (piperazin-1-yl) pyridin-3-yl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) - urea [0363] Obtained in a similar manner as Step C of Example 59, the title compound (28%) was obtained as the HCl salt. ¹H NMR (DMSO-d6) δ 11.33 (s, 1H), 10.76 (s, 1H), 9.09 (s, 1H), 8.74 (d, 1H, J = 6.8 Hz) , 8.57 (d, 1H, J = 2.4 Hz), 8.16 (dd, 1H, J = 8.8, 2 Hz), 7.91 (dd, 1H, J = 12.8, 2 Hz), 7.61 (t, 1H, J = 8.8 Hz), 7.55-7.50 (m, 1H), 7.42-7.38 (m, 2H), 7.28 (d , 1H, J = 6.5 Hz), 7.27-7.18 (m, 3H), 3.98 (m, 4H), 3.82 (s, 2H), 3.23 (m, 4H) ; MS (ESI⁺) m / z 545.19 (M + H)⁺.

Example 62

<img file="PL1737451T3_D0195.tif" />

N- (3-Fluoro-4- (3- (6- (piperazin-1-yl) pyridin-3-yl) pyridin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3 -carboxamide, the hydrochloride salt

[0365] To tert-butyl 4- (5- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate (Compound B from Example 61, 32 mg , 0.069 mmol) in THF / DMF (1 mL each) 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (Compound C of Example 57, 15 mg, 0.069 mmol) was added, DIPEA (60 µL , 0.35 mmol), then TBTU (Fluka, 33 mg, 0.10 mmol). After stirring at room temperature for 18 h, the reaction was diluted with EtOAc (5 mL), washed with 10% aqueous lithium chloride solution (2-5 mL), then saturated sodium bicarbonate solution (1-5 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was suspended in ether, cooled to 0 ° C, and treated with 4 N HCl in dioxane (5 mL). The solution was allowed to warm to rt and then stirred at room temperature for 2 h. The solution was concentrated in vacuo and the crude product obtained was purified by prep. HPLC. The appropriate fractions were concentrated to remove methanol and then basified with saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with EtOAc (2-10 mL) and the collected organic extracts were dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was dissolved in THF (2 mL), cooled to 0 ° C, and treated with 1N HCl in ether (0.5 mL). After stirring at 0 ° C for 5 min, the mixture was concentrated. The resulting white solid was lyophilized from acetonitrile / water to give the HCl salt of the title compound (26 mg, 56%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 12.16 (s, 1H), 8.92 (s, 1H), 8.59 (d, 1H, J =

6.4 Hz), 8.53 (dd, 1H, J = 7.2, 2 Hz), 8.47 (d, 1H, J = 2.4 Hz), 8.10 (dd, 1H, J = 6.4, 2 Hz), 8.04 (d, 1H, J = 12 Hz), 7.99 (dd, 1H, J = 8.8, 2.4 Hz), 7.54-7.46 ( m, 7H), 7.20 (d, 1H, J = 6.4 Hz), 7.97 (d, 1H, J = 9.2 Hz), 6.68 (t, 1H, J = 6.8 Hz), 3.82-3.80 (m, 4H), 3.12 (m, 4H); MS (ESI⁺) m / z 545.19 (M + H)⁺.

Example 63

<img file="PL1737451T3_D0196.tif" />

N - ((R) -2-Amino-2-oxo-1-phenylethyl) -N - (3-fluoro-4- (3- (6- (piperazin-1-yl) pyridin-3-yl) pyridin-4- yloxy) phenyl) malonamide, hydrochloride salt [0367] For tert-butyl 4- (5- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) pyridin-2-yl) piperazine-1-carboxylate (Compound B from Example 61, 32 mg, 0.069 mmol) in THF (1 mL) DIPEA (60 µL, 0.35 mmol) was added, followed by ethyl 3-chloro-3-oxopropionate (Aldrich, 10 µL, 0.076 mmol). After stirring at room temperature for 2 h, the reaction was diluted with EtOAc (5 mL), washed with saturated aqueous sodium bicarbonate solution (1 15 mL), dried over anhydrous Na 2 SO 4, and concentrated in vacuo. A yellow oil (65 mg) was obtained dissolved in THF (2 ml) and then a 1N aqueous sodium hydroxide solution (2 ml) was added. The solution was stirred at room temperature for 6 h. Solution

Concentrated to remove THF and then acidified to pH 4-5 with 1N aqueous HCl. The solid was filtered off with suction and washed with water to give the corresponding acid as a white solid (30 mg, 78%, 2 steps). MS (ESI⁺) m / z 552.21 (M + H)⁺.

[0368] The above acid was coupled to D (-) - phenylglycinamide (Bachem) using TBTU as described above to give the HCl salt of the title compound (32%) as a white solid. ¹H NMR (DMSO-d6) δ 10.64 (s, 1H), 8.89 (s, 1H), 8.74 (d, 1H, J = 8 Hz), 8.56 (d, 1H, J = 5.6 Hz), 8.46 (d, 1H, J = 2.4 Hz), 7.96 (d, 1H, J = 8.8 Hz), 7.84 (d, 1H, J = 12 Hz ), 7.74 (s, 1H), 7.46-7.37 (m, 4H), 7.31-7.22 (m, 5H), 7.06 (d, 1H, J = 9.2 Hz), 5.34 (d, 1H, J = 8 Hz), 3.813,78 (m, 4H), 3.40 (s, 2H), 3.12 (m, 4H); MS (ESI⁺) m / z 584.25 (M + H)⁺.

Example 64

<img file="PL1737451T3_D0197.tif" />

1- (3-Fluoro-4- (3- (pyridin-3-yl) pyridin-4-ylose) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

<img file="PL1737451T3_D0198.tif" />

A) 3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) pyridine [0371] Obtained in a similar manner as Step A of Example 59 to give the title compound as a colorless oil. ¹H NMR (CD3OD δ 8.83 (d, 1H, J = 1.6 Hz), 8.69 (s, 1H), 8.61 (d, 1H, J = 5 Hz), 8.56 (d, 1H, J = 5.8 Hz), 8.27 (dd, 1H, J = 10.4, 2.8 Hz), 8.20-814 (m, 2H), 7.72-7.55 (m , 1H), 7.53 (t, 1H, J = 8.6 Hz), 7.08 (d, 1H, J = 6 Hz); MS (ESI⁺) m / z 312.15 (M + H)⁺.

<img file="PL1737451T3_D0199.tif" />

B) 3-Fluoro-4- (3- (pyridin-3-yl) pyridin-4-yloxy) benzenamine

[0372] Obtained in a similar manner as Step C of Example 59 to give the title compound as a colorless oil. MS (ESI⁺) m / z 282.12 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (pyridin-3-yl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0373] the method as Step C of Example 59 to give the HCl salt of the title compound (47% combined yield for Steps B and C) as a yellow solid. ¹H NMR (DMSO-d6) δ 11.14 (s, 1H), 10.73 (s, 1H), 9.16 (d, 1H, J = 1.6 Hz), 9.08 (s, 1H) , 8.90 (dd, 1H, J = 5.2, 1.2 Hz), 8.78 (d, 1H, J = 6.4 Hz), 8.56 (d, 1H, J = 8 Hz) , 7.95-7.90 (m, 2H), 7.60 (t, 1H, J = 8.8 Hz), 7.55-7.52 (m, 1H), 7.44-7.41 (m, 2H), 7.26-7.21 (m, 3H), 3.82 (s, 2H); MS (ESI⁺) m / z 461.16 (M + H)⁺.

Example 65

<img file="PL1737451T3_D0200.tif" />

1- (3-Fluoro-4- (3- (4- (piperazin-1-yl) phenyl) pyridin-4-ylox) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trihydrochloride salt

<img file="PL1737451T3_D0201.tif" />

A) tert-Butyl 4- (4- (4- (2- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) piperazine-1-carboxylate. [0376] Obtained in a similar manner as Step A from Example 59 to give the title compound as colorless oil. ¹H NMR (CD3OD δ 8.48 (s, 1H), 8.32 (d, 1H, J = 5.6 Hz), 8.08 (dd, 1H, J = 12.4 Hz), 7.97 ( d, 1H, J = 8 Hz), 7.38 (d, 2H, J = 8.8 Hz), 7.21-7.18 (m, 1H), 6.95-6.92 (m, 3H ), 3.46 (m, 4H), 3.09-3.06 (m, 4H), 1.10 (s, 9H); MS (ESI⁺) m / z 495.23 (M + H)⁺.

<img file="PL1737451T3_D0202.tif" />

B) tert-Butyl 4- (4- (4- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) piperazine-1-carboxylate. [0377] Obtained in a similar manner as Step C from Example 59 to give compound title (94% combined yield for Steps A and B) as a colorless oil. ¹H NMR (CD3OD) δ 8.30 (s, 1H), 8.14 (d, 1H, J = 5.6 Hz), 7.45 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz), 6.83 (t, 1H, J = 8.8 Hz), 6.58 (d, 1H, J = 5.6 Hz), 6.48 (dd , 1H, J = 12.8, 2.4 Hz), 6.43-6.41 (m, 1H),

3.49 (m, 4H), 3.11-3.09 (m, 4H), 1.16 (s, 9H); MS (ESI⁺) m / z 465.24 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (4- (piperazin-1-yl) phenyl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [ 0378] Obtained in a similar manner to Step C of Example 59 to give the HCl salt of the title compound (37%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 11.01 (s, 1H), 10.60 (s, 1H), 8.77 (s, 1H), 8.51 (d, 1H, J = 6.4 Hz) , 7.78 (d, 1H, J = 12 Hz), 7.59 (d, 2H, J = 8.4 Hz),

7.44-7.40 (m, 2H), 7.31-7.28 (m, 2H), 7.13-7.08 (m, 4H), 7.03 (d, 1H, J = 6 , 4 Hz), 3.70 (s, 2H), 3.42 (m, 4H), 3.15 (m, 4H); MS (ESI⁺) m / z 544.26 (M + H)⁺.

Example 66

<img file="PL1737451T3_D0203.tif" />

N- (3-Fluoro-4- (3- (4- (piperazin-1-yl) phenyl) pyridin-4-yloxy) phenyl) -2-oxo-1-phenyl1,2-dihydropyridine-3-carboxamide, salt trihydrochloride [0380] Obtained in a similar manner to that of example 62 to give the HCl salt of the title compound (43%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 12.15 (s, 1H), 8.83 (s, 1H), 8.56-8.52 (m, 2H), 8.10 (dd, 1H, J = 6 , 8, 2.4 Hz), 8.04 (dd, 1H, J = 11.6, 2 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.55-7.45 (m, 7H), 7.15 (d, 1H, J = 6.8 Hz), 7.09 (d, 2H, J = 8.8 Hz), 6.61 (t, 1H, J = 6, 8 Hz), 3.44 (m, 4H), 3.15 (m, 4H); MS (ESI⁺) m / z 562.36 (M + H)⁺.

Example 67

<img file="PL1737451T3_D0204.tif" />

- 117 N- (3-Fluoro-4- (3- (4- (2-hydroxyethyl) phenyl) pyridin-4-yloxy) phenyl) -2-oxo-1-phenyl1,2-dihydropyridine-3-carboxamide

<img file="PL1737451T3_D0205.tif" />

A) 3- (4- (2- (tert-butyldimethylsilyloxy) ethyl) phenyl) -4- (2-fluoro-4-nitrophenoxy) pyridine [0383] Obtained in a similar manner as Step A of Example 59 to afford the title compound (77 %) as a colorless oil. ¹H NMR (CD3OD δ 8.67 (s, 1H), 8.56 (d, 1H, J = 8 Hz), 8.27 (dd, 1H, J = 12, 4 Hz), 8.16 (d, 1H, J = 8 Hz), 7.58 (d, 2H, J = 8 Hz), 7.39 (d, 2H, J = 8 Hz), 7.36 (m, 1H), 7.15 (d , 1H, J = 4 Hz), 3.91 (t, 2H, J = 8 Hz), 2.90 (t, 2H, J = 8 Hz), 0.90 (s, 9H), 0.00 ( s, 6H); MS (ESI⁺) m / z 469.25 (M + H)⁺.

<img file="PL1737451T3_D0206.tif" />

B) 3- (4- (2- (tert-butyldimethylsilyloxy) ethyl) phenyl) -4- (2-fluoro-4-nitrophenoxy) pyridine [0384] Obtained in a similar manner as Step C from Example 59 to give the title compound (76 %) as a light yellow oil. ¹H NMR (CD3OD) δ 8.44 (s, 1H), 8.32 (d, 1H, J = 4 Hz), 7.57 (d, 2H, J = 8 Hz), 7.36 (d, 2H , J = 8.4 Hz), 6.95 (t, 1H, J = 8 Hz), 6.75 (d, 1H, J = 4 Hz), 6.61 (d, 1H, J = 8 Hz) , 6.55 (d, 1H, J = 4 Hz), 3.90 (t, 2H, J = 6.8 Hz), 2.89 (t, 2H, J = 6.4 Hz), 0.87 (s, 9H), 0.00 (s, 6H); MS (ESI⁺) m / z 439.26 (M + H)⁺.

C) N- (3-Fluoro-4- (3- (4- (2-hydroxyethyl) phenyl) pyridin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [0385] Obtained in a similar manner to Step C of Example 62. After amide formation, the yellow oil obtained was dissolved in THF (2 mL) and then treated with TBAF (Aldrich, 180 µL, 1M in THF) at room temperature for 1 h. The reaction was diluted with EtOAc (10 mL), washed sequentially with water and brine (5 mL each), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% methanol / EtOAc) to give the title compound (72%) as a pale yellow solid. ¹H NMR (CD3OD) δ 8.59 (dd, 1H, J = 7.6, 2.0 Hz), 8.41 (s, 1H), 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 = 6.7 Hz), 7.29

- 118 (d, 2H, J = 8.1 Hz), 7.26 (m, 1H), 7.13 (t, 1H, J = 8.7 Hz), 6.69 (d, 1H, J = 6 Hz), 6.64 (t, 1H, J = 7.2 Hz), 3.73 (t, 2H, J = 7.2 Hz), 2.82 (t, 2H, J = 6.8 Hz ); MS (ESI⁺) m / z 522.27 (M + H)⁺.

Example 68 [0386] η₂ν

<img file="PL1737451T3_D0207.tif" />

Ν

N- (4- (3- (4- (2-Aminoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, dihydrochloride salt [0387 ] To N- (3-fluoro-4- (3- (4- (2-hydroxyethyl) phenyl) pyridin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (Compound C from Example 67, 40 mg, 0.077 mmol) in THF (1 mL) DIPEA (27 µL, 0.154 mmol) was added followed by methanesulfonyl chloride (Aldrich, 7 µL, 0.092 mmol). After stirring at room temperature for 30 min, the reaction was concentrated in vacuo. The 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 8h. After cooling to rt, the reaction was diluted with EtOAc (10 mL), washed with water (2 x 10 mL) then brine (1 x 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by prep. HPLC. The appropriate fractions were concentrated to remove methanol and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (2 χ 20 mL) and the collected organic extracts were washed with brine (1 χ 10 mL), dried over anhydrous Na 2 SO 4, and concentrated. The residue was dissolved in dioxane (2 mL) and filled with 1N HCl in ether (1 mL). The solution was concentrated and the obtained solid was lyophilized from acetonitrile / water to give the HCl salt of the title compound (24 mg, 53%) as a white solid.¹H NMR (DMSO-d6) δ 12.13 (s,

<img file="PL1737451T3_D0208.tif" />

Example 69 [0388]

ΗΝ

- 119 N- (4- (3- (4 - ((2- (Methylamino) ethyl) carbamoyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) 1- (4-fluorophenyl) -2-oxo-1 , 2-dihydropyridine-3-carboxamide, dihydrochloride salt

<img file="PL1737451T3_D0209.tif" />

A) Methyl 4- (4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) benzoate [0390] Obtained in a similar manner as Step A of Example 59 to give the title compound (77%) as a colorless oil. ¹H NMR (CD3OD) δ 8.66 (s, 1H), 8.52 (d, 1H, J = 6 Hz), 8.22 (dd, 1H, J = 10.4, 2.8 Hz), 8 , 16-8.13 (m, 1H), 8.10 (d, 2H, J = 8.4 Hz), 7.97 (d, 2H, J = 8 Hz),

7.44 (t, 1H, J = 8.5 Hz), 7.06 (d, 1H, J = 6 Hz), 3.93 (s, 3H); MS (ESI⁺) m / z 369.22 (M + H)⁺.

<img file="PL1737451T3_D0210.tif" />

B) Methyl 4- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) benzoate. [0391] Obtained in a similar manner as Step C of Example 59 to give the title compound (99%) as a yellow oil. ¹H NMR (CD3OD) δ 8.38 (s, 1H), 8.24 (d, 1H, J = 6 Hz), 8.01 (d, 2H, J = 8.4 Hz), 7.66 (d , 2H, J = 8.4 Hz), 6.85 (t, 1H, J = 9.2 Hz), 6.65 (d, 1H, J = 6 Hz), 6.48 (dd, 1H, J = 12.8, 2.4 Hz), 6.43 (d, 1H, J = 2.8 Hz), 3.82 (s, 3H); MS (ESI⁺) m / z 339.28 (M + H)⁺.

<img file="PL1737451T3_D0211.tif" />

C) Methyl 4- (4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) pyridin-3-yl) benzoate [0392] Obtained in a similar manner to Step C of Example 62 to afford the title compound (81%) as a yellow oil. ¹H NMR (CD3OD) δ 8.66 (dd, 1H, J = 7.2, 2 Hz), 8.56 (s, 1H), 8.40 (d,

1H, J = 6 Hz), 8.13 (d, 2H, J = 8.4 Hz), 7.97-7.95 (m, 2H), 7.78 (d, 2H, J = 8.4 Hz), 7.55-7.52 (m, 2H), 7.38-7.31 (m, 3H), 7.26 (t, 1H, J = 7.2 Hz), 6.82 (d , 1H, J = 5.6 Hz), 6.72 (t, 1H, J =

6.7 Hz), 3.94 (s, 3H); MS (ESI⁺) m / z 554.21 (M + H)⁺.

- 120 D) N- (4- (3- (4 - ((2- (Methylamino) ethyl) carbamoyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2- oxo-1,2-dihydropyridine-3-carboxamide [0393] To the above ester (159 mg, 0.29 mmol) in THF (5 mL) was added 1N aqueous NaOH (5 mL). After stirring at room temperature for 20 h, the reaction was concentrated to remove THF. The aqueous solution was acidified to pH 4 with 1N aqueous HCl. The acid was filtered off and washed with water to give the desired product (144 mg, 92%) as a beige solid. MS (ESI⁺) m / z 540.21 (M + H)⁺.

[0394] The amide was obtained as described above using TBTU to give the HCl salt of the title compound (62%) as a white solid. ¹H NMR (DMSO-d6) δ 12.21 (s, 1H), 8.93-8.90 (m, 2H), 8.68-8.64 (m, 2H), 8.21 (dd, 1H , J = 6.4, 2 Hz), 8.16 (m, 1H), 8.11 (d, 2H, J = 8 Hz),

7.90 (d, 2H, J = 8.4 Hz), 7.69-7.65 (m, 2H), 7.60-7.47 (m, 4H), 7.16 (d, 1H, J = 5.6 Hz), 6.80 (t, 1H, J = 7 Hz), 3.64 (t, 2H, J = 5.2 Hz), 3.17 (t, 2H, J = 5, 2 Hz), 2.65 (s, 3H); MS (ESI⁺) m / z

596.37 (M + H)⁺.

Example 70

<img file="PL1737451T3_D0212.tif" />

N- (4- (3- (4 - ((2-Aminoethyl) carbamoyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3 -carboxamide, dihydrochloride salt [0396] Obtained in a similar manner to Example 69 to give the HCl salt of the title compound as an off-white solid. ¹H NMR (DMSO-d6) δ 12.17 (s, 1H), 8.87-8.85 (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), 8.10 (m, 1H), 8.06 (d, 2H, J = 8.4 Hz), 8.00 (br s, 2H), 7.85 (d, 2H, J = 8.4 Hz), 7.64-7.60 (m, 2H), 7.55-7.42 (m, 4H), 7.13 (d, 1H, J = 6 Hz), 6.75 (t, 1H, J = 7.2 Hz), 3.56-3.53 (m, 2H), 3.042.99 (m, 2H); MS (ESI⁺) m / z 582.32 (M + H)⁺.

Example 71

<img file="PL1737451T3_D0213.tif" />

- 121 N- (4- (3- (4 - ((2- (Dimethylamino) ethyl) carbamoyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide, dihydrochloride salt [0398] Obtained in a similar manner to Example 69 to give the HCl salt of the title compound (56%) as an off-white solid. ¹H NMR (DMSO-d6) δ 12.08 (s, 1H), 8.87 (br s, 1H), 8.75 (s, 1H), 8.54-8.51 (m, 2H), 8 , 08 (dd, 1H, J = 6.8, 2.4 Hz), 8.02 (m, 1H), 7.99 (d, 2H, J = 8.4 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.56-7.53 (m, 2H), 7.47-7.34 (m, 4H), 6.99 (d, 1H, J = 5.6 Hz ), 6.67 (t, 1H, J = 6.8 Hz), 3.61-3.57 (m, 2H), 3.23-3.21 (m, 2H), 2.77 (s, 3H), 2.76 (s, 3H); MS (ESI⁺) m / z 610.30 (M + H)⁺.

Example 72

<img file="PL1737451T3_D0214.tif" />

1- (4- (3-Amino-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0215.tif" />

A) 3-Fluoro-4- (3-nitropyridin-4-yloxy) benzenamine To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol) in DMF (5 mL ) at room temperature under nitrogen atmosphere, sodium hydride (80 mg, 2 mmol, 60%) was added. After stirring at room temperature for 10 min, 4-chloro-3-nitropyridine hydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 1 h and then diluted with EtOAc (50 mL) and washed with water, 10% aqueous lithium chloride solution, and then with brine (1 χ 30 mL each). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc to give the title compound (150 mg, 60%) as a yellow-orange solid.¹H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.63 (d, 1H, J = 6 Hz), 7.09 (t, 1H, J = 9.2 Hz), 6.92 (d, 1H, J = 6 Hz), 6.55 (dd, 1H, J = 13.2, 2.4 Hz), 6.45 (dd, 1H, J = 9.2, 2.4 Hz) , 5.61 (s, 2H); MS (ESI⁺ m / z 250.18 (M⁺ H)⁺.

- 122 -

<img file="PL1737451T3_D0216.tif" />

B) 1- (3-Fluoro-4- (3-nitropyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0402] Solution of 3-fluoro-4- (3- nitropyridin-4-yloxy) benzenamine (158 mg, 0.63 mmol) in THF (3 mL) was treated with a solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 1.3 mmol) and stirred at room temperature for 2 h then at 50 ° C for 5 min. The mixture was concentrated and the residue treated with DMF (15 mL) and SiO2 (150 mg) and the mixture concentrated to dryness in vacuo and applied to a SiO2 column. The column was eluted with 20-60% EtOAc / hexanes to give the product, which was further purified by trituration with isopropyl ether to give a light yellow solid (120 mg, 25%).¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H), 8.67 (d, 1H, J =

5.6 Hz), 7.85 (d, 1H, J = 11.7 Hz), 7.46-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.18 ( dd, 2H, J = 8.6,

8.6 Hz), 7.01 (d, 1H, J = 6.1 Hz), 3.76 (s, 2H).

C) 1- (4- (3-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0403] Suspension 1- (3-fluoro-4- ( 3-nitropyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea (125 mg, 0.29 mmol) in 3: 1 MeOH / THF (20 mL) hydrogenated on Pt2O (50 mg) using H2 from a latex balloon for 6 h. The catalyst was filtered off using Celite^® and the filtrate was concentrated to give the title compound (85 mg, 74%) as a white solid. ¹H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.55 (s, 1H), 8.03 (s, 1H), 7.75 (dd, 1H, J = 2.5, 13 , 2 Hz), 7.65 (d, 1H, J = 5.1 Hz), 7.38-7.35 (m, 3H), 7.23-7.16 (m, 3H), 6.42 (d, 1H, J = 5.1 Hz), 5.26 (s, 2H), 3.75 (s, 2H); MS (ESI⁺): m / z 399.35 (M + H)⁺.

Example 73

<img file="PL1737451T3_D0217.tif" />

1- (4- (3 - ((1S, 4S) -4-Aminocyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) 3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [ 0405]

- 123 -

<img file="PL1737451T3_D0218.tif" />

A) tert-Butyl (1S, 4S) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) carbamoyl) - cyclohexylcarbamate [0406] A solution of N-Boc-cis-1,4-diaminocyclohexane carboxylic acid (Chem-Imprex International, 24 mg, 0.10 mmol) in THF (1 mL) was cooled to 0 ° C, and treated with Et3N and then isobutylchloroformate. After 5 min, the mixture was treated with a solution of 1- (4- (3-aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Compound C of example 72, 27 mg , 0.068 mmol) in THF (0.5 mL) and stirring was continued at 0 ° C for 10 min and then at room temperature for 2 h. The mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution and the EtOAc layer was separated, dried (MgSO 4) and concentrated under in vacuo to give a crude product. Purification of the residue by flash column chromatography on SiO2 eluting with 50-100% EtOAc / hexanes provided the title compound (13 mg, 21%) as a white solid. MS (ESI⁺): m / z 624.25 (M + H)⁺.

B) 1- (4- (3 - ((1S, 4S) -4-Aminocyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, salt with trifluoroacetic acid [0407] Tert-butyl (1S, 4S) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl solution ) carbamoyl) cyclohexylcarbamate (10 mg, 0.016 mmol) in anhydrous MeOH (0.5 ml) was cooled to 0 ° C and treated with 4 M HCl / 1,4-dioxane (2 ml). The mixture was stirred at 0 ° C for 1.5 h and then at room temperature for 20 min and finally concentrated in vacuo to give the crude product. Purification of the residue by preparative HPLC (Column A) provided the title compound (4 mg, 33%) as a yellow solid.¹H NMR (DMSO-d6) δ 11.07 (s, 1H),

10.64 (s, 1H), 9.28 (s, 1H), 8.40-8.3 7 (m, 1H), 7.94 (s, 1H), 7.83 (dd, 1H, J = 2.1, 12.7 Hz), 7.47-7.33 (m, 5H), 7.19-7.14 (m, 3H), 7.07-7.02 (m, 1H), 3.75 (s, 2H), 3.25-3.15 (m, 1H), 2.85-2.76 (m, 1H), 1.97-1.84 (m, 2H), 1, 85-1.61 (m, 5H); MS (ESI⁺): m / z 524.26 (M + H)⁺.

Example 74

<img file="PL1737451T3_D0219.tif" />

- 124 1- (4- (3 - ((1R, 4R) -4-Aminocyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) -urea, bis- trifluoroacetic acid salt

<img file="PL1737451T3_D0220.tif" />

A) tert-Butyl (1R, 4R) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) carbamoyl) - cyclohexylcarbamate [0410] The title compound was obtained from 1- (4- (3-aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Compound C of Example 72, 57 mg , 0.14 mmol) and N-Boc-trans-4-aminocyclohexane-1-carboxylic acid (Anaspec Inc., 51 mg, 0.21 mmol) in a similar manner as described for step A of example 73 to give the title compound (32 mg 66%) as a white solid. MS (ESI⁺): m / z 624.41 (M + H)⁺.

B) 1- (4- (3 - ((1R, 4R) -4-Aminocyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, bis- trifluoroacetic acid salt [0411] The title compound was obtained from tert-butyl (1S, 4S) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridine 3-yl) carbamoyl) -cyclohexyl-carbamate (25 mg) in a similar manner as described for Example 73. Purification of the reaction mixture by preparative HPLC (Column A) provided the title compound (7 mg, 23%) as a white solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.61 (s, 1H), 9.94 (s, 1H), 9.19 (s, 1H), 8.28 (d, 1H, J = 5.6 Hz), 7.82 (dd, 1H, J = 2.0, 13.2 Hz), 7.79-7.76 (m, 3H), 7.43 (dd, 1H , J = 2.0, 8.6 Hz), 7.38-7.33 (m, 2H), 7.17 (dd, 2H, J = 9.2, 6.6 Hz), 6.86 ( d, 1H, J = 5.6 Hz), 3.74 (s, 2H), 3.08-2.95 (m, 1H), 2.67-2.43 (m, 1H), 2.01 -1.88 (m, 4H), 1.53-1.43 (m, 2H), 1.37-1.27 (m, 2H); MS (ESI⁺): m / z 524.35 (M + H)⁺.

Example 75

<img file="PL1737451T3_D0221.tif" />

1- (4- (3 - ((1R, 4R) -4- (Aminomethyl) cyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0413 ]

- 125 -

<img file="PL1737451T3_D0222.tif" />

A) Benzyl ((1R, 4R) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) carbamoyl) -cyclohexylmethylcarbamate [0414] The title compound was obtained from 1- (4- (3-aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Compound C of Example 72, 50 mg, 0.13 mmol) and trans-4 - ((benzyloxycarbonyl) methyl) cyclohexane carboxylic acid (40 mg, 0.14 mmol), Obtained according to the synthetic route described in Schaus, JM et al. J. Med Chem. 1998, 41, 1943-1955) according to step A of example 73 to give the title compound (30 mg, 34%) as a white solid. MS (ESI⁺): m / z 672.34 (M + H)⁺.

B) 1- (4- (3 - ((1R, 4R) -4- (Aminomethyl) cyclohexane carboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0415] Benzyl ((1R, 4R) -4 - ((4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) carbamoyl) solution -cyclohexylmethylcarbamate (25 mg 0.037 mmol) in MeOH (1.5 mL) was hydrogenated on 10% palladium on carbon (15 mg) for 4 h using H2 from a rubber balloon. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound (18 mg, 90%) as a yellow solid. ¹H NMR (DMSO-d6) δ

10.62 (s, 1H), 9.64 (s, 1H), 9.01 (s, 1H), 8.17 (d, 1H, J = 5.6 Hz), 7.79 (dd, 1H , J = 2.5, 12.7 Hz), 7.42-7.3 5 (m, 4H), 7.30 (dd, 1H, J = 8.6, 9.2 Hz), 7.18 (m, 2H), 6.66 (d, 1H, J = 5.6 Hz),

3.75 (s, 2H), 2.39 (d, 2H, J = 6.6 Hz), 1.87-1.81 (m, 4H), 1.46-1.35 (m, 1H) , 1.33-1.10 (m, 1H), 0.95-0.77 (m, 4H); MS (ESI⁺): m / z 538.28 (M + H)⁺.

Example 76

<img file="PL1737451T3_D0223.tif" />

1- (4- (3- (Cyclohexanecarboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0417] Solution 1- (4- (3-aminopyridine -4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Compound C of Example 72, 25 mg, 0.062 mmol) in CH2Cl2 (2 mL) was treated with Et3N (10 g , 0.074 mmol) and cyclohexankarbonyl chloride (Aldrich, 11 mg,

- 0.074 mmol) and stirred at room temperature for 2 h. An additional portion of cyclohexankarbonyl chloride (11 mg, 0.074 mmol) was added to the mixture and the reaction continued for 18 h. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution, dried (MgSO4 and concentrated in vacuo The residue was purified by flash column chromatography on SiO2 eluting with 50-100% EtOAc / hexanes to give the title compound (19 mg, 61%) as a white solid. ¹H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.57 (m, 1H), 9.60 (m, 1H), 8.99 (s, 1H), 8.15 (d, 1H, J =

5.6 Hz), 7.76 (dd, 1H, J = 2.0, 13.2 Hz), 7.39-7.33 (m, 3H), 7.28 (dd, 1H, J = 8 , 6, 9.2 Hz), 7.18-7.14 (m, 2H), 6.65 (d, 1H, J = 5.1 Hz), 3.73 (s, 2H), 1.81 -1.71 (m, 5H), 1.64-1.61 (m, 1H), 1.43-1.34 (m, 2H), 1.29-1.14 (m, 3H); MS (ESI +): m / z 509.27 (M + H)⁺.

Example 77

<img file="PL1737451T3_D0224.tif" />

1- (4- (3- (4-Aminopiperidine-1-carboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, bis-trifluoroacetic acid salt

<img file="PL1737451T3_D0225.tif" />

A) 1- (3-Fluoro-4- (3- (4- (2-phenoxyacetamido) piperidine-1-carboxamido) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [ 0420] A solution of triphosgene (50 mg, 0.17 mmol) in CH2Cl2 (0.4 mL) was cooled to -10 ° C and treated with a solution of 1- (4- (3-aminopyridin-4-yloxy) -3-fluorophenyl ) -3- (2- (4-fluoro-phenyl) -acetyl) -urea (Compound C of Example 72, 67 mg, 0.17 mmol) and DIPEA (65 μ! 0.37 mmol) in CH₂cl₂ ( 0.4 ml). The mixture was stirred at -10 ° C for 10 min and then treated with a solution of 4 - ((carbobenzyloxy) amido) piperidine (40 mg, 0.17 mmol). Obtained using the procedure described in Schaus, JM et al. J. Med. Chem. 1998 , 41, 1943-1955) and DIPEA (65 μ! 0.37 mmol) in CH₂cl₂ (0.4 ml). After stirring for 2 minutes, the mixture was warmed to room temperature then heated to 40 ° C for 10 min. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The product was purified after

By flash column chromatography on SiO2 eluting with 0-5% MeOH / CH2Cl2 to give the title compound (50 mg, 45%) as a yellow solid. MS (ESI +) m / z 659.29 (M +

H)⁺.

B) 1- (4- (3- (4-Aminopiperidine-1-carboxamido) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, bis-acid salt trifluoroacetic [0421] Solution 1- (3-fluoro-4- (3- (4- (2-phenoxyacetamido) piperidine-1-carboxamido) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea (45 mg, 0.068 mmol) in absolute MeOH (2.5 mL) was hydrogenated on 10% palladium on carbon (15 mg) using H2 from a rubber balloon for 2.5 h. The catalyst was filtered off and the filtrate concentrated in vacuo and the residue purified by preparative HPLC (Column A) to afford the title compound. ¹H NMR (DMSO-d6) δ 10.57 (s, 1H), 8.55 (s, 1H), 8.27 (m, 1H), 8.14 (d, 1H, J =

5.6 Hz), 7.75 (dd, 1H, J = 2.0, 12.7 Hz), 7.37-7.33 (m, 3H), 7.23-7.14 (m, 3H ), 6.65 (d, 1H, J = 5.1 Hz), 4.05-3.98 (m, 2H), 3.73 (s, 2H), 3.05-2.91 (m, 1H), 2.88-2.83 (m, 2H), 1.83-1.74 (m, 2H), 1.34-1.20 (m, 2H); MS (ESI⁺) m / z 525.35 (M + H)⁺.

Example 78

<img file="PL1737451T3_D0226.tif" />

1- (4- (2-Amino-3- (4- (2-amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) - urea, salt with trifluoroacetic acid [0423]

<img file="PL1737451T3_D0227.tif" />

A) 2- (4- (2-Amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid [0424] A mixture of 4- (2-fluoro-4-nitrophenoxy) - 3-iodopyridin-2-amine (Compound C of Example 34, 88 mg, 0.23 mmol), 4- (dihydroxyborane) phenylacetic acid pinacol ester (Frontier Scientific Inc., 92 mg, 0.35 mmol), Na2CO3 (170 mg, 1.61 mmol), 1,4-dioxane (2 mL) and H2O (2 mL) was degassed using vacuum / argon purge and treated with tetrakis (triphenylphosphine) palladium (27 mg, 0.023 mmol). After heating at 100 ° C for 3h, the pH of the mixture was adjusted to pH 6 using 1N hydrochloric acid.

The mixture was concentrated in vacuo and the residue partitioned between EtOAc and pH 7 phosphate buffer. The aqueous layer was extracted with EtOAc and the combined extracts were dried (MgSO 4 and concentrated in vacuo to give the crude product. The product was triturated with 2: 1 EtOAc / MeOH to give the desired product (70 mg, 80%) as an orange-brown solid.¹H NMR (DMSO-d6) δ 12.34 (s, 1H), 8.23 ​​(dd, 1H, J = 3.1, 10.5 Hz), 8.05 (d, 1H, J = 10.2 Hz),

7.94 (d, 1H, J = 6.1 Hz), 7.32-7.25 (m, 5H), 6.26 (d, 1H, J = 6.1 Hz), 5.62 (s , 2H), 3.57 (s, 2H); MS (ESI⁺): m / z 384.16 (M + H)⁺.

<img file="PL1737451T3_D0228.tif" />

B) 2- (4- (2-Amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide [0425] 2- (4- (2-Amino-4- ( 2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid (65 mg, 0.17 mmol) in anhydrous DMF (1.2 ml) was treated with PyBOP (125 mg, 0.24 mmol) and HOBt ( 32 mg, 0.24 mmol), then DIPEA (60 μζ 0.35 mmol) and NH₄Cl (19 mg, 0.35 mmol). After stirring at room temperature for 20 min, the mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by flash column chromatography on SiO2 eluting with 0-8% MeOH / CH2Cl2 to give the title compound (40 mg, 62%) as an amber oil.¹H NMR (DMSO-d6) δ 8.23 ​​(dd, 1H, J = 10.7, 2.5 Hz), 8.05 (d, 1H, J = 9.2 Hz), 7.93 (d, 1H, J = 6.1 Hz), 7.42-7.32 (m, 2H), 7.33-7.25 (m, 4H), 6.92 (s, 1H), 6.25 (d , 1H, J = 5.6 Hz), 5.64 (s, 2H), 3.36 (s, 2H); MS (ESO: m / z 383.17 (M + H)⁺.

<img file="PL1737451T3_D0229.tif" />

C) 2- (4- (2-Amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide [0426] A mixture of 2- (4- (2-amino-4- (2 -fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide (32 mg, 0.086 mmol), DMF (1 ml), EtOH (1 ml) and H2O (1ml) was treated with Fe powder (67 mg, 1, 2 mmol), and NH4Cl (128 mg, 2.4 mmol) and the mixture was heated at 100 ° C for 20 min. The mixture was filtered through Celite^®, the pH of the filtrate was adjusted to pH 7 using phosphate buffer and then the mixture was extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated to give the desired product (20 mg, 67%) as a yellow-brown solid. MS (ESI⁺): m / z 353.32 (M + H)⁺.

- 129 D) ​​1- (4- (2-Amino-3- (4- (2-amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -3 (2- (4-fluorophenyl) ) acetyl) -urea trifluoroacetic acid salt [0427] The title compound was obtained from 2- (4- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide (19 mg, 0.054 mmol ) and a 0.3M solution of 2- (4-fluorophenyl) acetylisocyanate in toluene (Compound D from Example 11, 0.27 mL, 0.081 mmol) in a similar manner to that described for step D of Example 33. Purification of the reaction mixture by preparative HPLC (Column A) provided the title compound (9 mg, 26%) as a white solid. ¹H NMR (DMSO-d6): δ 11.03 (s, 1H), 10, 5 7 (s, 1H), 7.93 (d, 1H, J = 7.1 Hz),

7.76 (dd, 1H, J = 2.0, 13, 2 Hz), 7.44-7.42 (m, 3H), 7.37-7.29 (m, 6H), 7.16 ( dd, 2H, J = 8.6,

8.8 Hz), 6.94 (s, 1H), 6.31 (d, 1H, J = 7.1 Hz), 3.72 (s, 2H), 3.43 (s, 2H); MS (ESI⁺): m / z

532.24 (M + H)⁺.

Example 79

<img file="PL1737451T3_D0230.tif" />

1- (4- (2-Amino-3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, salt dihydrochloride

<img file="PL1737451T3_D0231.tif" />

A) 4- (2-Fluoro-4-nitrophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine [0430] A mixture of 4- (2-fluoro-4-nitrophenoxy) -3 iodopyridin-2-amine (Compound C of Example 34, 100 mg, 0.27 mmol) and 2-ethynylpyridine (Aldrich, 57 mg, 0.54 mmol), THF (2 mL) and Et3N (2 mL) were degassed using vacuum / argon purge and treated successively with CuI (6 mg, 0.032 mmol) and (Ph3P) 4Pd (20 mg, 0.017 mmol). The mixture was heated at 60 ° C for 45 minutes, cooled, partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4 and concentrated in vacuo to give the crude product. Purification of the residue by flash column chromatography on SiO2 eluting with 0-1.5% MeOH / CH2Cl2 provided the title compound (55 mg, 58%) as a brown solid.¹H NMR (DMSO-d6) δ

8.53 (d, 1H, J = 5.1 Hz), 8.39 (dd, 1H, J = 2.5, 10.7 Hz), 8.15 (dm, 1H, J = 8.1 Hz ), 7.97 (d,

- 130 -

<img file="PL1737451T3_D0232.tif" />

NK₂

F-

<img file="PL1737451T3_D0233.tif" />

h₂n

N

B) 4- (4-Amino-2-fluorophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine [0431] A mixture of 4- (2-fluoro-4-nitrophenoxy) -3 - (2- (pyridin-2-yl) ethynyl) pyridine-2-amine (35 mg, 0.1 mmol), THF (1.5 ml) and MeOH (1.5 ml) were treated with zinc dust (65 mg, 1 , 0 mmol) and NH4Cl (53 mg, 1.0 mmol) and heated at 60 ° C for 45 min. The reaction mixture was cooled, filtered and concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give the title compound (25 mg, 78%) as a brown solid. MS (ES⁺): m / z 321.2 (M + H)⁺.

C) 1- (4- (2-Amino-3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea , dihydrochloride salt [0432] A solution of 4- (4-amino-2-fluorophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine (25 mg, 0.078 mmol) in THF (2 mL ) was cooled to 0 ° C and treated with a 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.26 mL, 0.078 mmol). After 1 h, the mixture was warmed to room temperature and stirred for 15 min. The mixture was concentrated in vacuo and the residue purified by preparative HPLC (Column A) to give the title compound as a TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 M HCl / Et 2 O at 0 ° C and stirred for 5 min.

The mixture was then concentrated in vacuo to give the title compound (18 mg, 41%) as a brown solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J = 4.5

Hz), 8.22 (s, 2H), 7.99 (d, 1H, J = 7.1 Hz), 7.94-7.81 (m, 3H), 7.48-7.44 (m , 3H), 7.37-7.33 (m, 2H), 7.16 (dd, 2H, J = 6.2, 9.2 Hz), 6.30 (d, 1H, J = 7.1 Hz), 3.74 (s, 2H); MS (ESI⁺): m / z 500.21 (M + H)⁺.

Example 80 [0433]

- 131 1- (4- (2-Acetamidopyridin-4-ylose) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

<img file="PL1737451T3_D0234.tif" />

A) tert-Butyl 4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenylcarbamate [0435] Mixture of 4- (4-amino-2-fluorophenoxy) picolinamide (Compound B 'from Example 24, 190 mg, 0.76 mmol), tert-butyl alcohol (2 ml), 1,4-dioxane (1 ml), DMF (1 ml) and Boc2O (167 mg, 0.76 mmol) was heated at 65 ° C for 16 h. Additional portions of Boc2O (85 mg and 60 mg) were added after 16 h and 32 h, respectively, and the mixture was heated for 40 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was dried (MgSO4 and concentrated in vacuo to give the crude product. Purification of the residue by flash column chromatography on SiO2 eluting with 30-60% EtOAc / hexanes provided the title compound (180 mg, 68%) as a brown solid.¹H NMR (DMSO-d6) δ 9.74 (s, 1H), 8.52 (d, 1H, J = 5.6 Hz), 8.13 (s, 1H), 7.72 (s, 1H) , 7.62 (d, 1H, J = 13.7 Hz), 7.35-7.31 (m, 3H), 7.18 (dd, 1H, J = 5.6, 2.5 Hz), 1.39 (s, 9H); MS (ESI⁺): m / z 348.22 (M + H)⁺.

<img file="PL1737451T3_D0235.tif" />

B) tert-Butyl 4- (2-aminopyridin-4-yloxy) -3-fluorophenylcarbamate. A solution of KOH (280 mg, 5.0 mmol) in H2O (2 mL) was cooled to 0-5 ° C and bromine was added dropwise (162 mg, 1.0 mmol) and the mixture was stirred for 5 min. Tert-butyl 4- (2-carbamoyl-pyridin-4-yloxy) -3-fluorophenylcarbamate (347 mg, 1.0 mmol) was added to the mixture in one portion as a solid and then 1,4-dioxane (3 mL) was added to dissolve the solids . The reaction mixture was stirred at room temperature for 30 min, then at 55 ° C for 45 min. The mixture was then cooled to room temperature, treated with HOAc (0.5 mL) and stirred until foaming ceased. The mixture was again heated to 55 ° C for 20 min, cooled to room temperature, treated with KOH (350 mg) and extracted with CH 2 Cl 2. The organic extract was dried (MgSO4) and concentrated in vacuo. The residue was purified by type column chromatography

- 132 flash on SiO2 eluting with 30-70% EtOAc / hexanes to give the title compound (265 mg, 83%). ¹H NMR (DMSO-d6) δ 9.67 (s, 1H), 7.77 (d, 1H, 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, 6.1 Hz), 5.93 (s, 2H), 5.74 (d, 1H, J = 2.5 Hz), 1.47 (s, 9H); MS (ESI⁺): m / z 320.23 (M + H)⁺.

<img file="PL1737451T3_D0236.tif" />

C) tert-Butyl 4- (2-acetamidopyridin-4-yloxy) -3-fluorophenylcarbamate [0437] tert-Butyl 4- (2-aminopyridin-4-yloxy) -3-fluorophenylcarbamate (150 mg, 0.47 mmol) in anhydrous pyridine (0.5 ml) was cooled to 10 ° C and treated with acetyl chloride (33 µL, 0.47 mmol) and the mixture was stirred for 45 min. An additional portion of acetyl chloride (16 µL, 0.24 mmol) was added to the reaction and stirring continued for 25 min. The mixture was diluted with EtOAc (20 mL), washed with brine, dried (MgSO 4) and concentrated in vacuo to afford the title compound (115 mg, 68%). ¹H NMR (DMSO-d6) δ 10.55 (s, 1H), 9.71 (s, 1H), 8.16 (d, 1H, J = 5.5 Hz), 7.63-7.55 ( m, 2H), 7.29-7.23 (m, 2H), 6.68-6.63 (m, 1H), 2.02 (s, 3H), 1.48 (s, 9H); MS (ESI⁺): m / z 362.22 (M + M⁺) .

<img file="PL1737451T3_D0237.tif" />

D) N- (4- (4-Amino-2-fluorophenoxy) pyridin-2-yl) acetamide [0438] Solution of tert-butyl 4- (2-acetamidopyridin-4-yloxy) -3-fluorophenylcarbamate (110 mg, 0 , 30 mmol) in 4 M HCl / 1,4-dioxane (1.5 mL) was stirred at 0 ° C for 20 min, then at room temperature for 25 min. The mixture was diluted with EtOAc (25 mL) and saturated aqueous NaHCO3 (20 mL), and stirred vigorously for 5 min. The EtOAc layer was washed with brine, dried (MgSO 4 and concentrated in vacuo to give the title compound (69 mg, 87%) as a yellow solid. ¹H NMR (DMSO-d6) δ

10.49 (s, 1H), 8.13 (d, 1H, J = 5.6 Hz), 7.60 (m, 1H), 6.95 (dd, 1H, J = 8.6, 9, 2 Hz), 6.60 (dd, 1H, J = 2.5, 5.6 Hz), 6.48 (dd, 1H, J = 2.5, 13.2 Hz), 6.40 (dd, 1H, J = 2.0, 8.6 Hz), 5.44 (s, 2H), 2.02 (s, 3H).

E) 1- (4- (2-Acetamidopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

[0439] A solution of N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) acetamide (20 mg, 0.077 mmol) in THF (1 mL) was treated with a 0.3M solution of 2- (4 -fluorophenyl) acetylisocyanate in toluene (Compound D of Example 11, 0.26 mL, 0.77 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue purified by preparative HPLC (Column A) to give a compound title as TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 M HCl / Et 2 O at 0 ° C and stirred for 5 min. The mixture was then concentrated in vacuo to give the title compound (12 mg, 33%) as a white solid.¹H NMR (DMSO-d6): δ

<img file="PL1737451T3_D0238.tif" />

(s, 2H), 2.03 (s, 3H); MS (ESI⁺): m / z 441.18 (M + H)⁺.

Example 81 [0440]

N- (4- (2-Acetamidopyridin-4-yloxy) -3-fluorophenyl) -2,6-difluorobenzamide, hydrochloride salt [0441] N- (4- (4-amino-2-fluorophenoxy) pyridin-2- solution yl) acetamide (Compound B 'from Example 24, 15 mg, 0.057 mmol) in THF (0.5 mL) was treated with DIPEA (15 g, 0.086 mmol) and 2-6-diflurobenzoyl chloride (10 mg, 0.057 mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo and the residue purified by preparative HPLC (Column A) to give the title compound as a TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 M HCl / Et 2 O at 0 ° C and stirred for 5 min. The mixture was then concentrated in vacuo to give the title compound (15 mg, 60%) as an off-white solid.¹H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.79

<img file="PL1737451T3_D0239.tif" />

6.1 Hz), 2.06 (s, 3H); MS (ESI⁺): m / z 402.13 (M + H)⁺.

Example 82 [0442]

- 134 -

<img file="PL1737451T3_D0240.tif" />

1- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt

<img file="PL1737451T3_D0241.tif" />

A) N- (4- (2-Chloropyridin-4-yloxy) -3-fluorophenyl) acetamide [0444] A mixture of N- (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), K2CO3 (1.6 g, 11.8 mmol), and DMF (25 mL) heated at 100 ° C for 9 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 eluting with 3080% EtOAc in hexanes to give the title compound (1.6 g, 73%) as a pale yellow solid. ¹H NMR (DMSO-d6) δ 10.25 (s, 1H), 8.35 (d, 1H, J = 7 Hz), 7.80 (d, 1H, J = 14 Hz), 7.50 (d , 1H, J = 3 Hz), 7.33 (m, 2H), 7.02 (m, 1H), 2.06 (s, 3H); MS (ESI⁺: m / z 281.16 (M +

<img file="PL1737451T3_D0242.tif" />

B) N- (4- (2-Chloropyridin-4-yloxy-1-oxo) -3-fluorophenyl) acetamide [0445] A mixture of N- (4- (2-chloropyridin-4-yloxy) -3-fluorophenyl) acetamide (0.98 g, 3.5 mmol),&gt; 90%, m-chloroperbenzoic acid (1.3 g, 7.6 mmol), and CHCl 3 (50 mL) was stirred at room temperature for 60 h. The mixture was concentrated in vacuo and the residue was triturated with

- Et2O (2 χ 100 mL) to give the title compound (0.89 g, 86%) as a pale yellow solid. ¹H

NMR (DMSO-d6) δ 10.25 (s, 1H), 8.35 (d, 1H, J = 7.3 Hz), 7.80 (d, 1H, J = 13 Hz), 7.33- 7.32 (m, 3H), 7.02 (dd, 1H, J = 3.5, 7.5 Hz), 2.06 (s, 3H); MS (ESI): m / z 295.04 (M + H)⁺.

<img file="PL1737451T3_D0243.tif" />

C) N- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy-1-oxide) phenyl) acetamide [0446] Mixture of N- (4- (2-chloropyridin-4-yloxy hydrochloride) -1-oxide) -3-fluorophenyl) acetamide (205 mg, 0.62 mmol), 4- (2-aminoethyl) morpholine (Aldrich, 169 mg, 1.30 mmol), and absolute EtOH was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, and the residue was treated with H2O (3 mL) and applied to a 10 g Varian C-18 cartridge. The cartridge was eluted first with H2O, then with 30% MeOH in H2O. The eluent that contained the desired product was collected, concentrated to 5 mL volume, and extracted 3 times with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (100 mg, 40%).¹H NMR (DMSO-d6) δ 10.22 (s, 1H), 7.84 (d, 1H, J = 6 Hz), 7.77 (dd, 1H, J = 2, 12 Hz), 7.31 (dd, 1H, J = 2, 9 Hz), 7.24 (dd, 1H, J = 9, 9 Hz), 6.41 (m, 1H), 6.13 (dd, 1H, J = 2, 6 Hz), 5.81 (d, 1H, J = 2.5 Hz), 3.56-3.48 (m, 2H), 3.31-3.19 (m, 4H), 2.38 ( t, 2H, J = 7 Hz), 2.40-2.28 (m, 4H), 2.06 (s, 3H); MS (ESI⁺): m / z 405.22 (M + H)⁺.

<img file="PL1737451T3_D0244.tif" />

D) N- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy) phenyl) acetamide, trifluoroacetic acid salt [0447] A mixture of N- (3-fluoro-4- (2- ( 2-morpholinoethylamino) pyridin-4-yloxy-1-oxide) phenyl) acetamide (100 mg, 0.26 mmol), and triphenylphosphine deposited on a polymer (1.4-2.0 mmol / g) on ​​polystyrene (500 mg) and DMF (2 mL) was stirred at 135 ° C for 15 h. The mixture was filtered to remove the resin and the resin was washed with DMF and EtOAc. The filtrate and washing solutions were combined and concentrated. The crude product was purified by preparative HPLC (Column A) to give the title compound (45 mg, 24%) as a white solid. ¹H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.02 (d, 1H, J = 7 Hz) 7.84 (dd, 1H, J = 2, 13 Hz), 7.39- 136 7.31 (m, 2H), 6.52 (s, 1H), 6.10 (s, 1H), 3.83 (s, 4H), 3.60-3.48 (m, 2H), 3.32-3.18 (m, 6H), 2.08 (s, 3H); MS (ESI⁺): m / z 375.12 (M + H)⁺.

<img file="PL1737451T3_D0245.tif" />

E) 4- (4-Amino-2-fluorophenoxy) -N- (2-morpholinoethyl) pyridine-2-amine, hydrochloride salt [0448] Mixture of N- (3-fluoro-4- (2- (2-morpholinoethylamino) trifluoroacetate pyridin-4-yloxy) phenyl) acetamide (40 mg), MeOH (1 ml), and 6 M HCl (0.2 ml) was refluxed for 3h. The mixture was concentrated on a rotary evaporator and the residue was freeze dried to give the title compound (30 mg) as a white solid.¹H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.85 (s, 1H), 7.95 (d, 1H, J = 7 Hz), 7.08 (dd, 1H, J = 9, 9 Hz), 6.65-6.63 (m, 2H), 6.54 (d, 1H, J = 8 Hz), 6.31 (s, 1H), 3.90-3.75 ( m 6H), 3.37-3.21 (m, 6H); MS (ESI-): m / z 373.14 (M + H)⁺.

F) 1- (3-Fluoro-4- (2- (2-morpholinoethylamino) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0449] Hydrochloride solution 4- (4-amino-2-fluorophenoxy) -N- (2-morpholinoethyl) pyridin-2-amine (15 mg, 0.045 mmol) in MeOH (5 mL) was treated with Et3N (2 mL) and the mixture was stirred at room temperature for 5 hours. min. The mixture was concentrated in vacuo to remove MeOH, the residue was suspended in THF (1 mL) and treated with a solution of 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 180 mL, 0.054 mmol) . After stirring, the mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was separated, washed with brine, dried (MgSO4) and concentrated. The mixture was concentrated in vacuo and the residue purified by preparative HPLC (Column A) to give the title compound as a TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 N HCl / Et 2 O at 0 ° C and stirred for 5 min. The mixture was then concentrated in vacuo to give the title compound (10 mg, 43%) as a white solid.¹H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.61 (s, 1H), 7.98 (d, 1H, J = 7.1 Hz), 7.86-7.73 ( m, 1H), 7.48-7.38 (m, 1H), 7.37-7.30 (m, 3H), 7.247.04 (m, 2H), 6.60 (s, 1H), 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)⁺.

[0450] Examples 83-85 were prepared in a similar manner as described for example 82.

Example 83 [0451]

- 137 -

<img file="PL1737451T3_D0246.tif" />

1- (3-Fluoro-4- (2- (3-morpholinopropylamino) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0452] ¹1 H NMR (DMSO-d 6) δ m, 2H).

Example 84

<img file="PL1737451T3_D0247.tif" />

1- (4- (2- (3- (Dimethylamino) propylamino) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0454] ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.62 (s, 1H), 10.37 (s, 1H), 7.93 (d, 1H, J = 7.1 Hz) , 7.82 (dd, 1H, J = 2.0, 12.7 Hz), 7.45 (dd, 1H, J = 2.6, 8.6 Hz), 7.40 (d, 1H, J = 8.6 Hz),

7.37-7.33 (m, 2H), 7.16 (dd, 2H, J = 8.7, 9.1 Hz), 6.65 (s, 1H), 6.24 (s, 1H) , 3.75 (s, 2H),

3.45-3.36 (m, 2H), 3.13-3.03 (m, 2H), 2.73 (s, 3H), 2.72 (s, 3H), 1.94-1, 90 (m, 2H).

Example 85

<img file="PL1737451T3_D0248.tif" />

1- (4- (2- (4- (Dimethylamino) butylamino) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0456] MS (ESI⁺): m / z 498.2 (M + H)⁺.

Example 86

- 138 -

<img file="PL1737451T3_D0249.tif" />

1- (4- (2,6-Diaminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

<img file="PL1737451T3_D0250.tif" />

A) 4-Chloropyridine-2,6-dicarboxamide [0459] A mixture of chelidamic acid (3.19 g, 17.0 mmol), PCl5 (2.1 g) and CCl4 (30 ml) was heated to reflux for 6 h and then cooled to 65 ° C and treated with MeOH (5 mL) in mild reflux. The mixture was heated to reflux for 5 h and then concentrated in vacuo. The residue was treated with ice-water (50 mL) and the precipitated solid was filtered off and sucked dry to give a white 2.6-biscarbomethoxy-4-chloropyridine needle (2.4 g). The product was treated with ~ 7 M NH₃ / MeOH and stirred at room temperature for 1 h. The mixture was filtered to collect the title compound as a white solid (1.8 g, 53%). ¹H NMR (DMSO-d6) δ 8.91 (s, 2H), 8.15 (s, 2H), 7.87 (s, 2H).

<img file="PL1737451T3_D0251.tif" />

B) tert-Butyl 4- (2,6-dicarbamoylpyridin-4-yloxy) -3-fluorophenylcarbamate [0460] A solution of N-Boc-4-amino-2-fluorophenol (228 mg, 1.0 mmol) in DMF (2 ml) was treated with t-BuOK (124 mg, 1.1 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was treated with 4-chloropyridine-2,6-dicarboxamide (200 mg, 1.0 mmol) and K2CO3 ( 35 mg, 0.5 mmol) and heated at 80 ° C for 1.5 h. The mixture was concentrated in vacuo, treated with EtOAc (10 mL) and H2O (10 mL) and filtered to remove insoluble material. The EtOAc layer was washed with brine, dried (MgSO 4 and concentrated in vacuo. Purification of the residue by type column chromatography

Flash on SiO2 eluting with 30-100% EtOAc / hexanes provided the title compound (170 mg, 44%) as a white solid containing 10% starting chloropyridine. ¹H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.86 (s, 2H), 7.87 (s, 1H), 7.63 (d, 1H, J = 12.1 Hz) , 7.55 (s, 2H),

7.38-7.31 (m, 2H), 1.48 (s, 9H).

<img file="PL1737451T3_D0252.tif" />

C) tert-Butyl 4- (2,6-diaminopyridin-4-yloxy) -3-fluorophenylcarbamate [0461] The title compound was obtained from tert-butyl 4- (2,6-dicarbamoylpyridin-4-yloxy) -3-fluorophenylcarbamate (110 mg , 0.28 mmol) using a similar procedure as described for step B of example 80. Flash chromatography on SiO2 eluting with 0-2% MeOH / EtOAc provided the title compound (60 mg, 63%) as a white solid. ¹H NMR (DMSO-d6) δ 9.60 (s, 1H), 7.50 (dd, 1H, J = 1.8, 13.6 Hz), 7.21 (dd, 1H, J = 2.2 , 8.7 Hz), 7.13 (dd, 1H, 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 +

<img file="PL1737451T3_D0253.tif" />

D) 4- (4-Amino-2-fluorophenoxy) pyridine-2,6-diamine [0462] The title compound was obtained from tert-butyl 4- (2,6-diaminopyridin-4-yloxy) -3-fluorophenylcarbamate (30 mg, 0.089 mmol) in a similar manner to that described in step D of example 80 to give a clear oil (20 mg, 100%). MS (ESI⁺): m / z 235.22 (M + H)⁺.

E) 1- (4- (2,6-Diaminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0463] The title compound was obtained from 4- ( 4-amino-2-fluorophenoxy) pyridine-2,6-diamine (19 mg, 0.081 mmol) and a solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (0.3 M, Compound D from Example 11, 0, 27 ml, 0.081 mmol) in a similar manner to step D of the example

33. The reaction mixture was purified by preparative HPLC (Column A) to give the title compound as a TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 M HCl / Et 2 O at 0 ° C and stirred for 5 min. The mixture was then concentrated in vacuo to give the title compound (8 mg, 24%) as a pale yellow solid.¹H NMR (DMSO-d6) δ 11.01 (s, 1H), 10.51 (s, 1H), 7.68 (dd, 1H, J = 2.6, 12.7 Hz), 7.36- 7.30

- 140 (m, 3H), 7.22-7.14 (m, 3H), 5.52 (s, 4H), 5.15 (s, 2H), 3.73 (s, 2H); MS (ESI⁺): m / z 414.09 (M + H)⁺.

Example 87

<img file="PL1737451T3_D0254.tif" />

1- (4 - ((2- (3- (Dimethylamino) propylamino) pyridin-4-yl) methyl) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0465]

<img file="PL1737451T3_D0255.tif" />

A) tert-Butyl 4-bromo-3-fluoro-phenylcarbamate [0466] To a solution of 4-bromo-3-fluorobenzeneamine (Lancaster, 7.05 g, 37.1 mmol) in anhydrous tetrahydrofuran (40 ml) at room temperature (Boc) 2O was added (8.10 g, 37.1 mmol) and triethylamine (5.17 mL, 37.1 mmol). The reaction mixture was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO2 eluting with 20% dichloromethane in hexane, then 20% ethyl acetate in hexane to give tert-butyl 4-bromo-3-fluorophenylcarbamate (5.30 g, 49% yield). MS (ESI⁺): m / z 290.2 (M + H)⁺.

<img file="PL1737451T3_D0256.tif" />

B) tert-Butyl 4 - ((2-chloropyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate [0467] For tert-butyl solution of 4-bromo-3-fluorophenylcarbamate (2.60 g, 9.0 mmol) in anhydrous THF (30 ml) at -78 ° C MeMgBr (3.0 M in Et 2 O 3.1 ml, 9.3 mmol) was added via syringe. The solution was stirred for 10 min at this temperature, and then warmed to

0 ° C for 0.5 h. After cooling the solution again to -78 ° C, t-BuLi solution (1.7

M in hexane, 10.6 ml, 18.1 mmol) during 4 min. The resulting solution was left with

- stirring for 5 min before a solution of 2-chloroisonicotinaldehyde (1.41 g, 10 mmol) was added (for preparation see Frey, LF et al. Tetrahedron Lett. 2001, 42, 6815) in anhydrous THF (25 ml) over 3 min . The reaction mixture was stirred at -78 ° C for 20 min and 2.0 mL MeOH was added. The solution was then concentrated under reduced pressure and the residue was dissolved in 200 mL EtOAc. Then washed with H2O (2 χ 50 ml), brine (2 χ 50 ml) and dried over MgSO4. After filtration and concentration, the residue was purified by flash chromatography on SiO2 eluting with 0% -50% EtOAc in hexane to give tert-butyl 4 - ((2-chloropyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate ( 1.30 g, 41% yield). MS (ESI⁺): m / z 353.28 / 355.24 (M + H)⁺.

<img file="PL1737451T3_D0257.tif" />

C) tert-Butyl 4 - ((2-chloropyridin-N-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate [0468] For 4 - ((2-chloropyridin-4-yl) tert-butyl solution (hydroxy) methyl) -3-fluorophenylcarbamate (1.20 g, 3.40 mmol) in a mixture of dichloromethane (100 mL) and ethyl acetate (10 mL) m-CPBA (70%, 2.34 g, 9.48 mmol) was added . The reaction mixture was stirred at room temperature for 2 h, and then refluxed for 5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on SiO2 eluting with 50% EtOAc in hexane, 100% EtOAc and then 10% MeOH in EtOAc to give tert-butyl 4 - ((2-chloropyridin-N-oxide- 4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (840 mg, 67% yield). MS (ESI⁺): m / z

369.13 / 371.13 (M + H)⁺.

<img file="PL1737451T3_D0258.tif" />

D) tert-Butyl 4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate [0469] For 4 - ((2-chloropyridinyl tert-butyl solution 4-yl) (hydroxy) methyl) 3-fluorophenylcarbamate N-oxide (80 mg, 0.22 mmol) in EtOH (2.0 mL) added N¹N¹-dimethylpropane-1,3-diamine (225 mg, 2.2 mmol). The reaction mixture was heated at 80 ° C for 12 h and the solvent removed to give crude tert-butyl 4 - ((2- (3- (dimethylamino) propylamino) pyridin-N-oxide-4-yl) (hydroxy) methyl) - 3-fluorophenylcarbamate, which was directly used in the next step. MS (ESI⁺): m / z 435.37 (M + H)⁺.

[0470] For a solution of 4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (~ 0.22 mmol) in MeOH (2 - (3- (dimethylamino) propylamino) , 0 ml) zinc (114 mg, 1.75 mmol) and NH4CO2H (139 mg, 2.20 mmol) were added. The suspension was heated to reflux overnight. More zinc (114 mg) and NH4CO2H (139 mg) were added and the suspension was refluxed for 2 h. After cooling, the solution was filtered and the filtrate was concentrated under reduced pressure. The residue was then purified by flash chromatography on SiO2 eluting with 10-30% MeOH in DCM to give tert-butyl 4 - ((2- (3- (dimethylamino) propylamino) pyridine-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (80 mg, 87% yield). MS (ESI⁺): m / z 419.34 (M + H)⁺.

<img file="PL1737451T3_D0259.tif" />

E) 4- (4-Amino-2-fluorobenzyl) -N- (3- (dimethylamino) propyl) pyridin-2-amine [0471] For 4 - ((2- (3- (dimethylamino) propylamino tert-butyl solution ) pyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (80 mg, 0.19 mmol) in MeOH (5.0 mL) was added with 2 mL concentrated HCl and palladium on carbon (10%, 200 mg). The suspension was heated at 75 ° C under H 2 atmosphere for 24 h. The mixture was cooled, filtered and concentrated in vacuo. The residue was dissolved in 1 mL concentrated NH₄OH and extracted with DCM (5-5 ml). The combined organic layers were dried over Na2SO4. After filtration, it was concentrated in vacuo to give 4- (4-amino-2-fluorobenzyl) -N- (3- (dimethylamino) propyl) pyridine-2amine (31 mg, 40% yield). MS (ESI⁺): m / z 303.31 (M + H)⁺.

F) 1- (4 - ((2- (3- (Dimethylamino) propylamino) pyridin-4-yl) methyl) -3-fluorophenyl) -3 (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [ 0472] To a solution of 4- (4-amino-2-fluorobenzyl) -N- (3- (dimethylamino) propyl) pyridine-2-amine (30 mg, 0.1 mmol) in DCM (2 ml) was added a solution of 2- (4 -fluorophenyl) acetylisocyanate (Compound D from Example 11, 0.347 M in toluene, 0.25 mL). The mixture was stirred at room temperature for 0.5 h before it was complete after the addition of MeOH. The solution was concentrated in vacuo and the residue purified by prep. HPLC. The desired fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and polymeric diethylenetriamine (50 mg) was added to remove trifluoroacetic acid. After filtration and concentration, the residue was transformed into the hydrochloride salt after addition of 1N HCl (0.5 mL) and lyophilized to give 1- (4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl) methyl) -3- hydrochloride fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (8.0 mg, 14% yield). MS (ESI⁺): m / z 482.24 (M + H)⁺.

- Example 88 [0473]

<img file="PL1737451T3_D0260.tif" />

1- (4 - ((2- (3- (Dimethylamino) propylamino) pyridin-4-yl) (hydroxy) methyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0261.tif" />

A) tert-Butyl 4 - ((2-chloropyridin-4-yl) (hydroxy) methyl) phenylcarbamate [0475] Prepared in a similar manner to that described in step B of example 87. 2-Chloroisisonicotinaldehyde (141mg, 1.0 mmol ) converted to tert-butyl 4 - ((2-chloropyridin-4-yl) (hydroxy) methyl) phenylcarbamate (190 mg, 57% yield).

MS (ESI⁺): m / z 335.27 / 337.27 (M + H)⁺.

<img file="PL1737451T3_D0262.tif" />

B) tert-Butyl 4 - ((2-chloropyridin-N-4-yl) (hydroxy) methyl) phenylcarbamate [0476] Prepared in a similar manner to that described in step C of Example 87. tert-Butyl 4- ( (2-chloropyridin-4-yl) (hydroxy) methyl) phenylcarbamate (78 mg, 0.23 mmol) was converted to tert-butyl 4 - ((2-chloropyridin-N-4-yl) (hydroxy) methyl) phenylcarbamate (36 mg, 44% yield). MS (ESI⁺): m / z 351.28 / 353.27 (M + H)⁺.

- 144 -

<img file="PL1737451T3_D0263.tif" />

C) tert-Butyl 4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl) (hydroxy) methyl) phenylcarbamate [0477] Prepared in a similar manner to that described in step D of example 87. tert-Butyl 4 - ((2-chloropyridin-N-4-yl) (hydroxy) methyl) phenylcarbamate (36 mg, 0.1 mmol) converted to tert-butyl 4 - ((2- (3- (dimethylamino) propylamino pyridin-4-yl) (hydroxy) methyl) phenylcarbamate (16 mg, 40% yield). MS (ESI⁺): m / z

401.38 (M + H)⁺.

<img file="PL1737451T3_D0264.tif" />

D) (4-Aminophenyl) (2- (3- (dimethylamino) propylamino) pyridin-4-yl) methanol [0478] To 4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl tert-butyl solution ) (hydroxy) methyl) phenylcarbamate (16 mg, 0.04 mmol) in 1 mL of DCM added Et3SiH (0.1 mL) / TFA in DCM (10%, 0.2 mL). The mixture was stirred for ½ hr and no reaction was found by LC-MS. A further 0.1 mL Et3SiH and 0.8 mL TFA in DCM (10%) were added and the mixture was stirred for 2 h. The solvent was removed and purified by solid extraction (Waters Oasis^®MCX extraction cartridge) to give (4-aminophenyl) (2- (3 (dimethylamino) propylamino) pyridin-4-yl) methanol (6.0 mg, 50% yield). MS (ESI⁺): m / z 301.40 (M + H)⁺.

E) 1- (4 - ((2- (3- (Dimethylamino) propylamino) -pyridin-4-yl) (hydroxy) methyl) phenyl) 3- (2- (4-fluorophenyl) acetyl) urea [0479] Obtained in a similar manner to that described in step F of Example 87. 4 Aminophenyl- (2- (3- (dimethylamino) propylamino) pyridin-4-yl) methanol (6.0 mg, 0.02 mmol) was converted to 1. - (4 - ((2- (3- (dimethylamino) propylamino) pyridin-4-yl) (hydroxy) methyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, bis-trifluoroacetic acid ( 6.1 mg, 43% yield). ¹H NMR (CD3OD δ 7.82 (d, 1H, J = 6.4 Hz), 7.50 (m, 2H), 7.36 (m,

4H), 7.07 (m, 3H), 6.75 (m, 1H), 5.68 (s, 1H), 3.71 (s, 2H), 3.21-3.49 (m, 4H ), 2.90 (s, 6H),

2.08 (m, 2H); MS (ESI⁺): m / z 480.31 (M + H)⁺.

Example 89

- 145 [0480]

<img file="PL1737451T3_D0265.tif" />

1- (4 - ((2-Aminopyridin-4-yl) methyl) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt

<img file="PL1737451T3_D0266.tif" />

A) tert-Butyl 4 - ((2- (allylamino) pyridin-N-oxide-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate [0482] For tert-butyl solution 4 - ((2-chloropyridin-N -oxide-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (Step C from Example 87, 500 mg, 1.36 mmol) in EtOH (14 mL) added allylamine (1.0 mL, 13.6 mmol). The mixture was heated at 80 ° C overnight. After cooling, the solvent was removed and the residue was purified by flash chromatography on SiO2 eluting with 0% -15% MeOH in DCM to give tert-butyl 4 - ((2- (allylamino) pyridin-N-4-yl) (hydroxy) methyl ) -3-fluorophenylcarbamate (440 mg, 83% yield). MS (ESI⁺): m / z 390.19 (M + H)⁺.

<img file="PL1737451T3_D0267.tif" />

B) tert-Butyl 4 - ((2- (allylamino) pyridin-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate [0483] Prepared in a similar manner to that described in step D of Example 87. tertButyl 4 - ((2- (allylamino) pyridin-N-oxide-4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (440 mg, 10-13 mmol) was converted to tert-butyl 4 - ((2- (allylamino) pyridine) 146 4-yl) (hydroxy) methyl) -3-fluorophenylcarbamate (400 mg, 95% yield). MS (ESI⁺):

m / z 374.33 (M + H)⁺.

<img file="PL1737451T3_D0268.tif" />

C) (2- (Allylamino) pyridin-4-yl) (4- (tert-Butoxycarbonyl) -2-fluorophenyl) methyl acetate [0484] To tert-butyl solution 4 - ((2- (allylamino) pyridin-4- yl) (hydroxy) methyl) -3-fluorophenylcarbamate (400 mg, 1.1 mmol) in THF (10 mL) added diisopropylethylamine (DIEA) (0.2 mL, 1.1 mmol), 4-dimethylaminopyridine (DMAP) (360 mg , 3.0 mmol) and Ac2O (0.29 mL, 3.0 mmol). The mixture was stirred overnight and then heated at reflux for 1 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on SiO2 eluting with 0% -100% EtOAc in hexane to give (2- (allylamino) pyridin-4-yl) (4- (tert-butoxycarbonyl) - 2-fluorophenyl) methyl acetate (390 mg, 85% yield). MS (ESI⁺): m / z 416.33 (M + H)⁺.

<img file="PL1737451T3_D0269.tif" />

D) (2-Aminopyridin-4-yl) (4- (tert-butoxycarbonyl) -2-fluorophenyl) methyl acetate [0485] Solution (2- (allylamino) pyridin-4-yl) (4- (tert-butoxycarbonyl ) -2-fluorophenyl) methyl acetate (380 mg, 0.91 mmol) in a mixture of EtOH / H2O (10: 1, 40 ml) was degassed by bubbling N2 into the solution for 1 h. Rh (PPh3) 3Cl (80 mg , 0.09 mmol). The solution was heated to reflux to remove the solvent and the residue was purified by flash chromatography on SiO2, followed by purification by preparative HPLC to give (2-aminopyridin-4-yl) (4- (tert-butoxycarbonyl) -2-fluorophenyl) methyl acetate, trifluoroacetic acid salt (185 mg, 42% yield). MS (ESI⁺): m / z 376.26 (M + H)⁺.

<img file="PL1737451T3_D0270.tif" />

- 147 E) tert-Butyl 4 - ((2-aminopyridin-4-yl) methyl) -3-fluorophenylcarbamate [0486] To solution (2-aminopyridin-4-yl) (4- (tert-butoxycarbonyl) -2- fluorophenyl) methyl acetate as TFA salt (180 mg, 0.37 mmol) in MeOH (10 mL) was added 10% Pd / C (90 mg). The suspension was stirred under H2 atmosphere for 1 h. The catalyst was removed and the filtrate concentrated in vacuo. The residue was then purified by flash chromatography on SiO2 eluting with 3% MeOH in DCM to give tert-butyl 4 - ((2-aminopyridin-4-yl) methyl) -3-fluorophenylcarbamate as TFA salt (73 mg, 46% yield). MS (ESI⁺): m / z 318.24 (M + H)⁺.

<img file="PL1737451T3_D0271.tif" />

F) 4- (4-Amino-2-fluorobenzyl) pyridin-2-amine [0487] To tert-butyl solution 4 - ((2-aminopyridin-4-yl) methyl) -3-fluorophenylcarbamate as TFA salt (73 mg , 0.17 mmol) in DCM (4.0 mL) added TFA (1.0 mL). The solution was stirred at room temperature for 2 h and the solvent removed in vacuo to give 4- (4-amino-2-fluorobenzyl) pyridin-2-amine, bis-trifluoroacetic acid (70 mg, 93% yield). MS (ESI⁺): m / z 218.12 (M + H)⁺.

G) 1- (4 - ((2-Aminopyridin-4-yl) methyl) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [0488] Obtained in a similar manner to that which was described in step F of example 87. 4- (4-Amino-2-fluorobenzyl) pyridin-2-amine as 2 TFA salt (19 mg, 0.042 mmol) was converted to 1- (4 - ((2-aminopyridine) 4-yl) methyl) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, trifluoroacetic acid salt (19 mg, 88% yield). ¹H NMR (DMSO-d6) δ 10.94 (s, 1H), 10.47 (s, 1H), 7.76 (m, 3H), 7.50 (d, 1H, J = 11.5 Hz) , 7.10-7.26 (m, 4H), 7.10 (m, 2H), 6.65 (d, 1H, J = 6.5 Hz), 6.55 (s, 1H), 3, 89 (s, 2H), 3.65 (s, 2H); MS (ESI⁺): m / z 397.26 (M + H)⁺.

Example 90

<img file="PL1737451T3_D0272.tif" />

- 148 1- (4- (2-Carbamoylpyridin-4-yloxy) -3-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0273.tif" />

A) 4- (4-Amino-2-chlorophenoxy) picolinamide [0491] To a solution of 4-amino-2-chlorophenol (Aldrich, 430 mg, 3.0 mmol) in DMF (2.0 ml) at room temperature was added KOt -Bu (352 mg, 3.2 mmol). The mixture was stirred at room temperature for 1 h. To the solution, 4-chloropicolinamide (468 mg, 3.0 mmol) and K2CO3 (221 mg, 1.6 mmol) were then added. The resulting suspension was heated at 90 ° C overnight. After cooling, the suspension was diluted with 100 mL EtOAc and 50 mL H2O. The organic layer was separated and washed with brine (2 x 25 mL) and dried over MgSO₄. After filtration and concentration, the solid was triturated with 50 mL DCM. The solid was then collected and washed with DCM (2 x 20 mL), EtOAc (5.0 mL) and dried to give 4- (4-amino-2-chlorophenoxy) picolinamide (320 mg, 40% yield). MS (ESI⁺): m / z 264.12 / 266.07 (M + H)⁺.

<img file="PL1737451T3_D0274.tif" />

B) 1- (4- (2-Carbamoylpyridin-4-yloxy) -3-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0492] Prepared in a similar manner to that described in step F from Example 87. 4- (4-Amino-2-chlorophenoxy) picolinamide (79 mg, 0.30 mmol) in DMF (1.0 mL) was converted to 1- (4- (2-carbamoylpyridin-4-yloxy) -3- chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (65 mg, 49% yield). ¹H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.58 (s, 1H), 8.52 (d, 1H, J = 4.5 Hz), 8.15 (s, 1H) , 7.98 (s, 1H), 7.70 (s, 1H), 7.55 (m, 1H), 7.39 (m, 3H), 7.27 (m, 1H), 7.16 ( m, 3H), 3.73 (s, 2H); MS (ESI⁺): m / z 443.17 (M + H)⁺.

Example 91 [0493]

- 149 -

<img file="PL1737451T3_D0275.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0494] For solution 1- (4- (2- carbamoylpyridin-4-yloxy) -3-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (Example 90, 27 mg, 0.06 mmol) in DMF (1.0 mL) added H2O (2.2 mg, 0.12 mmol), pyridine (0.04 mL) and bis (trifluoroacetoxy) iiodenzene (Aldrich, 39 mg, 0.09 mmol) at room temperature. The solution was stirred overnight and then purified by prep. HPLC to give the desired product, which was further converted into 1- (4- (2-aminopyridin-4-yloxy) -3-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea hydrochloride (19 mg, 70% yield) by adding 1N HCl solution (0.5 ml). ¹H NMR (DMSO-d6) δ 13.50 (s, 1H), 11.02 (s, 1H), 10.57 (s, 1H), 7.80-7.95 (m, 4H), 7, 55 (m, 1H), 7.37 (m, 1H), 7.30 (m, 2H), 7.11 (m, 2H), 6.60 (m, 1H), 6.00 (s, 1H ), 3.70 (s, 2H); MS (ESI⁺): m / z 415.16 (M + H)⁺.

Example 92

<img file="PL1737451T3_D0276.tif" />

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

<img file="PL1737451T3_D0277.tif" />

A) 1- (4- (2-Carbamoylpyridin-4-yloxy) -2-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea

[0497] Obtained in a similar manner to that described in step A of Example 90. 4- (4-Amino-3-chlorophenoxy) picolinamide (39 mg, 0.19 mmol) in DMF (1.0 mL) was converted to 1- (4- (2-carbamoylpyridin-4-yloxy) -2-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (18 mg, 41% yield) after purification by prep. HPLC. MS (ESI⁺): m / z

443.13 / 445.14 (M + H)⁺.

B) 1- (4- (2-Aminopyridin-4-yloxy) -2-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0498] Obtained in a similar manner to that described in the example 91. 1- (4- (2-Carbamoyl-pyridin-4-yloxy) -2-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (18 mg, 0.04 mmol) in DMF (1, 0 ml) converted into 1- (4- (2-aminopyridin-4-yloxy) -2-chlorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (10 mg, 55% yield). ¹H NMR (DMSO-d6) δ 13.47 (s, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.37 (d, 1H, J = 8.5 Hz) , 7.95 (d, 1H, J = 7.5 Hz), 7.88 (s, 2H), 7.62 (s, 1H), 7.35 (m, 3H), 7.17 (m, 2H), 6.64 (d, 1H, J = 7.5 Hz), 6.13 (s, 1H), 3.76 (s, 2H); MS (ESI⁺): m / z 415.18 / 417.17 (M + H)⁺.

Example 93

<img file="PL1737451T3_D0278.tif" />

1- (4- (2-Carbamoylpyridin-4-yloxy) -3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea

<img file="PL1737451T3_D0279.tif" />

A) 4- (4-Amino-2-methylphenoxy) picolinamide [0501] Obtained in a similar manner to that described in step A of example 90. 4 Amino-2-methylphenol (246 mg, 2.0 mmol) was converted to 4 - (4-amino-2-methylphenoxy) picolinamide (230 mg, 47% yield). MS (ESI⁺): m / z 244.15 (M + H)⁺.

- 151 B) 1- (4- (2-Carbamoylpyridin-4-yloxy) -3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0502] Prepared in a similar manner to that described in step F of example 87. 4- (4-Amino-2-methylphenoxy) picolinamide (48 mg, 0.2 mmol) in DMF (1.0 mL) was converted to 1- (4- (2-carbamoylpyridin-4-yloxy) - 3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea (35 mg, 41% yield. ¹H NMR (DMSO-d6) δ 10.92 (s, 1H), 10.44 (s, 1H), 8.44 (d, 1H, J =

5.5 Hz), 8.06 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.42 (m, 1H), 7.31 (m, 2H) , 7.24 (d, 1H, J = 2.0 Hz), 7.06-7.12 (m, 4H), 3.69 (s, 2H), 2.02 (s, 3H); ), MS (ESI⁺): m / z 423.17 (M + H)⁺.

Example 94

<img file="PL1737451T3_D0280.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0504] Obtained in a similar manner to that described in step A of example 91. 1- (4 (2-Carbamoylpyridin-4-yloxy) -3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea (27 mg, 0.06 mmol) in DMF (1.0 mL) converted to 1- (4- (2-aminopyridin-4-yloxy) -3-methylphenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt (24 mg, 88% yield ) after purification by HPLC. ¹H NMR (DMSO-d6) δ 13.18 (s, 1H), 10.93 (s, 1H), 10.45 (s, 1H), 7.88 (d, 1H, J = 7.0 Hz) , 7.73 (s, 2H), 7.50 (m, 2H), 7.29 (m, 2H), 7.10 (m, 3H), 6.56 (d, 1H, J = 7.0 Hz), 5.91 (d, 1H, J = 2.5 Hz), 3.68 (s, 2H), 2.02 (s, 3H); MS (ESI⁺): m / z 395.20 (M + H)⁺.

Example 95

<img file="PL1737451T3_D0281.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

- 152 -

<img file="PL1737451T3_D0282.tif" />

A) 4-amino-3- (trifluoromethyl) phenol [0507] A solution of 4-nitro-3- (trifluoromethyl) phenol (Aldrich, 414 mg, 2.0 mmol) in 10 ml MeOH 10% Pd / C (100mg) was added . The suspension was stirred under H 2 atmosphere for 12 h and then filtered and concentrated in vacuo to give 4-amino-3- (trifluoromethyl) phenol (350 mg, 95% yield) which was pure enough for use in the next step. MS (ESI⁺): m / z 178.02 (M + H)⁺.

<img file="PL1737451T3_D0283.tif" />

B) 4- (4-Amino-3- (trifluoromethyl) phenoxy) picolinamide. [0508] Obtained in a similar manner to that described in step A of Example 90. 4Amino-3- (trifluoromethyl) phenol (177 mg, 1, 0 mmol) in DMF (2.0 mL) was converted to 4- (4 amino-3- (trifluoromethyl) phenoxy) picolinamide (180 mg, 61% yield). MS (ESI⁺): m / z

298.20 (M + H)⁺.

<img file="PL1737451T3_D0284.tif" />

C) 1- (4- (2-Carbamoylpyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0509] It was obtained in a similar manner to that which described in step F of example 87. 4- (4Amino-3- (trifluoromethyl) phenoxy) picolinamide (30 mg, 0.1 mmol) in DMF (1.0 ml)

Transformed into 1- (4- (2-carbamoylpyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea (30 mg, 63% yield). MS (ESI⁺): m / z 477.12 (M + H)⁺.

D) 1- (4- (2-Aminopyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0510] It was obtained in a similar manner to that which described in step A of Example 91. 1- (4 (2-Carbamoylpyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea (26 mg, 0.055 mmol) in DMF (1.0 ml) converted into 1- (4- (2 aminopyridin-4-yloxy) -2- (trifluoromethyl) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea hydrochloride (15 mg, 56% yield) after purification by prep. HPLC. ¹H NMR (DMSO-d6) δ

13.40 (s, 1H), 11.28 (s, 1H), 10.95 (s, 1H), 8.25 (d, 1H, J = 8.5 Hz), 7.97 (d, 1H , J = 7.0 Hz), 7.88 (s, 2H), 7.72 (d, 1H, J = 2.5 Hz), 7.65 (m, 1H), 7.35 (m, 2H ), 7.19 (m, 2H), 6.66 (d, 1H, J = 2.5 Hz), 3.75 (s, 2H); MS (ESI⁺): m / z 449.14 (M + H)⁺.

Example 96

<img file="PL1737451T3_D0285.tif" />

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

<img file="PL1737451T3_D0286.tif" />

A) 4- (3-Fluoro-4-pivalamidophenoxy) picolinamide [0513] To a solution of 4-amino-3-fluorophenol (Oakwood Products Inc., 252 mg, 2.0 mmol) in NMP (4.0 mL) was added 4 - chloropicolinamide (312 mg, 2.0 mmol) and DIEA (0.3 ml). The solution was heated at 250 ° C in a microwave. After cooling, the solution was diluted with H2O and the solution was extracted with EtOAc (3 χ 40 mL). The combined organic layers were washed with brine, dried over MgSO4. After filtration and concentration, the residue was purified by flash chromatography on SiO2 eluting with 0-30% MeOH in DCM to give

- 154 fraction containing 4- (4-amino-3-fluorophenoxy) picolinamide (50% pure, HPLC-UV detection). MS (ESI⁺): m / z 248.12 (M + H)⁺.

[0514] To a solution of 4- (4-amino-3-fluorophenoxy) picolinamide obtained from the previous step in THF (3.0 mL) and DCM (10.0 mL) was added 1 N NaOH (5.0 mL) and chloride trimethylacetyl (0.25 mL, 2 mmol) at room temperature. The solution was stirred for 2 h and then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by flash chromatography on SiO2 eluting with 0% -100% EtOAc in hexane to give 4- (3-fluoro-4-pivalamidophenoxy) picolinamide (110 mg, 17% yield for two steps). MS (ESI⁺): m / z 332.18 (M + H)⁺.

<img file="PL1737451T3_D0287.tif" />

B) N- (4- (2-Aminopyridin-4-yloxy) -2-fluorophenyl) pivalamide [0515] Prepared in a similar manner to that described in step A of example 91. 4- (3-Fluoro-4-pivalamidophenoxy) picolinamide (110 mg, 0.33 mmol) in acetonitrile (4 mL) was converted to N- (4- (2-aminopyridin-4-yloxy) -2-fluorophenyl) pivalamide (70 mg, 70% yield). MS (ESI⁺): m / z 304.21 (M + H)⁺.

<img file="PL1737451T3_D0288.tif" />

C) 4- (4-Amino-3-fluorophenoxy) pyridin-2-amine [0516] Solution of N- (4- (2-aminopyridin-4-yloxy) -2-fluorophenyl) pivalamide (70 mg, 0.23 mmol ) in 3 ml MeOH 2 ml 6N HCl was added. The mixture was then refluxed for 48 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by solid extraction (Waters Oasis^®MCX extraction cartridge) to give 4- (4-amino-3-fluorophenoxy) pyridin-2-amine (27 mg, 54% yield). MS (ESI⁺): m / z 220.21 (M + H)⁺.

D) 1- (4- (2-Aminopyridin-4-yloxy) -2-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [0517] Obtained in a similar manner to this which was described in step F of Example 87. 4- (4-Amino-3-fluorophenoxy) pyridine-2-amine (28 mg, 0.095 mmol) in THF (2.0 mL)

- 155 converted to 1- (4- (2-aminopyridin-4-yloxy) -2-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea trifluoroacetic acid (23 mg, 47% yield) after purification using prep. HPLC.¹H NMR (DMSO-d6) δ 11.20 (s, 1H), 10.77 (s, 1H), 8.23 ​​(m, 1H), 7.94 (d, 1H, J = 6.5 Hz) , 7.70 (s, 2H), 7.45 (m, 1H), 7.35 (m, 2H), 7.16 (m, 3H), 6.64 (d, 1H, J =

2.5 Hz), 6.11 (s, 1H), 3.75 (s, 2H); MS (ESI⁺): m / z 399.12 (M + H)⁺.

Example 97

<img file="PL1737451T3_D0289.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -2,3-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [0519]

<img file="PL1737451T3_D0290.tif" />

A) 4-Amino-2,3-difluorophenol [0520] To a solution of 1,2,3-trifluoro-4-nitrobenzene (Aldrich, 15.0 g, 84.7 mmol) in DMF (25.0 mL) was added K2CO3 (17.6 g, 127.8 mmol) and benzyl alcohol (8.8 mL, 85.0 mmol). The suspension was stirred overnight. H2O (100 mL) was then added to the reaction mixture, and the solution was kept at 4 ° C overnight. The precipitate was then collected and washed with H2O to give a mixture of two isomers (22.4 g) [1- (benzyloxy) -2,3-difluoro-4-nitrobenzene and 2- (benzyloxy) -3,4-difluoro-1-nitrobenzene in a ratio of 1: 1].

[0521] To a solution of [1- (benzyloxy) -2,3-difluoro-4-nitrobenzene and 2- (benzyloxy) -3,4-difluoro-1-nitrobenzene] (22.4 g, 84.5 mmol) in EtOAc ( 20.0 ml) and MeOH (100.0 ml) 10% Pd / C (1.0 g) was added. The suspension was stirred under H 2 atmosphere for 12 h. The suspension was then filtered and concentrated in vacuo to give a mixture of two isomers (12.6 g) [4 amino -2,3-difluorophenol and 6-amino-2,3-difluorophenol in a 1: 1 ratio] . MS (ESI⁺): m / z 146.00 (M + H)⁺.

- 156 -

<img file="PL1737451T3_D0291.tif" />

B) N- (4- (2-Aminopyridin-4-yloxy) -2,3-difluorophenyl) pivalamide [0522] Obtained in a similar manner to that described in step A of example 90. A mixture of 4-amino-2, 3-difluorophenol and 6-amino-2,3-difluorophenol (580 mg, 4.0 mmol) in DMF (3.0 mL) was converted into a mixture of 4- (4-amino-2,3-difluorophenoxy) picolinamide and

4- (6-amino-2,3-difluorophenoxy) picolinamide (300 mg). MS (ESI⁺): m / z 266.13 (M + H)⁺.

[0523] Obtained in a similar manner to that described in step A of example 96. A mixture of 4- (4-amino-2,3-difluorophenoxy) picolinamide and 4- (6-amino-2,3-difluorophenoxy) picolinamide ( 300 mg, 1.13 mmol) was converted into a mixture of 4- (2,3-difluoro-4-pivalamidophenoxy) picolinamide and 4- (2,3-difluoro-6-pivalamidophenoxy) picolinamide (406 mg). MS (ESI⁺): m / z 350.20 (M + H)⁺.

[0524] Prepared in a similar manner to that described in step A of example 91. A mixture of 4- (2,3-difluoro-4-pivalamidophenoxy) picolinamide and 4- (2,3-difluoro-6-pivalamidophenoxy) picolinamide ( 400 mg) was reacted with bis (trifluoroacetoxy) iodobenzene to give N- (4- (2-aminopyridin-4-yloxy) -2,3-difluorophenyl) pivalamide, trifluoroacetic acid salt (120 mg, 24% yield) after purification after prep. HPLC. MS (ESI⁺): m / z 322.23 (M + H)⁺.

<img file="PL1737451T3_D0292.tif" />

C) 4- (4-Amino-2,3-difluorophenoxy) pyridine-2-amine [0525] Prepared in a similar manner to that described in step C of Example 96. N (4- (2-Aminopyridin-4- yloxy) -2,3-difluorophenyl) pivalamide, trifluoroacetic acid salt (120 mg, 0.27 mmol) converted to 4- (4-amino-2,3-difluorophenoxy) pyridin-2-amine (52 mg, 81% yield) . MS (ESI⁺): m / z 238.11 (M + H)⁺.

D) 1- (4- (2-Aminopyridin-4-yloxy) -2,3-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt [0526] Obtained in a similar manner the one described in step F of example 87. 4- (4-Amino-2,3-difluorophenoxy) pyridin-2-amine (24 mg, 0.10 mmol) in THF (3.0 mL)

- 157 converted to 1- (4- (2-aminopyridin-4-yloxy) -2,3-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid (21 mg, 40% yield ). ¹H NMR (DMSO-d6) δ 11.27 (s, 1H), 10.84 (s, 1H), 8.02 (m, 1H), 7.96 (d, 1H, J = 8.5 Hz) , 7.73 (s, 2H), 7.34 (m, 3H), 7.17 (m, 2H), 6.70 (m, 1H), 6.20 (d, 1H, J = 2.0 Hz), 3.75 (s, 2H); MS (ESI⁺): m / z 417.10 (M + H)⁺.

Example 98

<img file="PL1737451T3_D0293.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1-benzyl-5-methyl-1H-pyrazole-3-carboxamide, hydrochloride salt

<img file="PL1737451T3_D0294.tif" />

A) 1-Benzyl-5-methyl-1H-pyrazole-3-carboxylic acid [0529] To a solution of 1-benzylhydrazine dihydrochloride (Aldrich, 0.98 g, 5.0 mmol) in EtOH (30 mL) was added DIEA (2 , 0 ml) and ethyl 2,4-dioxopentanoate (0.70 ml, 5.0 mmol). The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was dissolved in 1N NaOH (10 mL). The solution was heated at 60 ° C for 1 h. After cooling, the solution was extracted with DCM (3 x 50 mL). The aqueous layer was neutralized to pH 2.0 and then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtered and concentrated to give 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (1.0 g, 92% yield). MS (ESI⁺): m / z 217.12 (M + H)⁺.

B) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1-benzyl-5-methyl-1H-pyrazole-3-carboxamide, hydrochloride salt [0530] 4- (4-Amino-2- fluorophenoxy) pyridin-2-amine (Compound B from Example 24, 25 mg,

0.11 mmol) was coupled to 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (25 mg,

0.11 mmol) in a similar manner to that described in step C of Example 1 to give N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -1-benzyl-5-methyl-1H-pyrazolo hydrochloride -3-carboxamide (10 mg, 20% yield) after purification by prep. HPLC.

- 158 ¹H NMR (DMSO-d6) δ 10.64 (s, 1H), 7.8-7.98 (m, 3H), 7.00-7.65 (m, 9H), 6.71 (m, 1H ), 6.15 (s, 1H), 5.65 (s, 2H), 2.24 (s, 3H); MS (ESI⁺): m / z 418.21 (M + H)⁺.

Example 99

<img file="PL1737451T3_D0295.tif" />

2- (4-Fluorobenzylsulfinyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, hydrochloride salt

<img file="PL1737451T3_D0296.tif" />

A) Ethyl 2- (4-fluorobenzylthio) acetate [0533] To a solution of ethyl-2-mercaptoacetate (Aldrich, 1.0 mL, 9.1 mmol) in acetonitrile (10.0 mL) was added K2CO3 (2.76 g, 20.0 mmol) and 1- (bromomethyl) -4-fluorobenzene (2.27 g, 12.0 mmol). The mixture was stirred at room temperature for 12 h. After filtration and concentration, the residue was purified by flash column chromatography on SiO2 to give ethyl 2- (4-fluorobenzylthio) acetate (1.89 g, 91% yield). MS (ESI⁺): m / z 251.08 (M + H)⁺.

<img file="PL1737451T3_D0297.tif" />

B) Ethyl 2- (4-fluorobenzylsulfinyl) acetate [0534] To a solution of 2- (4-fluorobenzylthio) acetate (1.89 g, 8.29 mmol) in DCM (20.0 mL) at -40 ° C is added dropwise to solution of m-CPBA (77%, 1.86 g, 8.29 mmol) in DCM (20.0 mL). The solution was stirred from -40 ° C to room temperature overnight. The solution was then treated with diethylenetriamine deposited on the polymer to terminate the reaction. After filtration and concentration, the residue was purified by flash chromatography on SiO2 to give ethyl 2- (4-fluorobenzylsulfinyl) acetate (2.0 g, 98% yield). MS (ESI⁺): m / z 267.09 (M + H)⁺.

<img file="PL1737451T3_D0298.tif" />

- 159 C) 2- (4-Fluoro-benzyl sulfinyl) -acetic acid [0535] To a solution of 2- (4-fluoro-benzyl sulfinyl) acetate (1.60 g, 6.55 mmol) in THF (10.0 mL) and MeOH ( 20.0 mL) 1N NaOH (20.0 mmol) was added. The mixture was stirred at room temperature for 2 h. After removing the organic solvent under reduced pressure, the remaining aqueous solution was neutralized with 1 N HCl (25.0 mL).

Extracted with EtOAc (3 χ 100 mL) and the combined organic layers were dried over MgSO₄. The solution was then filtered and concentrated in vacuo to give 2- (4-fluoro-benzyl-sulfinyl) -acetic acid (1.25 g, 88% yield). MS (ESI⁺): m / z 217.05 (M + H)⁺.

D) 2- (4-Fluoro-benzyl sulfinyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, hydrochloride salt [0536] 4- (4-Amino-2-fluorophenoxy) pyridine-2 amine dihydrochloride (Compound B from Example 24, 29 mg, 0.10 mmol) was coupled to 2- (4-fluorobenzylsulfinyl) acetic acid (22 mg, 0.1 mmol) in a similar manner to that described in step C from Example 1 to give 2- (4-fluorobenzylsulfinyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, the hydrochloride salt (17 mg, 37% yield). ¹H NMR (DMSO-d6) δ 10.94 (s, 1H), 7.97 (d, 1H, J = 7.5 Hz), 7.85 (m, 3H), 7.39-7.45 ( m, 4H), 7.23 (t, 2H, J = 7.5 Hz), 6.70 (m, 1H), 6.13 (d, 1H, J = 2.5 Hz), 4.32 ( d, 1H, J = 11.0 Hz), 4.11 (d, 1H, J = 11.0 Hz), 3.98 (d, 1H, J = 13.0 Hz), 3.65 (d, 1H, J = 13.0 Hz); MS (ESI⁺): m / z 418.26 (M + H)⁺.

Example 100 [0537]

<img file="PL1737451T3_D0299.tif" />

2- (4-Fluorobenzylsulfonyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, hydrochloride salt

<img file="PL1737451T3_D0300.tif" />

A) Ethyl 2- (4-fluorobenzylsulfonyl) acetate [0539] To a solution of 2- (4-fluoro-benzylsulfinyl) -acetate ethyl (370 mg, 1.52 mmol) in DCM (5.0 mL) was added m-CPBA (77% , 450 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 h and then quenched by addition of polymer supported

- 160 diethylenetriamine (1.5 g). The reaction mixture was filtered and concentrated in vacuo to give ethyl 2- (4-fluorobenzylsulfonyl) acetate (360 mg, 91% yield). MS (ESI⁺):

m / z 283.10 (M + H)⁺.

<img file="PL1737451T3_D0301.tif" />

B) 2- (4-Fluorobenzylsulfonyl) acetic acid [0540] Obtained 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, 81% yield). MS (ESI⁺): m / z 255.05 (M +

H)⁺.

C) 2- (4-Fluoro-benzyl sulfonyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, hydrochloride salt [0541] 4- (4-Amino-2-fluorophenoxy) pyridine-2 amine dihydrochloride (50 mg, 0.17 mmol) was coupled with 2- (4-fluorobenzylsulfonyl) acetic acid (33 mg, 0.14 mmol) in a similar manner to that described in step C of Example 1 to give 2- (4-fluorobenzylsulfonyl) ) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) acetamide, hydrochloride salt (30 mg, 45% yield). ¹H NMR (DMSO-d6) δ 13.40 (s, 1H), 11.15 (s, 1H), 7.97 (d, 1H, J = 7.0 Hz), 7.80-7.90 ( m, 3H), 7.47 (m, 4H), 7.26 (t, 2H, J = 8.5 Hz), 6.72 (d, 1H, J = 7.0 Hz), 6.14 ( d, 1H, J = 2.0 Hz), 4.69 (s, 2H), 4.27 (s, 2H); MS (ESI⁺): m / z 434.15 (M + H)⁺.

Example 101

<img file="PL1737451T3_D0302.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt

<img file="PL1737451T3_D0303.tif" />

- 161 A) Methyl 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate [0544] For 2-oxo-2H-pyran-3-carboxylate methyl solution (Aldrich, 2.31 g , 15 mmol) in THF (40 mL) and DMF (10 mL) at room temperature, 4-fluoroaniline (1.67 g, 15 mmol) was added, and the reaction mixture was stirred for 2.5 h. A precipitate was observed. To the 4-fluoroaniline adduct, intermediate formed by Michael addition obtained in situ, EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) were added at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture, 1N aqueous HCl (50 mL) and EtOAc (150 mL) were added, the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL), the combined EtOAc layers were dried over MgSO 4 and concentrated in vacuo to give a semi-solid material (-4.4 g ). To this crude product, ether (100 mL) and methanol (15 mL) were added, stirred, and the solid filtered off to give the undesirable solid product (870 mg). The filtrate was concentrated to give a semi-solid crude desired product (2.95 g, crude 80%) which was sufficiently pure to be used in the next step without further purification.¹H NMR (DMSO-d6) δ 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, 1H, J = 7.1 Hz), 3.89 (s, 3H); MS (ES⁺) m / z 248.2 (M + H)⁺.

<img file="PL1737451T3_D0304.tif" />

B) 1- (4-Fluoro-phenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid [0545] Mixture of methyl 1- (4-fluoro-phenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate (crude 2.45 g, 12 mmol) and 6 N aqueous NaOH (2.5 mL) in methanol (60 mL) was stirred at room temperature for 4 h. To the reaction mixture, concentrated HCl (1 mL) was added slowly with stirring at room temperature, and the precipitated solid was filtered off, washed with a small amount of water and dried to give the desired acid product (2.1 g) as a yellow solid. The filtrate was concentrated in vacuo. The residue was mixed with water (50 ml) and washed with EtOAc (2 χ 130 ml). The EtOAc layers were dried over MgSO4 and concentrated in vacuo. The residue was triturated with a small amount of ether to give a second crop of the product (195mg, total 2.30 g, 82%). ¹H NMR (DMSO-d6) δ 8.47 (dd, 1H, J = 7.2, 2.2 Hz), 8.19 (dd, 1H, J = 6.6, 1.7 Hz), 7, 62-7.60 (m, 2H), 7.42 (t, 2H, J = 8.8 Hz), 6.78 (t, 1H, J = 7.1 Hz); MS (ESI⁺) m / z 234.2 (M + H)⁺.

C) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0546] 4 - (4-Amino-2-fluorophenoxy) pyridine-2-amine (Compound B of Example 24, 58 mg, 0.20 mmol) was coupled with 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine acid Carboxylic acid (47 mg, 0.20 mmol) in a similar manner to which was described in step C of example 1 to give N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) 2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt (22 mg, 23% yield). ¹H NMR (DMSO-d6) δ 13.40 (s, 1H), 12.13 (s, 1H), 8.58 (d, 1H, J = 5.0 Hz), 8.13 (d, 1H, J =

- 162 5.0 Hz), 8.07 (d, 1H, J = 10.0 Hz), 7.98 (d, 1H, J = 7.5 Hz), 7.89 (s, 2H), 7 , 40-7.60 (m, 6H),

6.72 (m, 2H), 6.17 (d, 1H, J = 2.5 Hz); MS (ESI⁺) m / z 435.18 (M + H)⁺ .

Example 102

<img file="PL1737451T3_D0305.tif" />

Τ (S) -N - (2-Amino-2-oxo-1-phenylethyl) -N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) malonamide, hydrochloride salt

<img file="PL1737451T3_D0306.tif" />

A) Ethyl 3- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropionate [0549] To a solution of 4- (4-amino-2-fluorophenoxy) picolinamide (Compound B 'of Example 24 , 1.0 g, 4.0 mmol) in DMF (10.0 mL), DIEA (2.0 mL) and ethyl 3-chloro-3-oxo propionate (Aldrich, 0.75 mL, 6.0 mmol) were added. The mixture was stirred at room temperature for 12 h and more ethyl 3-chloro-3-oxopropionate (0.20 mL, 1.6 mmol) was added. The mixture was stirred for 2 h and then diluted with EtOAc (200 mL). Washed with H2O and brine and then dried over MgSO4. After filtration and concentration, the residue was triturated with DCM and filtered to give ethyl 3- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropionate (900 mg, 62% yield). MS (ESI⁺) m / z 362.28 (M +

<img file="PL1737451T3_D0307.tif" />

B) Ethyl 3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropionate [0550] Prepared in a similar manner to that described in step A of Example 91. Ethyl 3- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropionate (900 mg, 2.5 mmol) in DMF (10.0 mL) was converted to ethyl 3- (4- (2-aminopyridine) -4-yloxy) 3-fluorophenylamino) -3-oxopropionate (710 mg, 86% yield). MS (ESI⁺) m / z 334.26 (M

<img file="PL1737451T3_D0308.tif" />

C) 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoic acid. [0551] Prepared in a similar manner to that described in step C of Example 99. Ethyl 3- (4 - (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropionate (700 mg, 2.10 mmol) was converted to 3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxypropane (630 mg, 98% yield). MS (ESI⁺) m / z 306.20 (M + H)⁺.

D) (S) -N - (2-Amino-2-oxo-1-phenylethyl) -N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) malonamide, hydrochloride salt [0552] 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoic acid (30 mg, 0.10 mmol) coupled with (S) -2-amino-2-phenylacetamide hydrochloride (Acros, 28 mg , 0.15 mmol) in a similar manner to that described in step C of Example 1 13 to give (S) -N - (2-amino-2-oxo-1-phenylethyl) -N - (4- (2- aminopyridin-4-yloxy) -3-fluorophenyl) malonamide, hydrochloride salt (25 mg, 53% yield). ¹H NMR (DMSO-d6) δ 10.68 (s, 1H), 8.80 (d, 1H, J = 8.0 Hz), 7.96 (d, 1H, J = 7.5 Hz), 7 , 77-7.90 (m, 4H), 7.207.45 (m, 8H), 6.70 (m, 1H), 6.12 (s, 1H), 5.39 (d, 1H, J = 7 , 5 Hz), 3.48 (d, 1H, J = 15.0 Hz), 3.41 (d, 1H, J = 15.0 Hz); MS (ESI⁺) m / z 438.26 (M + H)⁺.

Example 103 [0553]

<img file="PL1737451T3_D0309.tif" />

(R) -N - (2-Amino-2-oxo-1-phenylethyl) -N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) malonamide, hydrochloride salt

[0554] 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoic acid (Compound C of example 102, 30 mg, 0.10 mmol) was coupled to (R) - 2-amino-2-phenylacetamide hydrochloride (Bachem, 28 mg, 0.15 mmol) in a similar manner to that described in step C of example 1 to give (R) -N¹- (2-amino-2-oxo-1-phenylethyl)₃

N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) malonamide, hydrochloride salt (14 mg, 30% yield). ¹H NMR (DMSO-d6) δ 10.65 (s, 1H), 8.76 (d, 1H, J = 8.0 Hz), 7.92 (d, 1H, J = 7.0 Hz), 7 , 75-7.88 (m, 4H), 7.20-7.43 (m, 8H), 6.66 (m, 1H), 6.09 (s, 1H), 5.35 (d, 1H , J = 8.0 Hz), 3.45 (d, 1H, J = 15.0 Hz), 3.37 (d, 1H, J = 15.0 Hz); MS (ESI⁺) m / z 438.23 (M + H)⁺.

Example 104

<img file="PL1737451T3_D0310.tif" />

(S) -Methyl-2- (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanamido) -2-phenylacetate, hydrochloride salt [0556] Acid 3- (4- ( 2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropane (Compound C of example 102, 30 mg, 0.10 mmol) was coupled with (S) -methyl-2-amino-2-phenylacetate hydrochloride (Aldrich, 30 mg, 0.10 mmol) in a manner similar to which is described in step C of example 1 to obtain c (S) -methyl - (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanamido) -2-phenylacetate, the hydrochloride salt ( 21 mg, 43% yield). ¹H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.04 (d, 1H, J = 7.0 Hz), 7.97 (d, 1H, J = 7.0 Hz), 7 , 75-7.88 (m, 3H), 7.42 (m, 7H), 6.72 (d, 1H, J = 7.0 Hz), 6.12 (s, 1H), 5.45 ( d, 1H, J = 7.0 Hz), 3.63 (s, 3H), 3.43-3.38 (m, 2H); MS (ESI⁺) m / z 453.26 (M + H)⁺.

Example 105

<img file="PL1737451T3_D0311.tif" />

(R) -Methyl-2- (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanamido) -2-phenylacetate, hydrochloride salt

[0558] 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with the hydrochloride salt (R ) methyl-2-amino-2-phenylacetate (Aldrich, 30 mg, 0.10 mmol) in a similar manner to that described in step C of example 1 to give (R) -methyl-2- (3- (4- (2-aminopyridin-4-yloxy) 3-fluorophenylamino) -3-oxopropanamido) -2-phenylacetate, hydrochloride salt (25 mg, 51% yield). ¹H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.03 (d, 1H, J = 7.0 Hz), 7.96 (d, 1H, J = 7.0 Hz), 7 , 77-7.88 (m, 3H), 7.42 (m, 7H), 6.71 (d, 1H, J = 7.5 Hz), 6.12 (s, 1H), 5.44 ( d, 1H, J = 7.0 Hz), 3.63 (s, 3H), 3.44-3.38 (m, 2H); MS (ESI⁺) m / z 453.29 (M + H)⁺.

Example 106

<img file="PL1737451T3_D0312.tif" />

N - (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -N-cyclopentylmalonamide, hydrochloride salt 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) - 3-oxopropane (Compound C of example 102, 30 mg, 0.10 mmol) was coupled to cyclopentanamine (Aldrich, mg, 0.2 mmol) in a similar manner to that described in step C of example 1 to give N - (4 - (2-aminopyridin-4-yloxy) -3-fluorophenyl) -N-cyclopentyl malonamide, hydrochloride salt (18 mg, 44% yield). ¹H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.66 (s, 1H), 8.15 (d, 1H, J = 7.0 Hz), 7.96 (d, 1H, J = 7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 2H), 6.70 (d, 1H, J = 7.5 Hz), 6.12 ( s, 1H), 3.98 (m, 1H), 3.69 (s, 2H), 1.78 (m, 2H), 1.63 (m, 2H),

1.49 (m, 2H), 1.37 (m, 2H); MS (ESI⁺) m / z 373.30 (M + H)⁺.

Example 107

<img file="PL1737451T3_D0313.tif" />

hydrobromic acid 3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoic acid (Compound C of example 102, 30 mg, 0.10 mmol) was coupled with cyclohexanamine (Aldrich,

- 20 mg, 0.2 mmol) in a similar manner to that described in step C of example 1 to give N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -N-cyclohexyl malonamide, salt hydrochloride (22 mg, 52% yield). ¹H NMR (DMSO-d6) δ 14.00 (s, 1H), 10.72 (s, 1H), 8.10 (d, 1H, J = 7.0 Hz), 7.97 (d, 1H, J = 7.0 Hz), 7.88 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.14 (d, 1H, J = 2.0 Hz) , 3.54 (m, 1H), 3.27 (s, 2H), 1.66-1.75 (m, 4H), 1.52 (m, 1H),

1.15-1.25 (m, 5H); MS (ESI⁺) m / z 387.32 (M + H)⁺.

Example 108

<img file="PL1737451T3_D0314.tif" />

N - (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -N-neopentyl malonamide, hydrochloride salt 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenylamino) - 3-oxopropane (Compound C of example 102, 30 mg, 0.10 mmol) was coupled to 2,2-dimethylpropane-1-amine (Aldrich, 12 mg, 0.2 mmol) in a similar manner to that described in step C from example to give N - (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -N-neopentyl malonamide, hydrochloride salt (13 mg, 32% yield). ¹H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.69 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H, J = 7.0 Hz) , 7.87 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.13 (d, 1H, J = 2.0 Hz), 3.34 (s, 2H), 2.91 (d, 2H, J = 6.5 Hz), 0.84 (s, 9H); MS (ESI⁺) m / z 375.32 (M + H)⁺.

Example 109

<img file="PL1737451T3_D0315.tif" />

(S) -2- (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanamido) -2-phenylacetic acid, hydrochloride salt [0566] Following a procedure similar to that which described in step C of the example

99, (S) -methyl-2- (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-oxopropanoamido) -2-phenylacetate hydrochloride (Compound D from Example 102, 14 mg, 0.028 mmol ) was hydrolyzed to give (S) -2- (3- (4- (2-aminopyridin-4-yloxy) -3-fluorophenylamino) -3-167 oxopropaneamido) -2-phenylacetic acid, hydrochloride salt (13 mg, 97% yield) . ¹H NMR (DMSO-d6) δ 13.20 (s, 1H), 10.57 (s, 1H), 8.92 (d, 1H, J = 7.0 Hz), 7.95 (d, 1H, J = 7.0 Hz), 7.87 (d, 1H, J = 11.0 Hz), 7.70 (s, 2H), 7.41 (m, 8H), 6.69 (d, 1H, J = 7.5 Hz), 6.12 (d, 1H, J = 2.0 Hz), 5.35 (d, 1H, J = 7.5 Hz), 3.42 (s, 2H); MS (ESI⁺) m / z 439.27 (M + H)⁺.

Example 110

<img file="PL1737451T3_D0316.tif" />

N- (4- (2- (3- (Dimethylamino) propylamino) pyridin-4-yloxy) -3-fluorophenyl) -2,6-difluorobenzamide, hydrochloride salt

<img file="PL1737451T3_D0317.tif" />

A) N- (4- (2-Chloropyridin-4-yloxy) -3-fluorophenyl) -2,6-difluorobenzamide [0569] Solution 4- (2-chloropyridin-4-yloxy) -3-fluorobenzeneamine (Compound B with example

20, 64 mg, 0.27 mmol), THF (1 mL), Et₃N (100 g) 2,6-difluorobenzoyl chloride (Aldrich, 33 g, 0.27 mmol) was added dropwise and the mixture was stirred at room temperature for 30 min. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the EtOAc layer was separated, dried (MgSO4) and concentrated in vacuo to give the title compound (102 mg, 100%) as a white solid. MS (ESI⁺): m / z 418.18 (M + H)⁺.

B) N- (4- (2- (3- (Dimethylamino) propylamino) pyridin-4-yloxy) -3-fluorophenyl) -2,6-difluorobenzamide, hydrochloride salt [0570] Mixture N- (4- (2- chloropyridin-4-yloxy) -3-fluorophenyl) -2,6-difluorobenzamide (70 mg, 0.19 mmol), 3- (dimethylamino) propylamine (44 ml, 0.35 mmol), Cs2CO3 (85 mg, 0, 26 mmol) and CuCl (17 mg, 0.17 mmol) in a vial with a screw cap purged with N2. NMP and 2,2,6,6, -tetramethyl-3,5-heptanedione (31 mg, 0.17 mmol) were added to the mixture, which was then heated at 120 ° C for 4 h. The mixture was cooled, partitioned between EtOAc and saturated aqueous NaHCO3 solution and the EtOAc layer was separated, dried

168 (MgSO 4) and concentrated in vacuo to give the crude product. Purification of the residue by preparative HPLC (Column C) and conversion to the hydrochloride salt was carried out in a similar manner to step D of Example 33 to give the title compound (7 mg, 7%) as an off-white solid. MS (ESI⁺): m / z 517.37 (M + H)⁺.

Example 111

<img file="PL1737451T3_D0318.tif" />

N- (4- (2-Amino-3- (4- (2-amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1 2-dihydropyridine-3-carboxamide, hydrochloride salt [0572] Solution 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 DMF (1.5 mL) was treated with 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B from Example 101, 11 mg, 0.05 mmol), DIPEA (10 μ! 0.06 mmol) and TBTU (19 mg, 0.06 mmol). The mixture was stirred at room temperature for 40 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Column A) to give the title compound as a TFA salt. The TFA salt was dissolved in anhydrous MeOH and treated with 1 M HCl / Et 2 O at 0 ° C and stirred for 5 min. The mixture was then concentrated in vacuo to give the title compound (15 mg, 47%) as a yellow solid.¹H NMR (DMSO-d6) δ

12.11 (s, 1H), 8.56 (dd, 1H, J = 2.2, 7.1 Hz), 8.13 (dd, 1H, J = 2.2, 6.7 Hz), 8 , 00 (dd, 1H, J =

2.2, 12.6 Hz), 7.96 (d, 1H, J = 7.7 Hz), 7.60-7.57 (m, 2H), 7.48-7.33 (m, 10H ), 6.94 (s, 1H), 6.72 (dd, 1H, J = 7.2, 7.2 Hz), 6.38 (d, 1H, J = 7.2 Hz), 3.95 (s, 2H); MS (ESI⁺): m / z 568.23 (M + H)⁺.

Example 112

<img file="PL1737451T3_D0319.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0574]

- 169 -

<img file="PL1737451T3_D0320.tif" />

A) 1 - ((2,5-Difluoro-4-nitrophenoxy) methyl) benzene A mixture of 2,4,5-trifluoronitrobenzene (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), stirred at ambient temperature for 72 h. Water (60 ml) was added and the mixture was cooled at 4 ° C for 24 hours h. The resulting precipitate was filtered off, washed with water and dried in vacuo to afford the product (7.5 g, 92%) as a pale yellow solid. ¹H NMR (CDCl3) δ 7.90-7.94 (m, 1H), 7.387.44 (m, 5H), 6.85-6.90 (m, 1H), 5.22 (s, 2H).

<img file="PL1737451T3_D0321.tif" />

B) 4-Amino-2,5-difluorophenol [0576] To a flask filled with 1 - ((2,5-difluoro-4-nitrophenoxy) methyl) benzene (4.1 g, 15.6 mmol), which was subsequently treated vacuum and then purged with nitrogen three times, 10% palladium on carbon (0.40 g) added. Anhydrous methanol (100 mL) was added to the solids under a nitrogen atmosphere. The mixture was then stirred under a hydrogen atmosphere for 16 h. Nitrogen was bubbled through the reaction mixture for thirty minutes before filtering the mixture through a pad of Celite^®which was then washed with methanol. The filtrate was concentrated in vacuo, then azeotroped with toluene to give the title compound as a dark brown solid (2.2 g, 99%).¹H NMR (DMSO-d6) δ 9.05 (br s, 1H), 6.53-6.65 (m, 2H), 4.68 (s, 2H); MS (ESI⁺) m / z 146 (M + H)⁺.

<img file="PL1737451T3_D0322.tif" />

C) 4- (4-Amino-2,5-difluorophenoxy) picolinamide [0577] To a mixture of potassium hydride (30-35% dispersion in mineral oil, 1.9 g, 13.9 mmol) in DMF (30 ml) was added 4-amino-2,5-difluorophenol (1.7 g, 11.6 mmol) as a solution in DMF (5 mL). After one hour of stirring at ambient temperature, 4-chloropicolinamide (1.8 g, 11.6 mmol) was added and the reaction mixture was heated to 100 ° C for 135 h. The mixture was cooled to room temperature, quenched with 10% aqueous lithium chloride and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was partitioned between chloroform and water. The organic layer was washed with brine, dried (MgSO4),

- 170 filtered and concentrated in vacuo to a solid (3.0 g, 98%), ¹H NMR (DMSO-d6) δ

8.51-8.57 (m, 1H), 8.14 (br s, 1H), 7.74 (br s, 1H), 7.37-7.38 (m, 1H), 7.17- 7.30 (m, 2H), 6.74-6.80 (m, 1H), 5.62 (s, 2H); MS (ESI⁺) m / z 266 (M + H)⁺.

<img file="PL1737451T3_D0323.tif" />

D) 1- (4- (2-Carbamoylpyridin-4-yloxy) -2,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0578] For a homogeneous mixture of 4- (4-amino -2,5-difluorophenoxy) picolinamide (0.15 g, 0.57 mmol) in THF (5 mL) diisopropylethylamine (0.10 mL, 0.57 mmol) was added. The mixture was stirred for two minutes at ambient temperature before adding 2- (4-fluoro-phenyl) -acetyl-isocyanate (Compound D from Example 11, 0.36 M in toluene, 2.0 mL, 0.72 mmol). After 3.5 hours, 2- (4-fluorophenyl) acetylisocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. After an additional two hours, 2- (4-fluorophenyl) acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. The mixture was then stirred for 16 hours before concentrating in vacuo. The residue was treated with Et2O and ultrasound and the resulting white solid was filtered off. The solid was treated with Et2O and ultrasound twice before vacuum filtration to provide a white solid (0.23 g, 91%). ¹H NMR (DMSO-d6) δ 11.29 (s, 1H), 10.92 (s, 1H), 8.56 (d, 1H, J = 5.6 Hz), 8.21-8.26 ( m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H), 7.66-7.71 (m, 1H), 7.12-7.44 (m, 6H) , 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) acetyl) urea, hydrochloride salt [0579] Bis (trifluoroacetoxy) iodobenzene ( Aldrich, 0.18 g, 0.42 mmol) was added to the solution of 1- (4- (2-carbamoylpyridin-4-yloxy) -2,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) - urine (0.13 g, 0.30 mmol), water (0.01 mL, 0.60 mmol) and pyridine (0.05 mL, 0.66 mmol) in DMF (2 mL) at room temperature. After ten minutes, additional DMF (2 ml) was added. The reaction mixture was then stirred for 16 hours before concentrating in vacuo to about half the original volume. The resulting mixture was partitioned between 6 N HCl and Et2O, the aqueous solution was extracted with Et2O, and the combined organic layers were neutralized. The aqueous layer was neutralized with NaHCO3 (aqueous) and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (1 mL), cooled to 0 ° C and treated with HCl (4 N in dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for one hour before lyophilization to give the title compound (73 mg, 53%) as a white body

- 171 permanent. ¹H NMR (DMSO-d6) δ 13.54 (br s, 1H), 11.35 (s, 1H), 10.95 (s, 1H), 8.24-8.28 (m, 1H), 7 , 95-8.01 (m, 3H), 7.73-7.77 (m, 1H), 7.35-7.39 (m, 2H), 7.16-7.20 (m, 2H) , 6.72-6.74 (m, 1H), 6.25 (s, 1H), 3.78 (s, 2H); HRMS (ESI⁺): 417.1175 (M + H)⁺ calculated, 417.1877 (M + H)⁺stated.

Example 113

<img file="PL1737451T3_D0324.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3,5-difluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) urea, trifluoroacetic acid salt

<img file="PL1737451T3_D0325.tif" />

A) 2,6-Difluoro-4-nitrophenol [0582] 2,6-Difluorophenol (10.0 g, 76.9 mmol) was converted to the title compound (12.7 g, 94%) in a manner similar to the conditions described by Kirk et al. J. Heterocyclic Chem. 1976, 13, 1253.¹H NMR (CDCl3) δ 12.15 (br s, 1H), 8.01-8.10 (m, 2H).

<img file="PL1737451T3_D0326.tif" />

B) 4-Amino-2,6-difluorophenol [0583] 2,6-Difluoro-4-nitrophenol (2.1 g, 12.1 mmol) was converted to the title compound (1.7 g, 99%) in a similar manner to the one described by Demopoulos et al. J. Med. Chem. 2004, 47, 2706. MS (ESI⁺) m / z 146 (M + H)⁺.

<img file="PL1737451T3_D0327.tif" />

- 172 C) 4- (4-Amino-2,6-difluorophenoxy) picolinamide [0584] 4-Chloropicolinamide (0.47 g, 3.0 mmol) was converted to the title compound (0.23 g, 29%) in a manner similar to the preparation of compound C from example 112, except that

4-amino-2,6-difluorophenol (0.44 g, 3.0 mmol) was used instead of 4-amino-2,5-difluorophenol. ¹H NMR (DMSO-d6) δ 8.60 (d, 1H, J = 5.6 Hz), 8.22 (br s, 1H), 7.83 (br s, 1H), 7.45-7, 46 (m, 1H), 7.30-7.32 (m, 1H), 6.43-6.49 (m, 2H), 5.94 (s, 2H); MS (ESI⁺) m / z 266 (M + H)⁺.

<img file="PL1737451T3_D0328.tif" />

D) 1- (4- (2-Carbamoylpyridin-4-yloxy) -3,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0585] 4- (4-Amino-2, 6-difluorophenoxy) picolinamide (104 mg, 0.39 mmol) was converted to the title compound (91 mg, 52%) in a manner similar to the preparation of compound D from Example 112. ¹H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.50 (d, 1H, J = 5.6 Hz), 8.11 (br s, 1H ), 7.72 (br s, 1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J = 2.3 Hz), 7.23-7.31 (m , 3H), 7.11 (m, 2H), 3.69 (s, 2H); HRMS (ESI⁺), 445.1124 (M + H)⁺ calculated, 445.1117 (M + H)⁺ stated.

E) 1- (4- (2-Aminopyridin-4-yloxy) -3,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, salt with trifluoroacetic acid [0586] 1- (4 - (2-Carbamoylpyridin-4-yloxy) -3,5-difluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea (87 mg, 0.20 mmol) was converted to the title compound in a manner similar to the preparation compound E from Example 112, except that the crude product was purified by preparative HPLC (YMC S10 ODS, 30 x 500mm, 30 minutes gradient from 58% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to afford the title compound (23 mg, 22%) as a white solid. ¹H NMR (DMSO-d6) δ 11.09 (s, 1H),

10.63 (s, 1H), 7.92 (d, 1H, J = 7.2 Hz), 7.62-7.72 (m, 4H), 7.27-7.31 (m, 2H) , 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 114

<img file="PL1737451T3_D0329.tif" />

- 173 N- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0588]

<img file="PL1737451T3_D0330.tif" />

A) 4- (2,5-Difluoro-4- (2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido) -phenoxy) picolinamide [0589] For a homogeneous mixture of 2-oxo-1-phenyl acid -1,2-dihydropyridine-3-carboxylic acid (Compound C of Example 57, 43 mg, 0.20 mmol) in DMF (4 mL) 1-hydroxy-benzotriazole hydrate (22 mg, 0.16 mmol) was added. The mixture was stirred until homogeneous before adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (102 mg, 0.53 mmol). After two minutes, 4- (4-amino-2,5-difluorophenoxy) picolinamide (Compound C of Example 112, 53 g, 0.20 mmol) was added and the reaction mixture was stirred at ambient temperature for 17 h. The reaction mixture was then heated to 40 ° C and stirred for an additional 143 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and 10% LiCl (aqueous). The organic layer was washed twice with 10% LiCl (aqueous) then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1: 3 hexane / EtOAc) and the appropriate fractions concentrated in vacuo to afford the title compound (45 mg, 49%). MS (ESI⁺) m / z 463 (M + H)⁺.

B) N- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0590] 4- ( 2,5-Difluoro-4- (2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido) phenoxy) picolinamide (45 mg, 0.10 mmol) was converted to the title compound (19 mg, 40%) in a method similar to the preparation of compound E from example 112. ¹H NMR (DMSO-d6) δ 13.40 (br s, 1H), 12.47 (s, 1H), 8.53-8.57 (m, 2H), 8.12-8.13 (m, 1H), 7.92-7.93 (m, 1H), 7.83 (s, 2H), 7.66-7.71 (m, 1H), 7.46-7.53 (m, 5H) , 6.66-6.72 (m, 2H), 6.19 (s, 1H); HRMS (FSI⁺), 435.1269 (M + H)⁺ calc., 435.1258 (M + H)⁺ stated.

Example 115 [0591]

- 174 -

<img file="PL1737451T3_D0331.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -1- (4-Fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0592]

<img file="PL1737451T3_D0332.tif" />

A) 4- (2,5-Difluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) picolinamide [0593] To a homogeneous mixture of 1- (4) acid -fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B from Example 101, 50 mg, 0.21 mmol) and 4- (4-amino-2,5-difluorophenoxy) picolinamide (Compound C from Example 112, 69 mg, 0.26 mmol) in DMF (3 mL) added DIPEA (0.05 mL, 0.26 mmol) and O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) hexafluorophosphate - uranium (TBTU) (83 mg, 0.26 mmol). The resulting solution was stirred for 18 hours before the reaction was completed after adding 10% LiCl (aqueous). The mixture was partitioned between EtOAc and 10% LiCl (aqueous), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aqueous) then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1: 3 hexane / EtOAc) and the appropriate fractions concentrated in vacuo to afford the title compound (22 mg, 22%). MS (ESI⁺) m / z 481 (M + H)⁺.

B) N- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0594] 4 - (2,5-Difluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) picolinamide (22 mg, 0.04 mmol) was converted to the title compound ( 21 mg, 95%) in a manner similar to the preparation of compound E from Example 112. ¹H NMR (DMSO-d6) δ 13.71 (br s, 1H), 12.43 (s, 1H), 8.48-8.57 (m, 2H), 8.10-8.13 (m, 1H), 7.93-7.95 (m, 3H), 7.61-7.70 (m, 1H), 7.53-7.56 (m, 2H), 7.29-7.39 ( m, 2H), 6.64-6.72 (m, 2H), 6.10 (s, 1H); HRMS (ESI⁺), 453.1175 (M + H)⁺ calcd ,, 453,1168 (M + H)⁺ stated.

Example 116

- 175 -

<img file="PL1737451T3_D0333.tif" />

the hydrochloride salt

<img file="PL1737451T3_D0334.tif" />

A) Ethyl 3- (4- (2-carbamoylpyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropionate 4- (4-Amino-2,5-difluorophenoxy) picolinamide (Compound C of the example 112, 1.0 g, 3.9 mmol) was converted to the title compound (320 mg, 22%) in a manner similar to the preparation of compound A from example 102. ¹H NMR (DMSO-d6) δ 10.32 (s, 1H), 8.54 (d, 1H, J = 5.5 Hz), 8.14-8.17 (m, 2H), 7.75 ( br s, 1H), 7.61-7.65 (m, 1H), 7.42-7.43 (m, 1H), 7.247.25 (m, 1H), 4.12 (q, 2H, J = 7.2 Hz), 3.60 (s, 2H), 1.20 (t, 3H, J = 7.2 Hz); MS (ESI⁺) mlz

<img file="PL1737451T3_D0335.tif" />

B) 3- (4- (2-carbamoylpyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropanoic acid [0598] To the heterogeneous mixture of 3- (4- (2-carbamoylpyridin-4-yloxy) ethyl 2,5-difluorophenylamino) -3-oxopropionate (305 mg, 0.80 mmol) in MeOH (8 mL) was added aqueous 1 M NaOH (1.70 mL, 1.70 mmol). After one hour of stirring, the mixture was acidified with aqueous 1N HCl (5 mL). The reaction was extracted with EtOAc before the combined organic layers were dried (MgSO 4), filtered and concentrated in vacuo to give the title compound (317 mg) which was used without further purification. HRMS (ESI⁺), 352.0745 (M + H)⁺ calcd, 352,0752 (M + H)⁺ stated.

- 176 -

<img file="PL1737451T3_D0336.tif" />

N CONH₂

C) (±) -4- (2,5-Difluoro-4- (3-oxo-3- (1-phenylethylamino) propanamido) -phenoxy) picolinamide [0599] For a homogeneous mixture of 3- (4- (2- carbamoylpyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropane (89 mg, 0.25 mmol) and (±) -1-phenylethanamine (Aldrich, 0.05 mL, 0.38 mmol) in DMF (3 mL ) DIPEA (0.07ml, 0.38mmol) and O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) uranium (TBTU) hexafluorophosphate (TBTU) (121 mg, 0.38 mmol). The resulting solution was stirred for 15 hours before the reaction was completed after adding 10% LiCl (aqueous). The mixture was partitioned between EtOAc and 10% LiCl (aqueous), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aqueous) then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1: 3 hexane / EtOAc) and the appropriate fractions concentrated in vacuo to afford the title compound (42 mg, 37%). HRMS (ESI⁺), 455.1532 (M + H)⁺ calc., 455.1528 (M + H)⁺ stated.

D) (±) N - (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -N- (1-phenylethyl) malonamide, hydrochloride salt [0600] (±) -4- (2, 5-Difluoro-4- (3-oxo-3- (1-phenylethylamino) propanamido) phenoxy) picolinamide (41 mg, 0.09 mmol) was converted to the title compound (26 mg, 62%) in a manner similar to the preparation of the compound E from example 112. ¹H NMR (DMSO-d6) δ 10.46 (s, 1H),

<img file="PL1737451T3_D0337.tif" />

2H), 1.35 (d, 3H, J = 7.0 Hz); HRMS (ESI⁺), 427.1582 (M + H)⁺ calcd, 427.1574 (M + H)⁺stated.

Example 117 [0601]

CN

Ν ΝΗ₂ (±) -N - (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -N - (cyano (phenyl) methyl) malonamide, trifluoroacetic acid salt

- 177 -

<img file="PL1737451T3_D0338.tif" />

A) (±) -4- (4- (3- (Cyano (phenyl) methylamino) -3-oxopropanoamido) -2,5-difluorophenoxy) picolinamide [0603] Acid 3- (4- (2-carbamoylpyridin-4- yloxy) -2,5-difluorophenylamino) -3-oxopropane (Compound B from Example 116, 70 mg, 0.20 mmol) was converted to the title compound (67 mg, 72%) in a manner similar to the preparation of Compound C from Example 116, except that (±) -2-amino-2-phenylacetonitrile hydrochloride (Aldrich, 47 mg, 0.28 mmol) was used instead of (±) -1-phenylethanamine. MS (ESI⁺) m / z 466 (M + H)⁺.

B) (±) -N1- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -N3- (cyano (phenyl) methyl) malonamide, trifluoroacetic acid salt [0604] (±) -4- (4- (3- (Cyano (phenyl) methylamino) -3-oxopropanaxinide) -2,5-difluoro-phenoxy) picolinamide (65 g, 0.14 mmol) was converted to the title compound in a similar manner to that of the compound E from Example 112, except that the crude product was purified by preparative HPLC (YMC S10 ODS, 30 x 500mm, 30 minutes gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to afford the title compound (38 mg, 49%) as a white solid. ¹H NMR (DMSO-d6) δ 10.40 (s, 1H), 9.47 (d, 1H, J = 7.63 Hz), 8.21-8.26 (m, 1H), 7.99 ( d, 1H, J =

7.2, Hz), 7.86 (br s, 2H), 7.68-7.73 (m, 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⁺), 438.1788 (M + H)⁺ calc., 438.1374 (M + H)⁺ stated.

Example 118

<img file="PL1737451T3_D0339.tif" />

(±) -N - (2-Amino-1-phenylethyl) -N - (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenyl) malonamide, bis-trifluoroacetic acid salt [0606] (± ) -N¹- (4- (2-Aminopyridin-4-yloxy) -2,5-difluorophenyl) -N³- (cyano (phenyl) methyl) malonamide, trifluoroacetic acid salt (Compound B from Example 117, 21 mg, 0.04 mmol) was converted to the title compound in a manner similar to the conditions described by

- 178 Campiani, et al. (Tetrahedron 2002, 58, 3689). Cobalt borek was purchased at Alfa Aesar. The crude product was purified by preparative HPLC (YMC S5 ODS, 10 x 250mm, 30 minutes gradient from 10% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to afford the title compound (5 mg, 21%) as a white solid.¹H NMR (DMSO-d6) δ 10.39 (s, 1H), 8.72 (d, 1H, J = 8.5 Hz), 8.12-8.17 (m, 1H), 7.907.94 ( m, 3H), 7.59-7.63 (m, 2H), 7.27-7.34 (m, 4H), 6.60-6.62 (m, 1H), 6.09-6, 10 (m, 1H), 5.09-5.10 (m, 1H), 3.10-3-50 (m, 6H); HRMS (ESI⁺), 442.1691 (M + H)⁺ cal. 442.1678 (M + H)⁺ stated.

Example 119

<img file="PL1737451T3_D0340.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-pyrrolidine-3karboksamid

<img file="PL1737451T3_D0341.tif" />

A) 1- (4-Fluoro-phenyl) -2-oxopyrrolidine-3-carboxylic acid [0609] To a solution of 6,6-dimethyl-5,7-dioxaspiro [2.5] octane-4,8-dione (Aldrich, 51 mg , 0.3 mmol) in DMF (0.5 ml) at room temperature added 4-fluoroaniline (Aldrich, 33 mg, 0.3 mmol). The reaction mixture was heated at 90 ° C for 2 h, cooled to room temperature, and used directly in the next step.

B) N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide [0610] To a mixture of 1- (4-fluorophenyl) -2 acid -oxopyrrolidine-3-carboxyl (0.3 mol), 4- (4-amino-2-fluorophenoxy) pyridin-2-amine (Compound B from Example 24, 21.9 mg, 0.1 mmol) in DMF (0 , 5 ml), HATU (76 mg, 0.2 mmol) was added followed by diisopropylethylamine (0.1 ml, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of 2 mL methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with us. water

- 179 with NaHCO3 solution and concentrated in vacuo to give the title compound (18 mg, 43%) as a white solid. ¹H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.95 (d, 1H, J = 7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H ), 7.50 (m, 1H), 7.44 (t, 1H, J = 10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d , 1H, J = 2.8 Hz), 3.91 (m, 2H), 3.78 (t, 1H, J = 5.0 Hz), 2.41 (m, 2H); MS (ESI⁺) m / z 425.15 (M + H)⁺.

Example 120

<img file="PL1737451T3_D0342.tif" />

N- (4- (3-Amino-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2dihydropirydyno-3-carboxamide

<img file="PL1737451T3_D0343.tif" />

A) N- (3-Fluoro-4- (3-nitropyridin-4-yloxy) phenyl) -1- (4-Fluoro-phenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide [0613] Obtained from 3 -fluoro-4- (3-nitropyridin-4-yloxy) benzenamine (Compound A from Example 72) in a similar manner to that of Example 62 to give the title compound (89%) as a beige solid. ¹H NMR (CD3OD) δ 9.13 (s, 1H), 8.72 (dd, 1H, J = 8, 4 Hz), 8.60 (d, 1H, J = 6 Hz), 8.07 (d , 1H, J = 12 Hz), 8.01-7.99 (m, 1H), 7.58-7.55 (m, 2H), 7.45 (t, 1H, J = 8 Hz), 7 , 40-7.32 (m, 3H), 6.99 (d, 1H, J = 4 Hz), 6.76 (t, 1H, J = 8 Hz); MS (ESI⁺) m / z 465.18 (M + H)⁺.

B) N- (4- (3-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide [0614] Obtained in a similar manner as step C of example 59. The crude product was purified by flash chromatography on silica gel (10% MeOH /

EtOAc) to obtain the HCl salt of the title compound (58%) as an off-white solid. ¹H NMR (DMSO-d6) δ 12.07 (s, 1H), 8.59 (dd, 1H, J = 7.6, 2.4 Hz), 8.14 (dd, 1H, J = 6.4 , 2 Hz), 8.04 (s, 1H), 7.99 (dd, 1H, J = 13.2, 2.4 Hz), 7.66 (d, 1H, J = 5.2 Hz), 7.63-7.60 (m, 2H), 7.46-7.41

- 180 (m, 3H), 7.22 (t, 1H, J = 9.2 Hz), 6.74 (t, 1H, 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 121 [0615]

<img file="PL1737451T3_D0344.tif" />

N- (3-fluoro-4- (3-pyrrolidin-3-ylmethylamino) pyridin-4-yloxy) phenyl) -1- (4-fluorophenyl) 2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0616] To N- (4- (3-aminopyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide (Example 120, 30 mg, 0.07 mmol) in DCE (1 ml) 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CB Research and Development Inc., 28 mg, 0.14 mmol), acetic acid (5 µL, 0.084 mmol) then sodium triacetoxyborohydride (23 mg, 0.104 mmol). After stirring at room temperature for 6 h, a second portion (23 mg) of sodium triacetoxyborohydride was added. After stirring at room temperature for 2 h, 4N HCl in dioxane (5 mL) was added to the reaction mixture, and an additional 1 h was stirred at room temperature. The reaction was diluted with 10% MeOH / EtOAc (10 mL) and washed with saturated sodium bicarbonate solution (10 mL). The aqueous layer was re-extracted with 10 mL of 10% MeOH / EtOAc and the combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The resulting crude product was purified by prep. HPLC. The appropriate fractions were concentrated to remove methanol and then basified with saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with 10% MeOH / EtOAc (3 x 20 mL) and the collected organic extracts were dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was lyophilized from acetonitrile (1 mL) / water (3 mL) / 1N aqueous HCl (0.2 mL) to give the HCl salt of the title compound (25 mg, 60%) as a white solid. ¹H NMR (DMSO-d6) δ 12, 17 (s, 1H), 8.59 (dd, 1H, J = 7.6, 2 Hz), 8.30 (s, 1H), 8.16 (dd, 1H, J = 6.4, 2 Hz), 8.10 (dd, 1H, J = 12.2.2 Hz), 8.00 (d, 1H, J = 6.4 Hz), 7.64- 7.58 (m, 3H), 7.52 (t, 1H, J =

9.2 Hz), 7.46-7.42 (m, 2H), 7.00 (d, 1H, J = 6 Hz), 6.75 (t, 1H, J = 7.2 Hz), 3 , 72-3.64 (m, 3H), 3.37-3.26 (m, 1H), 3.17-3.10 (m, 1H), 2.97-2.92 (m, 1H) , 2.74-2.66 (m, 1H), 2.10-2.03 (m, 1H), 1.75-1.68 (m, 1H); MS (ESI⁺) m / z 518.29 (M + H)⁺.

Example 122 [0617]

- 181 -

<img file="PL1737451T3_D0345.tif" />

N- (4- (3- (2-Aminoethylamino) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0618] Obtained in a similar manner to Example 121 to give the HCl salt of the title compound (52%) as a white solid. ¹H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.52 (dd, 1H, J = 7.6, 2.4 Hz), 8.25 (s, 1H), 8.09 ( dd, 1H, J = 6.8, 2.4 Hz), 8.06-8.02 (m, 1H), 7.96 (d, 1H, J = 6.4 Hz), 7.56-7 , 52 (m, 3H), 7.42-7.34 (m, 3H), 6.92 (d, 1H, J = 6 Hz), 6.68 (t, 1H, J = 6.8 Hz) , 3.50-3.48 (m, 2H), 3.00-2.99 (m, 2H); MS (ESI⁺) m / z 478.29 (M + H)⁺.

<img file="PL1737451T3_D0346.tif" />

[0619] N- (3-Fluoro-4- (3- (piperidin-2-ylmethylamino) pyridin-4-yloxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide , hydrochloride salt [0620] Obtained in a similar manner to Example 121 to give the HCl salt of the title compound (71%) as a yellow solid. ¹H NMR (DMSO-d6) δ 12.17 (s, 1H), 8.59 (dd, 1H, J = 7.2, 2 Hz), 8.51 (s, 1H), 8.16 (dd, 1H, J = 6.8, 2 Hz), 8.11 (dd, 1H, J = 13.2, 2.4 Hz), 8.02 (d, 1H, J = 6.4 Hz), 7, 63-7.58 (m, 3H), 7.51 (t, 1H, J = 8.8 Hz), 7.46-7.41 (m, 2H), 7.01 (d, 1H, J = 6 Hz), 6.75 (t, 1H, J = 6.8 Hz), 3.70-3.63 (m, 1H), 3.52-3.45 (m, 1H), 3.30- 3.27 (m, 2H), 2.86-2.84 (m, 1H), 1.95-1.93 (m, 1H), 1.80-1.62 (m, 3H), 1, 58-1.44 (m, 2H); MS (ESI⁺) m / z 532.31 (M + H)⁺.

Example 124

<img file="PL1737451T3_D0347.tif" />

- 182 N- (4- (3- (3- (Dimethylamino) -2,2-dimethylpropylamino) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2 dihydropyridine-3-carboxamide hydrochloride salt [0622] Obtained in a similar manner to Example 121 to give the HCl salt of the title compound (58%) as a white solid. ¹H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.57 (s, 1H),

8.52 (dd, 1H, J = 7.6, 2 Hz), 8.09 (dd, 1H, J = 6.8, 2.4 Hz), 8.03 (dd, 1H, J = 13, 2, 2.4 Hz),

7.90 (d, 1H, J = 6.4 Hz), 7.56-7.51 (m, 3H), 7.44 (t, 1H, J = 8.8 Hz), 7.39-7 , 35 (m, 2H), 6.92 (d, 1H, J = 6.4 Hz), 6.68 (t, 1H, J = 7.2 Hz), 3.33 (s, 2H), 3 , 10 (s, 2H), 2.77 (s, 3H), 2.76 (s, 3H), 1.07 (s, 6H); MS (ES⁺) m / z 548.34 (M + H)⁺.

Example 125

<img file="PL1737451T3_D0348.tif" />

N- (4- (3- (2-Amino-3-hydroxypropylamino) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, salt hydrochloride [0624] Obtained in a similar manner to Example 121 to give the HCl salt of the title compound (65%) as a white solid. ¹H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.52 (dd, 1H, J = 7.2, 2 Hz), 8.30 (s, 1H), 8.09 (dd, 1H, J = 6.8, 2.4 Hz), 8.03 (dd, 1H, J = 12.8, 2 Hz), 7.96 (d, 1H, J = 6.4 Hz), 7, 56-7.52 (m, 3H), 7.43-7.35 (m, 3H), 6.93 (d, 1H, J = 6 Hz), 6.68 (t, 1H, J = 7, 2 Hz), 3.65-3.56 (m, 2H), 3.48-3.45 (m, 3H); MS (ESI⁺) m / z 508.27 (M + H)⁺.

Example 126

<img file="PL1737451T3_D0349.tif" />

1- (4- (2-Amino-3- (hydroxymethyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0626]

- 183 -

<img file="PL1737451T3_D0350.tif" />

A) Tert-Butyl 4-chloro-3-formylpyridin-2-ylcarbamate [0627] For (4-chloro-pyridin-2-yl) -carbamic acid tert-butyl ester (CB Research and Development Inc., 2.0 g , 8.75 mmol) in THF (18 ml) under a nitrogen atmosphere at -78 ° C, n-BuLi (13.7 ml, 21.9 mmol, 1.6 M in hexanes) was added dropwise. After stirring at -78 ° C for 45 min, a solution of DMF (1.93 mL) in THF (2 mL). The reaction was stirred at -78 ° C for 30 min and then allowed to warm slowly to room temperature. The reaction was quenched with 1N aqueous HCl and then basified with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc) to afford the title compound (0.95 g, 42%) as a white solid.¹H NMR (DMSO-d6) δ 10.44 (s, 1H), 10.13 (s, 1H), 8.47 (d, 1H, J = 5.2 Hz), 7.40 (d, 1H, J =

5.6 Hz), 1.48 (s, 9H).

<img file="PL1737451T3_D0351.tif" />

B) tert-Butyl 4- (2-fluoro-4-nitrophenoxy) -3-formylpyridin-2-ylcarbamate [0628] To 2-fluoro-nitrophenol (Aldrich, 700 mg, 4.44 mmol) in DMF (5 mL) sodium hydride (60%, 180 mg, 4.44 mmol) was added. After stirring at room temperature for 5 min, a solution of tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (0.95 g, 3.7 mmol) in 5 ml DMF was added to the mixture. The reaction mixture was stirred at 60 ° C for 20 h. After cooling to rt, the reaction was diluted with EtOAc (50 mL), washed with 10% aqueous lithium chloride (2 x 40 mL) then saturated aqueous sodium bicarbonate (40 mL), dried over anhydrous Na 2 SO 4, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (50% EtOAc / hexanes) to give the title compound (1.0 g, 72%) as a yellow oil.¹H NMR (CD3OD δ 10.59 (s, 1H), 8.37-8.25 (m, 2H), 7.67 (t, 1H, J = 7.6 Hz), 6.60 (d, 1H , J = 6 Hz), 1.59 (s, 9H).

<img file="PL1737451T3_D0352.tif" />

- 184 C) tert-Butyl 4- (2-fluoro-4-nitrophenoxy) -3- (hydroxymethyl) pyridin-2-ylcarbamate [0629] For tert-butyl 4- (2-fluoro-4-nitrophenoxy) -3- formylpyridin-2-ylcarbamate (75 mg, 0.2 mmol) in methanol (1 mL) at 0 ° C, sodium borohydride (7.6 mg, 0.20 mmol) was added. After stirring at 0 ° C for 30 min, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (1 mL). The reaction was diluted with EtOAc (5 mL) and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (65 mg, 86%) as a white solid which was used without further purification. ¹H NMR (CD3OD) δ 8.28 (dd, 1H, J = 10.4, 2.8 Hz), 8.22-8.18 (m, 2H), 7.45 (t, 1H, J = 8 , 4 Hz), 6.68 (d, 1H, J = 6 Hz), 4.81 (s, 2H), 1.57 (s, 9H); MS (ESD⁺) m / z 380.27 (M + H)⁺.

<img file="PL1737451T3_D0353.tif" />

D) tert-Butyl 4- (4-amino-2-fluorophenoxy) -3- (hydroxymethyl) pyridin-2-ylcarbamate [0630] Obtained in a similar manner as Step C of Example 59 to give the title compound as a white solid. ¹H NMR (CD3OD δ 8.14 (d, 1H, J = 6 Hz), 6.97 (t, 1H, J = 8.8 Hz), 6.62-6.54 (m, 2H), 6, 46 (d, 1H, J = 6.4 Hz), 4.64 (s, 2H), 1.55 (s, 9H); MS (ESI⁺) m / z 350.11 (M + H)⁺.

E) 1- (4- (2-Amino-3- (hydroxymethyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0631] in a similar manner to Step C of Example 59 to give the HCl salt of the title compound as a white solid. ¹H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.56 (s, 1H), 7.82 (d, 1H, J = 7.2 Hz), 7.74 (dd, 1H, J = 13.6, 2.8 Hz), 7.31-26 (m, 3H), 7.19-7.02 (m, 3H), 6.16 (d, 1H, J = 7.2 Hz ), 4.57 (s, 2H), 3.69 (s, 2H); MS (ESI⁺) m / z 429.16 (M + H)⁺.

Example 127

<img file="PL1737451T3_D0354.tif" />

1- (4- (2-Amino-3 - ((methylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

- 185 -

<img file="PL1737451T3_D0355.tif" />

A) tert-Butyl (2-bis-BOC-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (methyl) carbamate [0634] For tert-butyl 4- (2-fluoro- 4-nitrophenoxy) -3-formylpyridin-2-ylcarbamate (Compound B from Example 126, 75 mg, 0.2 mmol) in dichloroethane (1 mL) at 0 ° C added methylamine (240 μΐ, 0.24 mmol, 2M in THF), acetic acid (14 μΐ, 0.24 mmol), followed by sodium triacetoxyborohydride (400 mg, 1.89 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with EtOAc (5 mL), washed with saturated aqueous sodium bicarbonate solution (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% MeOH / EtOAc) to give tert-butyl 4- (2-fluoro-4-nitrophenoxy) -3 - ((methylamino) methyl) pyridin-2-ylcarbamate (37 mg, 47%) as a yellow oil.

[0635] For tert-butyl 4- (2-fluoro-4-nitrophenoxy) -3 - ((methylamino) methyl) pyridin-2-ylcarbamate (48 mg, 0.122 mmol) and DMAP (16 mg, 0.134 mmol) in dichloromethane (1 ml) di-tert-butyl dicarbonate (Aldrich, 32 mg, 0.15 mmol) was added. After stirring at room temperature 30 min, a mixture of bis- and tris-BOC material (2: 1) was observed. An additional portion of DMAP and di-tert-butyl dicarbonate was added. After stirring at room temperature for 30 min, the reaction was purified directly by flash column chromatography on silica gel (EtOAc) to give the title compound (44 mg, 61%) as a yellow oil. ¹H NMR (CD3OD δ 8.50 (d, 1H, J = 5.2 Hz), 8.15-7.97 (m, 2H), 7.43 (d, 1H, J = 5.6 Hz), 7.07 (t, 1H, J = 8.4 Hz), 4.64 (s, 2H), 2.83 (s, 3H), 1.44 (s, 27H); MS (ESI⁺) m / z 593.34 (M + H)⁺.

B) 1- (4- (2-Amino-3 - ((methylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, hydrochloride salt [0636] Obtained in a similar manner to Step C of Example 59 to give the HCl salt of the title compound (60%) as a white solid. ¹H NMR (DMSO-d6) δ 10.88 (s, 1H), 10.35 (s, 1H),

7.45-7.42 (m, 1H), 7.30 (m, 3H), 7.11-7.07 (m, 4H), 6.52 (d, 1H, J = 7.2 Hz) , 4.02 (s, 2H), 3.66 (s, 2H), 2.54 (s, 3H); MS (ESI⁺) mlz 442.30 (M + H)⁺.

Example 128 [0637]

- 186 -

<img file="PL1737451T3_D0356.tif" />

1- (4- (2-Amino-3 - ((2-hydroxyethylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trifluoroacetic acid salt

<img file="PL1737451T3_D0357.tif" />

A) tert-Butyl (2-BOC-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (2-hydroxyethyl) carbamate. [0639] Obtained in a similar manner as step A from example 127 to give title compound (14%) as a yellow oil. ¹H NMR (CD3OD) δ 8.30 (dd, 1H, J = 10.4, 2.8 Hz), 8.238.20 (m, 2H), 7.52 (t, 1H, J = 8.4 Hz) , 6.64 (d, 1H, J = 7.2 Hz), 4.71 (s, 2H), 3.65 (t, 2H, J = 6 Hz), 3.40 (m, 2H), 1 , 57 (s, 18H); MS (ESI⁺) m / z 523.32 (M + H)⁺.

B) 1- (4- (2-Amino-3 - ((2-hydroxyethylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -3 (2- (4-fluorophenyl) acetyl) urea, salt with trifluoroacetic acid [0640] Obtained in a similar manner as Step C of Example 59 to give the TFA salt of the title compound (45%) as a white solid. ¹H NMR (DMSO-d6) δ 11.12 (s, 1H), 10.69 (s, 1H), 8.01 (d, 1H, J = 6.8 Hz), 7.87 (dd, 1H, J = 12.8.2.4 Hz), 7.53- 7.40 (m, 4H), 7.26-7.20 (m, 2H),

6.68 (d, 1H, J = 7.2 Hz), 4.34 (s, 2H), 3.81 (s, 2H), 3.75 (t, 2H, J = 7.2 Hz), 3.18 (m, 2H); MS (ESI⁺) m / z 472.24 (M + H)⁺.

Example 129

<img file="PL1737451T3_D0358.tif" />

- 187 N- (4- (2-Amino-3 - ((2-aminoethylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine 3-carboxamide, trifluoroacetic acid salt [0642]

<img file="PL1737451T3_D0359.tif" />

A) tert-Butyl (2-BOC-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (2BOC-aminoethyl) carbamate. [0643] Obtained in a similar manner as step A from example 127 to give title compound (19%) as a yellow oil. ¹H NMR (CD3OD) δ 8.30 (dd, 1H, J = 10, 2.4 Hz), 8.23-8.20 (m, 2H), 7.52 (t, 1H, J = 8.4 Hz), 6.61 (d, 1H, J = 7.2 Hz), 4.65 (s, 2H), 3.39 (m, 2H), 3.25 (m, 2H), 1.61 ( s, 27H); MS (ESI⁺) m / z 622.47 (M + H)⁺.

B) N- (4- (2-Amino-3 - ((2-aminoethylamino) methyl) pyridin-4-yloxy) -3-fluorophenyl) -1 (4-fluorophenyl) -2-oxo-1,2-dihydropyridine -3-carboxamide, trifluoroacetic acid salt [0644] The nitro group was reduced in a similar manner to Step C of Example 59 and then the amide formed in a similar manner to Example 62 to give the TFA salt of the title compound (28%) as a white solid. ¹H NMR (DMSO-d6) δ 12.09 (s, 1H), 8.52 (dd, 1H, J = 7.2, 2 Hz), 8.09 (dd, 1H, J = 6.4, 2 Hz), 7.99 (dd, 1H, J = 12.8, 2.4 Hz), 7.89 (d, 1H, J = 6.4 Hz), 7.56-7.52 (m, 2H), 7.49-7.47 (m, 1H), 7.39-7.33 (m, 3H), 6.68 (t, 1H, J = 7.2 Hz), 6.07 (d, 1H, J = 7.2 Hz), 4.25 (s, 2H), 3.20 (m, 2H), 3.08 (m, 2H); MS (ESI⁺) m / z 507.23 (M + H)⁺.

Example 130

<img file="PL1737451T3_D0360.tif" />

N- (4- (2-Amino-3- (hydroxymethyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) 2-oxo-1,2-dihydropyridine-3-carboxamide, salt with trifluoroacetic acid [0646]

- 188 -

<img file="PL1737451T3_D0361.tif" />

A) tert-Butyl 3 - ((tert-butyldimethylsilyloxy) methyl) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-ylcarbamate [0647] For tert-butyl 4- (2-fluoro-4-nitrophenoxy) -3- (hydroxymethyl) pyridin-2-ylcarbamate (Compound C of Example 126, 100 mg, 0.26 mmol) in dichloromethane (3 mL), imidazole (21 mg, 0.31 mmol) was added, followed by tert-butyldimethylsilyl chloride (40 mg , 0.26 mmol). After stirring at room temperature for 1 h, a second equivalent of tert-butyldimethylsilyl chloride (40 mg, 0.26 mmol) was added. The reaction was stirred at room temperature for 3h and then diluted with dichloromethane (10ml), washed with water (10ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (50% EtOAc / hexanes) to give the title compound (102 mg, 79%) as a white solid.¹H NMR (CD3OD) δ 8.16 (dd, 1H, J = 10.4, 2.8 Hz), 8.09-8.05 (m, 2H), 7.29 (t, 1H, J = 8 , 4 Hz),

6.53 (d, 1H, J = 5.6 Hz), 4.84 (s, 2H), 1.43 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H ); MS (ESI⁺) m / z 494.29 (M + H)⁺.

<img file="PL1737451T3_D0362.tif" />

B) tert-Butyl 4- (4-amino-2-fluorophenoxy) -3 - ((tert-butyldimethylsilyloxy) methyl) pyridin-2-ylcarbamate [0648] Obtained in a similar manner as Step C from Example 59 to give the title compound ( 95 mg, 98%) as a yellow oil. ¹H NMR (CD3OD δ 7.90 (d, 1H, J = 6 Hz), 6.76 (t, 1H, J = 8.8 Hz), 6.43 (dd, 1H, J = 12.8, 2 , 8 Hz), 6.39-6.37 (m, 1H), 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)⁺.

<img file="PL1737451T3_D0363.tif" />

- 189 C) tert-Butyl 3 - ((tert-butyldimethylsilyloxy) methyl) -4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) pyridin-2-ylcarbamate [0649] Obtained in a similar manner to that of example 62 to give the title compound (86%) as a colorless oil. ¹H NMR (CD3OD) δ 8.51 (dd, 1H, J = 7.6, 2.4 Hz), 7.93 (d, 1H, J = 6 Hz), 7.84-7.80 (m, 2H), 7.40-7.37 (m, 2H), 7.21-7.15 (m, 3H), 7.06 (t, 1H, J = 8.8 Hz), 6.57 (t , 1H, J = 6.8 Hz), 6.26 (d, 1H, J = 5.6 Hz), 4.86 (s, 2H), 1.40 (s, 9H), 0.82 (s , 9H), 0.00 (s, 6H); MS (ESI⁺) m / z 679.34 (M + H)⁺.

<img file="PL1737451T3_D0364.tif" />

D) tert-Butyl 4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) -3- (hydroxymethyl) pyridin-2-ylcarbamate [0650] For tert-butyl 3 - ((tert-butyldimethylsilyloxy) methyl) -4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) pyridin-2-ylcarbamate (119 mg, 0.176 mmol) in THF (2 mL) at room temperature was added tetrabutylammonium fluoride (260 μ! 0.264 mmol, 1M in THF). After stirring at room temperature for 30 min, the reaction was diluted with ethyl acetate (20 mL), washed with water then brine (10 mL each), dried over anhydrous MgSO 4, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (5% MeOH / EtOAc) to give the title compound (66 mg, 66%) as a yellow oil.¹H NMR (CD3OD δ 8.62 (dd, 1H, J = 7.2, 2 Hz), 8.04 (d, 1H, J = 6 Hz), 7.94-7.90 (m, 2H), 7.50-7.46 (m, 2H), 7.33-7.25 (m, 3H), 7.20 (t, 1H, J = 8.8 Hz), 6.67 (t, 1H, J = 6.8 Hz), 6.40 (d, 1H, J = 5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS (ESI⁺) m / z 565.17 (M + H)⁺.

E) N- (4- (2-Amino-3- (hydroxymethyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide , trifluoroacetic acid salt [0651] For tert-butyl 4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) -3- (hydroxymethyl) pyridin-2-ylcarbamate (33 mg 0.058 mmol) in THF (2 mL) was added 4N HCl in dioxane (10 mL) at room temperature. After stirring at room temperature for 8 h, the reaction was concentrated in vacuo. The resulting crude product was purified by prep. HPLC. The appropriate fractions were concentrated and toluene (2 x 3 mL) was added and the resulting mixture was concentrated again. The residue was lyophilized from acetonitrile (1 mL) / water (3 mL) to give the TFA salt of the title compound (14 mg, 42%) as a white solid.¹H NMR (DMSO-d6) δ 12.08 (s, 1H), 8.52 (dd, 1H, J = 7.2, 2 Hz), 8.09 (dd, 1H, J = 6.8, 2 Hz), 7.99 (dd, 1H, J = 12.8, 2.4 Hz), 7.81 (d, 1H, J = 7.2 Hz), 7.56-7.52 (m, 2H ), 7.48-7.46 (m, 1H), 7.39-7.34 (m, 2H), 7.30 (t, 1H, J = 9.2 Hz), 6.67 (t, 1H, J = 7.2 Hz), 6.21 (d, 1H, J =

7.2 Hz), 4.58 (s, 2H); MS (ESI⁺) m / z 465.17 (M + H)⁺.

- Example 190 [0652]

<img file="PL1737451T3_D0365.tif" />

1- (4- (2-Amino-3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea, salt dihydrochloride

<img file="PL1737451T3_D0366.tif" />

A) 4- (2-Fluoro-4-nitrophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine [0654] Solution 4- (2-fluoro-4-nitrophenoxy) -3 iodopyridin-2-amine (Compound C of Example 34, 100 mg, 0.27 mmol), 2-ethynylpyridine (Aldrich, 56 gl, 0.54 mmol), Et₃N (2 mL), and THF (2 mL) was degassed using vacuum / argon purge and then treated with CuI (6 mg, 0.032 mmol) and (Ph3P) 4Pd (20 mg, 0.017 mmol). The reaction mixture was heated at 60 ° C for 45 min, cooled to RT and diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO3, brine, dried (MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using 0-1.5% MeOH / CH2Cl2 to give the title compound (55 mg, 57%) as a green-olive solid. ¹H NMR (DMSO-d6) δ 8.53 (d, 1H, J = 5.1 Hz), 8.42-8.37 (m, 1H), 8.19-8.12 (m, 1H), 7.96 (d, 1H, J = 5.6 Hz), 7.85-7.78 (m, 1H), 7.71 (d, 1H, J = 7.6 Hz),

7.52 (t, 1H, J = 8.6 Hz), 7.36 (ddd, 1H, J = 7.6, 5.1, 1.0 Hz), 6.71 (s, 2H), 6 , 21 (d, 1H, J = 5.6 Hz); MS (ESI⁺): m / z 351.25 (M + H)⁺.

<img file="PL1737451T3_D0367.tif" />

B) 4- (4-Amino-2-fluorophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine

[0655] The title compound was obtained from the reduction of 4- (2-fluoro-4-nitrophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine (35 mg, 0.10 mmol) using dust zinc (65 mg, 1.0 mmol) and NH4Cl (53 mg, 1.0 mmol) in the same manner as Step C of Example 11. This provided the title compound (25 mg, 78%) as a brown oil. MS (ESI⁺): m / z 321.25 (M + H)⁺.

C) 1- (4- (2-Amino-3- (2- (pyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluoro-phenyl) -acetyl) -urea , dihydrochloride salt [0656] The title compound was obtained from 4- (4-amino-2-fluorophenoxy) -3- (2- (pyridin-2-yl) ethynyl) pyridin-2-amine (25 mg, 0.078 mmol) and 0.3M solution of 2- (4-fluorophenyl) acetyl isocyanate in toluene (Compound D from Example 11, 0.26 mL, 0.078 mmol) in the same manner as Step E from Example 11. The crude product was obtained by preparative HPLC (Column B) . The TFA salt was converted to the hydrochloride salt in the same manner as in Step E of Example 36 to give the title compound (18 mg, 40%) as a brown solid. ¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J = 4.6 Hz), 8.23 ​​(s, 1H) , 7.99 (d, 1H, J = 7.1 Hz), 7.94-7.84 (m, 3H), 7.87-7.76 (m, 1H), 7.51-7.42 (m, 3H), 7.39-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.30 (d, 1H, J = 7.1 Hz), 3, 74 (s, 2H) MS (ESI⁺): m / z 498.11 (M + H)⁺.

Example 132

<img file="PL1737451T3_D0368.tif" />

N- (4- (2-Amino-3- (4- (2-amino-2-oxoethyl) phenyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1 2-dihydropyridine-3-carboxamide, hydrochloride salt [0658] The title compound was obtained from 2- (4- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide (Compound C from example 78.18 mg, 0.05 mmol) and 1- (4-fluoro-phenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B from Example 101, 11 mg, 0.05 mmol) in the same manner as Example 62. The crude product was obtained by preparative HPLC (Column B) followed by conversion of the TFA salt to the hydrochloride salt (15 mg, 50%). ¹H NMR (DMSO-d6) δ 12.11 (s, 1H), 8.58-8.54 (m, 1H), 8.13 (dd, 1H, J = 6.6,

2.2 Hz), 8.00 (dd, 1H, J = 12.6, 2.2 Hz), 7.96 (d, 1H, J = 7.7 Hz), 7.59 (dd, 2H, J = 8.8, 4.9 Hz), 7.47-7.41 (m, 6H), 7.40-7.35 (m, 3H), 6.94 (s, 1H), 6.72 (t, 1H, J = 7.1 Hz), 6.38 (d, 1H, J = 7.1 Hz), 3.44 (s, 2H); MS (ESI⁺): m / z 568.23 (M + H)⁺.

Example 133 [0659]

- 192 -

<img file="PL1737451T3_D0369.tif" />

1- (4- (2-Amino-3- (2- (5-aminopyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) - urea, dihydrochloride salt

<img file="PL1737451T3_D0370.tif" />

A) 6- (2- (Trimethylsilyl) ethynyl) pyridin-3-amine A mixture of 3-amino-6-bromopyridine (Alfa Aesar, 1.0 g, 5.8 mmol), ethynyltrimethylsilane (1.7 mL, 17.3 mmol), CH3CN (3 mL), DMF (2 mL) and Et3N (2 mL) were treated with CuI (60 mg, 0.32 mmol) and (Ph3P) 4Pd (114 mg, 0.10 mmol) and the mixture was stirred at 45 ° C for 1.5 h. More ethynyl trimethylsilane (1.7 mL, 17.3 mmol) was added to the reaction and the mixture was stirred for 2 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using 0-6% EtOAc / hexanes to give the title compound (0.75 g, 68%) as a brown solid.¹H NMR (DMSO-d6) δ 7.85 (s, 1H), 7.15 (d, 1H, J = 8.1 Hz), 6.81 (d, 1H, J = 8.1 Hz), 5 , 76 (s, 2H), 0.19 (s, 9H); MS (ESI⁺): m / z 191.20 (M + H)⁺.

<img file="PL1737451T3_D0371.tif" />

B) tert-Butyl 6- (2- (trimethylsilyl) ethynyl) pyridin-3-ylcarbamate [0662] Solution of 6- (2- (trimethylsilyl) ethynyl) pyridin-3-amine (0.5 g, 2.6 mmol) in THF was cooled to -50 ° C and 1.0 M NaHMDS in THF (5.3 mL, 5.5 mmol) was added dropwise. The mixture was warmed to -20 ° C, treated with BOC anhydride in one portion and allowed to warm to RT over 25 min. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the EtOAc layer was separated and washed with brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using 0-25% EtOAc / hexanes to give the product (0.5 g, 67%) as a white solid.¹H NMR (DMSO-d6) δ 9.80 (s, 1H), 8.58 (d, 1H, J = 2.0 Hz),

- 193 7.86 (dd, J = 8.6, 2.5 Hz, 1H), 7.44 (d, 1H, J = 8.6 Hz), 1.47 (s, 9H), 0.22 (s, 9H); MS (ESI⁺): mlz 291.34 (M + H)⁺.

<img file="PL1737451T3_D0372.tif" />

C) tert-Butyl 6-ethynylpyridin-3-ylcarbamate [0663] A solution of tert-butyl 6- (2- (trimethylsilyl) ethynyl) pyridin-3-ylcarbamate (62 mg, 0.21 mmol) in THF (5 mL) was cooled to -15 ° C and treated with 1.0 M tetrabutylammonium fluoride (Aldrich, 0.25 mL, 0.25 mmol) and stirred for 40 min. The mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (45 mg, 100%) as an off-white solid. ¹H NMR (DMSO-d6) δ 9.78 (s, 1H), 8.58 (d, 1H, J = 2.5 Hz), 7.92-7.84 (m, 1H), 7.46 ( d, 1H, J = 8.6 Hz), 4.17 (s, 1H), 1.47 (s, 9H); MS (ESI⁺) m / z 219.20 (M + H)⁺.

<img file="PL1737451T3_D0373.tif" />

D) tert-Butyl 6- (2- (2-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridin-3-ylcarbamate [0664] The title compound was obtained from tert-butyl -ethynylpyridin-3-ylcarbamate and

4- (2-fluoro-4-nitrophenoxy) -3-iodo-pyridin-2-amine (Compound C of Example 34) in the same manner as Step A of Example 46 in 44% yield. ¹H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.56 (s, 1H), 8.40-8.36 (m, 1H), 8.14 (d, 1H, J = 8 , 8 Hz), 7.94 (d, 1H, J = 5.5 Hz), 7.89 (d, 1H, J = 8.2 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.53-7.47 (m, 1H), 6.63 (br s, 2H), 6.21 (d, 1H, J = 6.0 Hz), 1.47 (s, 9H) ; MS (ESI⁺): m / z 466.22 (M + H)⁺.

<img file="PL1737451T3_D0374.tif" />

E) tert-Butyl 6- (2- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) ethynyl) pyridin-3-ylcarbamate

[0665] The title compound was obtained from tert-butyl 6- (2- (2-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridin-3-ylcarbamate in the same manner as step C of example 11 in quantitative yield. MS (ESI⁺): m / z 436.29 (M + H)⁺.

<img file="PL1737451T3_D0375.tif" />

F) tert-Butyl 6- (2- (2-amino-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) ethynyl) pyridine -3-ylcarbamate [0666] The title compound was obtained from tert-butyl 6- (2- (2-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) ethynyl) pyridin-3-ylcarbamate in the same manner as step E from example 11 in 80% yield. ¹H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.56 (s, 1H), 9.78 (s, 1H), 8.59 (d, 1H, J = 2.5 Hz) , 7.91 (dd, 1H, J = 8.6, 2.5 Hz), 7.81 (d, 1H, J = 5.6 Hz), 7.75 (dd, 1H, J = 12.7 , 2.5 Hz), 7.68 (d, 1H, J = 8.6 Hz,), 7.44-7.27 (m, 5H), 7.19-7.13 (m, 2H), 6.47 (s, 2H), 5.86-5.81 (m, 1H), 1.48 (s, 9H); MS (ESI⁺): m / z 615.34 (M + H)⁺.

G) 1- (4- (2-Amino-3- (2- (5-aminopyridin-2-yl) ethynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0667] Tert-butyl solution 6- (2- (2-amino-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) ethynyl) pyridin-3-ylcarbamate (23 mg, 0.037 mmol) in CH2Cl2 (2 mL) and treated with TFA (0.5 mL) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Column B) and converted to its hydrochloride salt (11 mg, 52%) in the same manner as step E of example 36. ¹H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.62 (s, 1H), 8.05 (s, 1H), 7.97 (d, 1H, J = 2.7 Hz) , 7.94 (d, 1H, J = 7.1 Hz), 7.82 (d, 1H, J =

12.1 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.45-7.45 (m, 2H), 7.35 (dd, 2H, J = 8.2, 5 , 5 Hz), 7.20 (d, 1H, J = 6.6 Hz), 7.16 (t, 2H, J = 8.8 Hz), 6.24 (d, 1H, J = 6.6 Hz), 3.74 (s, 2H); MS (ESI⁺): m / z 515.19 (M + H)⁺.

Example 134 [0668]

- 195 -

<img file="PL1737451T3_D0376.tif" />

N- (4- (2-Amino-3- (3 - ((3R, 4R) -3-hydroxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl) -3-methylbut-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, trihydrochloride salt

<img file="PL1737451T3_D0377.tif" />

A) (3R, 4R) -1- (2-Methylbut-3-yn-2-yl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol [0670] Mixture (3R, 4R) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol (Lexicon Pharma, 1.56 g, 10.0 mmol) and 3-chloro-3-methyl-1-butyn (GFS Chmeical, Inc., 1.36 g, 13.2 mmol), THF (15 mL) and Et3N (13.3 mmol) were treated with CuI (77 mg, 0.78 mmol). An exothermic reaction occurs with simultaneous formation of a precipitate. After stirring at room temperature for 15 h, the mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous layer was extracted twice with EtOAc and the combined EtOAc layers were dried (MgSO4) and concentrated to give a light brown solid (1.0 g, 45%).¹H NMR (CDCl3) δ 4.20 (br s, 1H), 3.13-3.04 (m, 1H), 2.95 (dd, 1H, J = 10.1, 6.6 Hz), 2 , 77 (dd, 1H, J = 10.1, 2.6 Hz), 2.64 (m, 3H), 2.61 (m, 2H), 2.55-2.46 (m, 1H), 2.26 (s, 1H), 1.85-1.74 (m, 4H), 1.38 (s, 3H), 1.36 (s, 3H); MS (ESI⁺): m / z 223.29 (M + H)⁺.

<img file="PL1737451T3_D0378.tif" />

B) (3R, 4R) -1- (4- (2-Amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) -2-methylbut-3-yn2-yl) -4- ( pyrrolidin-1-yl) pyrrolidin-3-ol

[0671] The title compound was obtained from (3R, 4R) -1- (2-methylbut-3-yn-2-yl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol and 4- (2-fluoro -4-nitrophenoxy) -3-iodopyridin-2-amine (Compound C of Example 34) in the same manner as step D of Example 35 in 57% yield. ¹H NMR (CDCl3) δ 8.10 (dd, 1H, J = 10.2, 2.5 Hz), 8.03 (d, 1H, J = 9.2 Hz), 7.99 (d, 1H, J = 5.6 Hz), 7.13-7.06 (m, 1H), 6.26 (d, 1H, J = 6.1 Hz), 5.18 (br s, 2H), 4.21 (m, 1H), 3.10-2.99 (m, 1H), 2.96 (s, 1H), 2.70 (dd, 2H, J = 9.7, 3.1 Hz), 2, 66-1.15 (m, 2H), 1.87-1.76 (m, 5H), 133-1.32 (m, 2H), 1.32 (m, 3H); 1.34 (m, 3H); MS (ESI⁺): m / z 470.20 (M + H)⁺.

<img file="PL1737451T3_D0379.tif" />

C) (3R, 4R) -1- (4- (2-Amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) -2-methylbut-3-yn2-yl) -4- ( pyrrolidin-1-yl) pyrrolidin-3-ol [0672] The title compound was obtained from (3R, 4R) -1- (4- (2-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl ) -2-methylbut-3-yn-2-yl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol in the same manner as Step C of Example 11 in 95% yield. MS (ESI⁺): m / z 440.37 (M + H)⁺.

D) N- (4- (2-Amino-3- (3 - ((3R, 4R) -3-hydroxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl) -3-methylbut-1- ynyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide, trihydrochloride salt [0673] The title compound was obtained from (3R, 4R) -1- (4- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) -2-methylbut-3-yn -2-yl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol and 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B from Example 101) in the same way as Example 62 with 50% yield. ¹H NMR (DMSO-d6) δ 12.14 (s, 1H), 8.62-8.54 (m, 1H), 8.14 (dd, 3H, J = 6.6, 2.0 Hz), 8.05 (d, 1H, J = 13.2 Hz), 7.99 (d, 1H, J = 7.1 Hz), 7.62-7.51 (m, 5H), 7.42 (t , 2H, J = 8.6 Hz), 6.78-6.70 (m, 1H), 6.32 (d, 1H, J =

7.1 Hz), 4.65 (br s, 1H), 3.94-3.84 (m, 1H), 3.71 (d, 2H, J = 16.8 Hz), 3.60 (m , 2H), 3.52 (m, 1H), 3.22-3.08 (m, 2H), 2.00-1.91 (m, 2H), 1.88-1.78 (m, 2H), 1.70 (s, 6H); MS (ESI⁺): m / z

655.40 (M + H)⁺.

Example 135 [0674]

- 197 -

<img file="PL1737451T3_D0380.tif" />

1- (4- (2-Amino-3- (3 - ((3R, 4R) -3-hydroxy-4- (pyrrolidin-1-yl) pyrrolidin-1-yl ) -3-methylbut-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, trihydrochloride salt [0675] The title compound was obtained from (3R, 4R) -1- (4- (2- amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) -2-methylbut-3-yn-2-yl) -4- (pyrrolidin-1-yl) pyrrolidin-3-ol with 40% yield in the same manner as Step E of Example 11.¹H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.62 (s, 1H), 7.97 (d, 2H, J = 6.6 Hz), 7.80 (d, 1H, J = 11.7 Hz), 7.51-7.40 (m, 2H),

7.38-7.32 (m, 2H), 7.16 (t, 2H, J = 8.6 Hz), 6.25 (d, 1H, J = 6.6 Hz), 4.63-4 , 53 (m, 1H), 3.793,68 (m, 1H), 3.74 (s, 2H), 3.68-3.56 (m, 2H), 3.51-3.43 (m, 2H), 3.08-2.99 (m, 4H), 1.981.92 (m, 2H), 1.89-1.77 (m, 2H), 1.64 (s, 6H); MS (ESI⁺): m / z 619.41 (M + H)⁺.

Example 136

<img file="PL1737451T3_D0381.tif" />

1- (3-Fluoro-4- (3- (3-hydroxyprop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

<img file="PL1737451T3_D0382.tif" />

A) 3- (4- (2-Fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol [0678] The title compound was obtained from 4- (2-fluoro-4-nitrophenoxy) - 3-iodopyridine (Compound

A from example 33) and propargyl alcohol (Aldrich) in 77% yield in the same manner as step A from example 36. ¹H NMR (DMSO-d6) δ 8.69 (s, 1H), 8.49 (d, 1H, J = 5.6 Hz), 8.43

- 198 (dd, 1H, J = 10,7,2,5 Hz), 8.17 (d, 1H, J = 9.2 Hz), 7.57 (t, 1H, J = 8.6 Hz) , 7.04 (d, 1H, J =

5.6 Hz), 5.40 (t, 1H, J = 6.1 Hz), 4.28 (d, 2H, J = 6.1 Hz); MS (ESI⁺): m / z 289.15 (M + H)⁺.

<img file="PL1737451T3_D0383.tif" />

B) 3- (4- (4-Amino-2-fluorophenoxy) pyridin-3-yl) prop-2-yn-1-ol [0679] The title compound was obtained as 3- (4- (2-fluoro-4 -nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol in 95% yield in the same manner as step C of example 11. MS (ESI⁺): m / z 259.21 (M + H)⁺.

C) 1- (3-Fluoro-4- (3- (3-hydroxyprop-1-ynyl) pyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [ 0680] The title compound was obtained from 3- (4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2in-1-ol in 36% yield in the same manner as Step E of Example 11. ¹H NMR (DMSOd6) δ 11.06 (s, 1H), 10.63 (s, 1H), 8.79 (s, 1H), 8.49 (d, 1H, J = 6.1 Hz), 7 , 82 (d, 1H, J = 12.2 Hz), 7.45-7.40 (m, 2H), 7.38-7.33 (m, 2H), 7.23-7.13 (m , 2H), 6.89 (d, 1H, J = 6.1 Hz), 4.37 (s, 2H), 3.74 (s, 2H); MS (ESI⁺): m / z 438.23 (M + H)⁺.

Example 137

<img file="PL1737451T3_D0384.tif" />

N- (4- (2-Amino-3- (3-amino-prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine -3-carboxamide, dihydrochloride salt

<img file="PL1737451T3_D0385.tif" />

- 199 A) tert-Butyl 3- (2-amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynylcarbamate [0683] The title compound was obtained from N-Boc propargylamine (Compound A from example 42) and

4- (2-fluoro-4-nitrophenoxy) -3-iodopyridin-2-amine (Compound C of Example 34) in the same manner as step A of Example 42 in 59% yield. ¹H NMR (DMSO-d6) δ 8.35 (dd, 1H, J = 10.7, 2.5 Hz), 8.12 (d, 1H, J = 9.2 Hz), 7.88 (d, 1H, J = 5.6 Hz), 7.39 (t, 1H, J = 8.6 Hz),

7.31 (t, 1H, J = 5.1 Hz), 6.53 (s, 2H), 6.15 (d, 1H, J = 5.6 Hz), 3.92 (d, 2H, J = 5.6 Hz), 1.36 (s, 9H); MS (ESI⁺): m / z 403.34 (M + H)⁺.

<img file="PL1737451T3_D0386.tif" />

B) tert-Butyl 3- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynylcarbamate [0684] The title compound was obtained from tert-butyl 3- (2-amino -4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-ynylcarbamate in quantitative yield in the same manner as step C of example 11. MS (ESI⁺): m / z 373.35 (M + H)⁺.

<img file="PL1737451T3_D0387.tif" />

C) tert-Butyl 3- (2-amino-4- (2-fluoro-4- (1- (4-Fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy) pyridin-3- yl) prop-2-ynylcarbamate [0685] The title compound was obtained from tert-butyl 3- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynylcarbonate and 1- (4-acid -fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxyl (Compound B from Example 101) in the same manner as Example 62 in 48% yield. ¹H NMR (DMSO-d6) δ 12.07 (s, 1H), 8.57 (dd, 1H, J = 7.1, 2.0 Hz), 8.12 (dd, 1H, J = 6.6 , 2.0 Hz), 8.00-7.93 (m, 1H), 7.75 (d, 1H, J = 6.1 Hz), 7.61 (d, 2H, J = 5.1 Hz ), 7.59 (d, 1H, J = 4.6 Hz), 7.48-7.37 (m, 4H), 7.30-7.25 (m, 1H), 6.72 ( t, 1H, J = 7.1 Hz), 6.37 (br s, 1H), 5.80 (d, 1H, J = 6.1 Hz), 4.00 (d, 2H, J = 5, 1 Hz), 1.38 (s, 9H); MS (ESI⁺): m / z 588.26 (M + H)⁺.

D) N- (4- (2-Amino-3- (3-aminoprop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2 dihydropyridine-3-carboxamide dihydrochloride salt

[0686] The title compound was obtained from tert-butyl 3- (2-amino-4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamido) phenoxy pyridin-3-yl) prop-2-ynylcarbamate in 80% yield in the same manner as step E from Example 36. ¹H NMR (DMSO-d6) δ 12.13 (s, 1H), 8.57 (dd, 1H, J = 7.1, 2.0 Hz), 8.51 (s, 2H), 8.14 (dd, 1H, J = 6.6, 2.0 Hz), 8.11-8.02 (m, 1H), 7.98-7.90 (m, 1H), 7.60 (dd, 2H , J = 9.2, 5.1 Hz), 7.53 (d, 1H, J =

9.2 Hz), 7.46-7.37 (m, 3H), 6.76-6.71 (m, 1H), 6.20 (d, 1H, J = 6.6 Hz), 4, 11-4.04 (m, 2H); MS (ESI⁺): m / z 488.16 (M + H)⁺.

Example 138

<img file="PL1737451T3_D0388.tif" />

1- (4- (2-Amino-3- (3-aminoprop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt

<img file="PL1737451T3_D0389.tif" />

A) tert-Butyl 3- (2-amino-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) prop-2-ynylcarbamate [ 0689] The title compound was obtained from tert-butyl 3- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-ynylcarbonate in 38% yield in the same manner as Step E of Example 11 . ¹H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.55 (s, 1H), 7.807.73-7.69 (m, 2H), 7.38-7.29 (m, 3H ), 7.33 (d, 1H, J = 5.1 Hz), 7.30-7.21 (m, 1H), 7.21-7.13 (m, 2H), 6.37 (br s , 1H), 5.76 (d, 1H, J = 6.1 Hz), 4.00 (s, 2H), 3.73 (s, 2H), 1.38 (s, 9H); MS (ESI⁺): m / z 552.24 (M + H)⁺.

B) 1- (4- (2-Amino-3- (3-aminoprop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0690] The title compound was obtained from tert-butyl 3- (2-amino-4- (2-fluoro-4- (3- (2- (4-fluorophenyl) acetyl) ureido) phenoxy) pyridin-3-yl) prop-2 -ynylcarbamate in 65% yield in the same manner as step E of example 11. ¹H NMR (DMSO-d6) δ 11.05 (s,

1H), 10.61 (s, 1H), 8.48 (br s, 3H), 7.90 (d, 1H, J = 6.6 Hz), 7.84-7.76 (m, 2H) , 7.45-7.39 (m,

- 201 1H), 7.39-7.32 (m, 3H), 7.20-7.13 (m, 2H), 6.11 (d, 1H, J = 6.1 Hz), 4.09 -4.03 (m, 2H), 3.74 (s, 2H); MS (ESI⁺): m / z 452.12 (M + H)⁺.

Example 139

<img file="PL1737451T3_D0390.tif" />

1- (4- (2-Amino-3- (3-hydroxyprop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

<img file="PL1737451T3_D0391.tif" />

A) 3- (2-Amino-4- (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol [0693] The title compound was obtained from propargyl alcohol (Aldrich) and 4- (2-fluoro-4-nitrophenoxy) -3-iodo-pyridin-2-amine (Compound C of Example 34) with 46% in the same manner as step A of Example 36. ¹H NMR (DMSO-d6) δ 8.40-8.34 (m, 1H), 8.13 (d, 1H, J = 8.6 Hz), 7.88 (d, 1H, J = 5.6 Hz), 7.42 (t, 1H, J = 8.6 Hz), 6.49 (s, 2H), 6.14 (d, 1H, J = 6.1 Hz),

<img file="PL1737451T3_D0392.tif" />

B) 3- (2-Amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-yn-1-ol [0694] The title compound was obtained from 3- (2-amino-4 - (2-fluoro-4-nitrophenoxy) pyridin-3-yl) prop-2-yn-1-ol in 65% yield. MS (ESI⁺): m / z 274.21 (M + H)⁺.

C) 1- (4- (2-Amino-3- (3-hydroxyprop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt

[0695] The title compound was obtained in 3- (2-amino-4- (4-amino-2-fluorophenoxy) pyridin-3-yl) prop-2-yn-1-ol in 48% yield. ¹H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.60 (s, 1H), 7.86 (d, 1H, J = 7.1 Hz), 7.83-7.77 ( m, 1H), 7.44-7.37 (m, 2H), 7.37-7.32 (m, 3H), 7.20-7.13 (m, 2H), 6.14 (d , J = 6.6 Hz, 1H), 4.37 (s, 2H), 3.74 (s, 2H); MS (ESI⁺): m / z 453.28 (M + H)⁺.

Example 140

<img file="PL1737451T3_D0393.tif" />

N- (4- (2-Amino-3- (3- (dimethylamino) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -1- (4-fluorophenyl) -2-oxo-1,2 dihydropyridine-3-carboxamide dihydrochloride salt

<img file="PL1737451T3_D0394.tif" />

A) 3- (3- (Dimethylamino) prop-1-ynyl) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine [0698] The title compound was obtained from 1-dimethylamin-2-propyn (Aldrich) and 4- (2-fluoro-4-nitrophenoxy) -3-iodo-pyridin-2-amine (Compound C of example 34) in 64% yield in the same manner as step A of example 42. ¹H NMR (DMSO-d6) δ 8.36 (dd, 1H, J = 10.7, 2.5 Hz),

8.11 (d, 1H, J = 8.6 Hz), 7.93 (d, 1H, J = 5.6 Hz), 7.30 (t, 1H, J = 8.6 Hz), 6, 43 (br s, 2H),

6.28 (d, 1H, J = 6.1 Hz), 3.41 (s, 2H), 2.05 (s, 6H); MS (FSI⁺): m / z 331.28 (M + H)⁺.

<img file="PL1737451T3_D0395.tif" />

B) 4- (4-Amino-2-fluorophenoxy) -3- (3- (dimethylamino) prop-1-ynyl) pyridin-2-amine [0699] The title compound was obtained from 3- (3- (dimethylamino) prop- 1-ynyl) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine in 77% yield in the same manner as step C of example

11. MS (ESI⁺): m / z 301.30 (M + H)⁺.

- 203 C) N- (4- (2-Amino-3- (3- (dimethylamino) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) 1- (4-fluorophenyl) -2-oxo -1,2-dihydropyridine-3-carboxamide, dihydrochloride salt [0700] The title compound was obtained from 4- (4-amino-2-fluorophenoxy) -3- (3- (dimethylamino) prop-1-ynyl) pyridine-2- amine and 1- (4-fluoro-phenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (Compound B from Example 101) in the same manner as Example 62 in 71% yield. ¹H NMR (DMSO-d6) δ 12.14 (s, 1H), 11.39 (s, 1H), 8.60-8.53 (m, 1H), 8.33 (s, 1H), 8 , 14 (dd, 1H, J = 6.6, 2.2 Hz), 8.05 (dd, 1H, J = 12.7, 2.2 Hz), 7.98 (d, 1H, J = 7 , 0 Hz), 7.61 (d, 1H, J = 5.3 Hz), 7.58 (d, 1H, J = 4.8 Hz), 7.56-7.50 (m, 1H), 7.37-7.47 (m, 3H), 6.766.69 (m, 1H), 6.30 (d, 1H, J = 7.0 Hz), 4.39 (s, 2H), 2.84 (s, 6H); MS (ESI⁺): m / z 480.28 (M + H)⁺.

Example 141

<img file="PL1737451T3_D0396.tif" />

1- (4- (2-Amino-3- (3- (dimethylamino) prop-1-ynyl) pyridin-4-yloxy) -3-fluorophenyl) -3- (2- (4-fluorophenyl) acetyl) urea, dihydrochloride salt [0702] The title compound was obtained from 4- (4-amino-2-fluorophenoxy) -3- (3- (dimethylamino) prop-1-ynyl) pyridin-2-amine in a similar manner to step E of Example 11 of 70 % efficiency. ¹H NMR (DMSO-d6) δ 11.46 (br s, 1H), 11.07 (s, 1H), 10.64 (s, 1H), 8.37 br (s, 1H), 7.98 ( t, 1H, J = 7.5 Hz), 7.81 (d, 1H, J = 13.6 Hz), 7.43-7.32 (m, 4H), 7.207.09 (m, 2H), 6.27 (d, 1H, J = 7.0 Hz), 4.38 (s, 2H), 3.75 (s, 2H), 2.84 (s, 6H); MS (ESI⁺): m / z

516.31 (M + H)⁺.

Example 142

<img file="PL1737451T3_D0397.tif" />

1- (4- (2-Aminopyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0704]

- 204 -

<img file="PL1737451T3_D0398.tif" />

A) 4- (4-Aminophenoxy) picolinamide [0705] The title compound was prepared in a similar manner to that described in Step B 'of Example 24, starting from 4-aminophenol. Yield: 85%. MS (ESI⁺) m / z 230 (M + H)⁺.

<img file="PL1737451T3_D0399.tif" />

B) 1- (4- (2-Carbamoylpyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea [0706] The title compound was prepared in a similar manner to that described in Step C 'of Example

24. Yield: 95%. MS (ESI⁺) m / z 409 (M + H)⁺.

C) 1- (4- (2-Aminopyridin-4-yloxy) phenyl) -3- (2- (4-fluorophenyl) acetyl) urea, hydrochloride salt [0707] The title compound was obtained in a similar manner to that described in step D 'from example 24. Yield: 58%. ¹H NMR (DMSO-d6) δ 12.86 (s, 1H), 10.97 (s, 1H), 10.51 (s, 1H), 7.91 (d, 1H, J = 6.0 Hz) , 7.67 (d, 3H, J = 9.0 Hz), 7.34 (dd, 2H, J = 9.0, 5.0 Hz), 7.21 (d, 2H, J = 9.0 Hz), 7.16 (t, 2H, J = 9.0 Hz), 6.63 (dd, 1H, J = 9.5, 2.0 Hz), 6.05 (d, 1H, J = 2 , 0 Hz), 3.73 (s, 2H); MS (ESI⁺) m / z 381 (M + H)⁺.

Example 143

<img file="PL1737451T3_D0400.tif" />

1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (3-hydroxyphenyl) acetyl) urea [0709]

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<img file="PL1737451T3_D0401.tif" />

A) 2- (3- (Benzyloxy) phenyl) acetic acid [0710] To a solution of 3-hydroxyphenylacetic acid (Acros, 3.04 g, 20 mmol) in 20 ml DMF was added K2CO3 (6.90 g, 50 mmol) and benzyl bromide (4.75 mL, 40 mmol) at room temperature. The reaction mixture was stirred for 24 h. The suspension was filtered and washed with diethyl ether. The filtrate was then washed with brine and dried over MgSO4. Filtration followed by concentration provided crude benzyl 2- (3- (benzyloxy) phenylacetate which was used in the next step MS (ESI⁺) m / z 355 (M + Na)⁺.

[0711] Crude benzyl 2- (3- (benzyloxy) phenylacetate was dissolved in a mixture of MeOH (20 mL) and THF (50 mL). To this solution was added 40 mL of 1N NaOH (40 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo The remaining aqueous solution was extracted with diethyl ether (2 x 50 mL) The aqueous solution was then acidified with 1N HCl (50 mL) and the title compound precipitated. The solid was filtered off (4.35 g, 90% two stages) MS (ESI⁺) m / z 265 (M + Na)⁺.

<img file="PL1737451T3_D0402.tif" />

B) 2- (3- (Benzyloxy) phenyl) acetyl isocyanate [0712] To a solution of 2- (3- (benzyloxy) phenylacetic acid (484 mg, 2.0 mmol) in DCM (10 ml) at room temperature was added 1 drop of DMF and thionyl chloride (0.30 mL, 4 mmol) The reaction mixture was stirred at room temperature for 1 h and then at 50 ° C for 0.5 h. The mixture was cooled and the solvent removed in vacuo. The residue was dissolved in 5 mL toluene and AgOCN was added (600 mg, 4.0 mmol). The suspension was stirred for 0.5 h and filtered to give a solution of 2- (3- (benzyloxy) phenyl) acetyl isocyanate in toluene (0.40 M).

<img file="PL1737451T3_D0403.tif" />

C) 1- (2- (3- (Benzyloxy) phenyl) acetyl) -3- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenyl) urea [0713] The title compound was obtained in a similar manner to that described in step C 'of the example

24, using the solution of Step B of this Example. Yield: 63%. MS (ESI⁺) m / z 515 (M + H)⁺.

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<img file="PL1737451T3_D0404.tif" />

Η₂Ν Ν

D) 1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (3- (benzyloxy) phenyl) acetyl) urea [0714] The title compound was obtained in a similar manner to that described in step D 'of example 24. Yield: 61%. MS (ESI⁺) m / z 487 (M + H)⁺.

E) 1- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -3- (2- (3-hydroxyphenyl) acetyl) urea [0715] To a solution of 1- (4- (2-aminopyridine) 4-yloxy) -3-fluorophenyl) -3- (2- (3- (benzyloxy) phenyl) acetyl) urea (150 mg, 0.31 mmol) in a mixture of 5 ml EtOAc and 3 ml MeOH 10% Pd / C (200 mg). The suspension was stirred under H2 atmosphere for 1 h. Filtration, then concentration, provided the title compound (77 mg, 63%).¹H NMR (DMSO-d6) δ

<img file="PL1737451T3_D0405.tif" />

Example 144 [0716]

<img file="PL1737451T3_D0406.tif" />

η₂ν ν

3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (2- (4-fluorophenyl) acetyl) -1-methyl urea, hydrochloride salt [0717]

ΗΝ

A) 2- (4-Fluoro-phenyl) -N-methyl-acetamide [0718] To a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) was added 4-fluoro-phenylacetyl chloride (518 mg, 3.0 mmol) at -78 ° C . The reaction mixture was stirred from -78 ° C

- 207 to room temperature over 1 h. The solution was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtration followed by concentration provided the title compound (490 mg, 98%). MS (ESI⁺) m / z 168 (M + H)⁺.

<img file="PL1737451T3_D0407.tif" />

B) 3- (4- (2-Carbamoylpyridin-4-yloxy) -3-fluorophenyl) -1- (2- (4-fluorophenyl) acetyl) -1-methyl urea [0719] For 2- (4-fluorophenyl) -N solution -methylacetamide (89 mg, 0.53 mmol) in 2 mL THF at -78 ° C was added MeLi in Et 2 O (1.6 M, 0.34 mL, 0.55 mmol). The solution was stirred at -78 ° C for 5 min and then 20% phosgene in toluene (1.9 M, 0.29 mL, 0.55 mmol) was quickly introduced. After 2 min, 4- (4-amino-2-fluorophenoxy) picolinamide (Compound B 'from Example 24, 100 mg, 0.40 mmol) was added, then DMF (2 mL) and DIEA (0.4 mL) were added. The reaction mixture was stirred at room temperature for 1 h and quenched with H2O. The solution was then extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the title compound (77 mg, 33%). MS (ESI⁺) m / z 441 (M + H)⁺.

C) 3- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1- (2- (4-fluorophenyl) acetyl) -1-methylurea, hydrochloride salt [0720] The title compound was obtained in a similar manner to the one described in step D 'of the example

24. Yield: 24%. ¹H NMR (DMSO-d6) δ 13.20 (s, 1H), 11.17 (s, 1H), 7.90 (d, 1H, J = 7.0 Hz), 7.78-7.74 ( m, 3H), 7.39-7.34 (m, 2H), 7.23-7.21 (m, 2H), 7.10-7.05 (m, 2H), 6.63 (dd, 1H, J = 7.0, 2.0 Hz), 6.08 (d, 1H, J = 2.0 Hz), 4.00 (s, 2H), 3.24 (s, 3H); MS (ESI⁺) m / z 413 (M + H)⁺.

Example 145

<img file="PL1737451T3_D0408.tif" />

(R) -N - (2-Amino-2-oxo-1-phenylethyl) -N - (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenyl) malonamide, trifluoroacetic acid salt [0722]

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<img file="PL1737451T3_D0409.tif" />

A) Ethyl 3- (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropionate Ethyl 3- (4- (2-carbamoylpyridin-4-yloxy) -2,5 -difluorophenylamino) -3-oxopropionate (Compound A from Example 116, 0.73 g, 1.9 mmol) was converted to the title compound (0.24 g, 35%) in a manner similar to the preparation of Compound E from Example 112. MS ( ESI⁺) mlz 352 (M + H)⁺.

<img file="PL1737451T3_D0410.tif" />

B) 3- (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropanoic acid [0724] Ethyl 3- (4- (2-aminopyridin-4-yloxy) -2.5 -difluorophenylamino) -3-oxopropionate (0.24 g, 0.68 mmol) was converted to the title compound (0.039 mg, 18%) in a manner similar to the preparation of compound B from example 116, HRMS (ESI⁺), Calculated: 324.0796 (M + H)⁺found: 324.0795 (M + H)⁺.

<img file="PL1737451T3_D0411.tif" />

C) (R) -N¹- (2-Amino-2-oxo-1-phenylethyl) -N³- (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenyl) malonamide trifluoroacetic acid salt [0725] 3- (4- (2-aminopyridin-4-yloxy) -2,5-difluorophenylamino) -3-oxopropane (0.039 g, 0.12 mmol) was coupled with (R) -2-amino-2-phenylacetamide hydrochloride (Bachem, 0.023 g, 0.12 mmol) in a similar manner to that of Example 103 to give compound title (0.0048 g, 7%). ¹H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.77 (d, 1H, J = 7.8 Hz), 8.10-8.19 (m, 1H), 7.90 ( d, 1H, J = 7.2 Hz), 7.60-7.75 (m, 4H), 7.17-7.39 (m, 6H), 6.66-6.69 (m, 1H) , 6.11 (s, 1H), 5.35 (d, 1H, J = 7.8 Hz); ERMS (ESI⁺), Calculated: 456.1483 (M + H)⁺, found: 456.1487 (M + H)⁺.

Example 146

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<img file="PL1737451T3_D0412.tif" />

N- (4- (2-Aminopyridin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0727]

<img file="PL1737451T3_D0413.tif" />

A) 4- (4- (2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido) phenoxy) picolinamide 4- (4-Aminophenoxy) picolinamide (Compound A of Example 142, 0.030 g, 0.13 mmol) was coupled with Compound C of Example 57 (0.028 g, 0.13 mmol) in a similar manner to the preparation of Compound A of Example 115 to afford the title compound (0.057 g, 100%) which was used without further purification. MS (ESI⁺) m / z 427 (M + H)⁺.

<img file="PL1737451T3_D0414.tif" />

B) N- (4- (2-Aminopyridin-4-yloxy) phenyl) -2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0729] 4- (4- (2- Oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido) phenoxy) picolinamide (0.055, 0.13 mmol) was converted to the title compound (0.0093 g, 16%) in a manner similar to the preparation of compound E from example 112 . ¹H NMR (CD3OD δ 12.10 (s, 1H), 8.59-8.61 (m, 1H), 7.88-7.90 (m, 1H), 7.69-7.76 (m, 3H), 7.39-7.53 (m, 5H), 7.10-7.13 (m, 2H), 6.66 (t, 1H, J = 6.9 Hz), 6.53-6 , 55 (m, 1H), 6.07-6.08 (m, 1H), 4.75 (br s, 2H); HRMS (ESI⁺), Obl,: 399.1457 (M + H)⁺, found: 399.1453 (M + H)⁺.

- 210 Example 147 [0730]

<img file="PL1737451T3_D0415.tif" />

N- (4- (2-Aminopyridin-4-yloxy) -3-fluorophenyl) -1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt

<img file="PL1737451T3_D0416.tif" />

A) Methyl 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylate [0732] A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.0 g, 13 mmol, 1, 0 eq) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 3h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq.) And DMAP (0.11 g, 9.91 mmol, 0.07 eq.) At room temperature and the resulting solution was stirred for 12 h. The reaction was quenched by adding 1N aqueous HCl to the reaction mixture, and the solution was extracted with ethyl acetate (4 x 50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3 x 70 mL), dried (Na2SO4) filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid which was used without further purification.¹H NMR (DMSO-d6) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H), 7.16 -7.22 (m, 2H), 6.37 (dd, 1H, J = 6.94 Hz),

5.13 (s, 2H), 3.73 (s, 3H); HRMS (ESI⁺), Calcd .: 262.0879, found: 262.0885.

<img file="PL1737451T3_D0417.tif" />

B) 1-Benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [0733] ​​Solution of methyl 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylate (2.4 g,

9.2 mmol, 1.0 equiv.) In MeOH (25 ml) was treated with 5N aqueous sodium hydroxide (4.6 ml, 24 mmol, 2.6 equiv.) At room temperature and the reaction mixture was stirred

- 211 for 15 h. The reaction mixture was then concentrated in vacuo, diluted with water and the solution extracted with ethyl acetate, discarding the organic fraction. The aqueous fraction was cooled to 0 ° C and acidified with concentrated HCl. The resulting solid was filtered, washed with water and the solid was dried in vacuo to give the product (1.6 g, 70%) which was used without further purification.¹H NMR (DMSO-d6) δ 8.39-8.44 (m, 2H), 7.42-7.46 (m, 2H), 7.18-7.24 (m, 2H), 6.78 (dd, 1H, J = 6.98 Hz), 5.31 (s, 2H); HRMS (ESI⁺), Obl,: 248.0723, found: 248.0718.

<img file="PL1737451T3_D0418.tif" />

C) 4- (4- (1-Benzyl-2-oxo-1,2-dihydropyridine-3-carboxamido) -2-fluorophenoxy) picolinamide [0734] Homogeneous solution of 1-benzyl-2-oxo-1,2-acid dihydropyridine-3-carboxylic acid (0.10 g, 0.41 mmol, 1.0 eq), 4- (4-amino-2-fluorophenoxy) picolinamide (0.10 g, 0.41 mmol, 1.0 eq. .) and TBTU (0.17 g, 0.45 mmol, 1.1 eq.) in DMF (2 mL) were treated with DIPEA (0.18 mL, 1.0 mmol, 2.5 eq.) at room temperature and the reaction mixture was stirred for 12 h. The reaction was quenched with 10% aqueous LiCl (15 mL) and the resulting solution was extracted with ethyl acetate (4 x 40 mL). The combined organic extracts were washed with 10% aqueous LiCl (4 x 50 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, eluting with ethyl acetate) to give the product (0.13 g, 67%) as a solid.¹H NMR (DMSO-d6) δ 12.26 (s, 1H), 8.49-8.56 (m, 2H), 8.33-8.36 (m, 1H), 8.15 (br m, 1H), 8.03-8.07 (m, 1H), 7.74-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.46 ( m, 4H), 7.20-7.24 (m, 3H), 6.71 (dd, 1H, J = 6.89 Hz), 5.32 (s, 2H) HRMS (ESI⁺), Obl,: 477.1374, found: 477.1378.

D) N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) -1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt [0735] Bis (trifluoroacetoxy) iodobenzene (0.12 g, 0.28 mmol, 1.1 equiv) was added to the solution

4- (4- (1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamido) -2-fluorophenoxy) picolinamide (0.12 g, 0.26 mmol, 1.0 eq), and water (0.01 ml, 0.51 mmol, 20 eq) in DMF (1 ml) at room temperature. Pyridine (0.065 mL, 0.77 mmol, 3.0 eq) was added to the homogeneous mixture and the reaction mixture was stirred at room temperature for 12 h. The reaction was quenched by adding 1N aqueous HCl (1 mL) to the reaction mixture, and the resulting solution was extracted with diethyl ether (3 x 5 mL), discarding the organic layer. The aqueous fraction was neutralized with 1N aqueous NaOH and the resulting solution was extracted with 9/1 CHCl3 / MeOH (4 x 10 mL). The combined organic extracts were dried

212 (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with 0-3% MeOH in CHCl3) and the appropriate fractions concentrated in vacuo. The free base was dissolved in THF, cooled to 0 ° C, and the homogeneous solution was treated with anhydrous 4N HCl in dioxane. The reaction mixture was warmed to room temperature, concentrated in vacuo and the residue was triturated with diethyl ether, discarding the filtrate. The solid was dried in vacuo to give the title compound (0.082 g, 66%) as a HCl salt, ¹H NMR (DMSO-d6) δ 13.66 (br s, 1H), 8.49-8.51 (m, 1H), 8.39-8.49 (m, 1H), 8.37-8, 39 (m, 1H), 8.00-8.09 (m, 3H), 7.54-7.56 (m, 1H), 7.43-7.48 (m, 3H), 7.197.24 ( m, 2H), 6.69-6.72 (m, 2H), 6.21-6.22 (m, 1H), 5.32 (s, 2H); HRMS (ESI⁺), Calculated: 449.1425, found: 449.1406.

Example 148

<img file="PL1737451T3_D0419.tif" />

N- (4-fluorobenzyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) cyclopropane-1,1-dicarboxamide

<img file="PL1737451T3_D0420.tif" />

A) 1- ((4-Fluorobenzyl) carbamoyl) cyclopropane carboxylic acid [0738] To a solution of 1,1-cyclopropane carboxylic acid (Aldrich, 390 mg, 3.0 mmol) in THF (5 mL) at 0 ° C triethylamine (0.42 mL, 3.0 mmol) was added. After stirring for 30 min at 0 ° C, thionyl chloride (0.219 mL, 3.0 mmol) was added to the reaction mixture. The mixture was stirred at 0 ° C for an additional 30 min and a solution of 4-fluorobenzylamine (Aldrich, 375 mg, 3.0 mmol) in THF (2 mL) was added. The reaction mixture was stirred at 0 ° C for 2 h, diluted with ethyl acetate (100 mL) and extracted with 1N NaOH (10 mL). The aqueous layer was acidified with 1 N HCl to pH 1-2. The solid that formed was filtered off (343 mg, 48%). MS (ESI⁺) m / z 238.24 (M + H)⁺.

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<img file="PL1737451T3_D0421.tif" />

B) N- (4-Fluorobenzyl) -N- (4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenyl) cyclopropane-1,1-dicarboxamide [0739] For 4- (4-amino-2- solution) fluorophenoxy) picolinamide (Compound B 'from Example 24, 49 mg, 0; 2 mmol) in DMF (2 mL) at room temperature added 1 - ((4-fluorobenzyl) carbamoyl) cyclopropane carboxylic acid (47 mg, 0.2 mmol), HATU (Perseptive Biosystem, 114 mg, 0.3 mmol), and DIEA (0.2 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 2 h, and then quenched by the addition of 4 mL methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aqueous K2HPO4 and concentrated in vacuo. The solid that formed was filtered off (29 mg, 31%).¹H NMR (DMSO-d6) δ 10.78 (br s, 1H), 8.53 (d, 1H, J = 5.5 Hz), 8.47 (t, 1H, J = 5.5 Hz), 8.11 (s, 1H), 7.88 (dd, 1H, J = 13.2, 2.3 Hz), 7.70 (s, 1H), 7.47 (d, 1H, J = 9, 2 Hz), 7.38 (t, 1H, J = 9.2 Hz), 7.34-7.29 (m, 3H), 7.22 (dd, 1H, J = 5.5, 2.8 Hz), 7.13 (t, 2H, J = 8.8 Hz), 4.30 (d, 2H, J = 5.5 Hz), 1.37 (d, 4H, J = 10.6 Hz) ; MS (ESI⁺) m / z 467.12 (M + H)⁺.

C) N- (4-Fluorobenzyl) -N- (4- (2-aminopyridin-4-yloxy) -3-fluorophenyl) cyclopropane-1,1-dicarboxamide [0740] To the N- (4-fluorobenzyl) -N- ( 4- (2-carbamoylpyridin-4-yloxy) -3-fluorophenyl) cyclopropane-1,1-dicarboxamide (25 mg, 0.05 mmol) in DMF (1 ml) at room temperature pyridine (0.2 ml) was added, water (0.1 ml), and [bis (trifluoroacetoxyl) iodo] benzene (Aldrich, 34 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 2 h, and then the reaction was quenched with 2 mL methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aqueous K2HPO4, concentrated and extracted with ethyl acetate. The organic extracts were dried over MgSO 4 and concentrated in vacuo. The residue was dissolved with a small amount of CH3CN / H2O and lyophilized to dryness to give the title compound (21 mg, 90%) as a white solid.¹H NMR (DMSO-d6) δ 10.87 (br s, 1H), 8.44 (t, 1H, J = 6.0 Hz), 7.91 (d, 1H, J = 6.6 Hz), 7.88 (d, 1H, J = 13.2 Hz), 7.37-7.29 (m, 6H), 7.13 (t, 2H, J = 8.8 Hz), 4.29 (d , 2H, J = 6.1 Hz),

1.38 (d, 4H, J = 2.2 Hz); MS (ESI⁺) m / z 439.14 (M + H)⁺.

Prepared and verified

Danuta Stefani-Iwanow Patent Attorney

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