DESCRIPTION

NOVEL PYRIMIDINE DERIVATIVE FOR INHIBITING THE GROWTH OF

CANCER CELLS FIELD OF THE INVENTION

The present invention relates to a novel pyrimidine derivative or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same as an active ingredient.

BACKGROUND OF THE INVENTION

Multiple signal transduction systems in cells which are functionally linked to each other control the proliferation, growth and apoptosis of cells via complex mechanisms (William G. Kaelin Jr, Nature Reviews Cancer 5, 689, 2005). The breakdown of the intracellular control system by genetic and environmental factors causes abnormal amplification or destruction of the signal transduction system, leading to the tumor cell generation (Douglas Hanahan and Robert A. Weinberg, Cell 100, 57, 2000).

Protein tyrosine kinases play important roles in such intracellular signal transduction (Irena Melnikova and James Golden, Nature Reviews Drug Discovery 3, 993, 2004), and their abnormal expression or mutation has been observed in cancer cells. The protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on protein substrates. Many growth factor receptor proteins transport cellular signals through tyrosine kinases. The interaction between growth factors and their receptors normally controls the cell growth, but abnormal signal transduction caused by the mutation or overexpression of the receptors often induces tumor cells and cancers.

With regard to the roles of these protein tyrosine kinases, various growth factors and their receptors, in particular, epithelial cell growth factor (EGF) and EGF receptor (EGFR) tyrosine kinase have been intensely studied (Nancy E. Hynes and Heidi A. Lane, Nature Reviews Cancer 5, 341, 2005). An EGFR tyrosine kinase is composed of a receptor and a tyrosine kinase, and delivers extracellular signals into a cell through the cell membrane. Various EGFR tyrosine kinases are classified based on their structural differences into EGFR (Erb-Bl), Erb-B2, Erb-B3 and Erb-B4, each of which can form a homodimer- or heterodimer-signal delivery complex.

Gefitinib is the first developed small-molecule EGFR tyrosine kinase inhibitor, which selectively and reversibly inhibits an EGFR subtype (Erb-Bl). Another drug for targeting EGFR, Erlotinib, provides therapeutic advantages for the treatment of non-small cell lung carcinoma (NSCLC).

It has been reported that about 50% of the patients administered with Gefinitib or Erlotinib shows a secondary mutation such as EGFR T790M mutation, resulting in resistance to these drugs (William Pao et al., Public Library of Science Medicine, 2(3), 225, 2005; and Jeffrey A. Engelman et al., Cancer Res, 67(24), 11924, 2007).

Recently, it has been found that irreversible inhibitors to target EGFRs are more advantageous in overcoming the problem of resistance development, as compared to the conventional reversible inhibitors such as Gefitinib and Erlotinib (Danan Li et al., Cancer Cell 12, 81, 2007; and Anja Michalczyk et al., Bioorganic & Medicinal Chemistry 16, 3482, 2008). For example, irreversible inhibitors such as BIBW-2992(C H Mom et al., British Journal of Cancer 98, 80, 2007), HKI- 272(Sridhar K. Rabindran, et al., Cancer Research 64, 3958, 2004) and AV- 412(Tsuyoshi Suzuki et al., Cancer Sci. 98(12), 1977, 2007) are currently in clinical trial phases. The structures of the irreversible inhibitors are shown below:

The compounds shown above share a common structural feature of an acrylamide group at the position C-6 of the quinazoline or cyanoquinoline residue, which form a covalent bond with Cystein773 (Cys773) positioned at an ATP domain of EGFR, thereby irreversibly blocking the autophosphorylation of EGFR and efficiently inhibiting the signal transduction of cancer cells (David W. Fry et al., Proc. Natl. Acad. Sci. U.S.A. 95, 12022, 1998). They exhibit higher in vitro and in vivo inhibitory activities as compared with the conventional reversible inhibitors (Jeff B. Smaill et al., J. Med. Chem. 42, 1803, 1999). However, these drugs are still less effective against drug resistant cancers.

Accordingly, there has been a continued need to develop a novel drug that is effective against drug resistant cancers without causing adverse side effects.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide a novel compound which selectively and effectively inhibits the growth of cancer cells and the drug resistance induced by an epidermal growth factor receptor (EGFR) and the mutation thereof, having reduced adverse side effects.

It is another object of the present invention to provide a pharmaceutical composition for inhibiting the growth of cancer cells, comprising said compound as an active ingredient.

In accordance with one aspect of the present invention, there is provided a novel pyrimidine derivative.

In accordance with another aspect of the present invention, there is provided a pharmaceutical composition for inhibiting the growth of cancer cells, comprising said compound as an active ingredient.

The inventive pyrimidine derivative may selectively and effectively inhibit the growth of cancer cells induced by the overexpression of an epidermal growth factor receptor (EGFR) and the drug resistance induced by the mutation of EGFR tyrosine kinase.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pyrimidine derivative or pharmaceutically acceptable salt thereof:

wherein,

X is or , X _t being N, CH or CH ₂ and X ₂ being N or CH;

Z is an aryl or heterocyclic group substituted with one to five A, or Ci _-6 alkyl substituted with aryl;

n _a and n _b are each an integer ranging from 0 to 6, in which when both n _a and i¾

are 0, is -X-CH ₂ -NH-R, when n _a is 0, is -X-CH ₂ -

(CH ₂ )n _b -NH-R, and when ι¼ is 0, is -X-CH ₂ -N(CH ₂ )n

the symbol '— ' indicates a bond which can exist when n _a and n _b are each an integer other than 0; and

R is or j Ri, ¾ and R ₃ being each independently hydrogen or C _1-3 alkyl substituted with B, R4 being hydroxy or Cj _-6 alkoxy group, and ¾ being an integer ranging from 1 to 6;

A is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkyl substituted with aryl, C _1-6 alkyloxy substituted with aryl or heterocyclic group, aryloxy, heterocyclyloxy, or heterocyclylthio;

B is hydroxy, S-Ci^alkylsulfonyl, heterocyclic group, amino, or amino substituted with C _1-6 dialkyl, C-C _1-6 alkylcarbonyl or 5-C _1-6 alkylsulfonyl; aryl is C _5-12 monocyclic or bicyclic aromatic group; and

said heterocyclic group is C _5- i2 monocyclic or bicyclic aromatic or non- aromatic group containing one to four moieties selected from the group consisting of N, O, S, SO, and S0 ₂ ; said aryl and heterocyclic group being unsubstituted, or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, C^aU yl, trihalogenoCi _-6 alkyl, C _2- 6alkenyl, C _2-6 alkynyl, Q. ₆ alkoxy, Ci _-6 monoalkylamino and Ci-edialkylamino.

Hereinafter, the present invention is described in detail.

In a preferred embodiment of the present invention, X is

Y is H, NH ₂ or N(C=0)CH ₃ ;

Z is phenyl, phenyl Q-ealkyl, or fluorobenzylindazole containing one to three substituents selected from the group consisting of halogen, fluorobenzyloxy, pyridinylmethoxy, phenoxy, chlorophenoxy, dichlorophenoxy, fluorophenoxy, pyridinyloxy, methylpyridinyloxy, memylimidazolthio, methylpyrazolyloxy and 1- methyl-3-trifluoromethyl pyrazolyloxy;

n _a and ¾ are each independently an integer ranging from 0 to 3;

R is or , Ri, R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, dimethylaminomethyl, diemylaminomethyl, hydroxymethyl, morpholinomethyl, pyrrolidin-l-ylmethyl, 4- methylpiperazin-l-ylmethyl, methylsulfonylmethyl, aminomethyl, acetamidomethyl and methylsulfonamidomethyl, R4 is hydroxy or methoxy; ¾ is an integer ranging from 1 to 3.

More preferred pyrimidine derivative of formula (I) is a compound in which Z is 3-chloro-4-fluorophenyl, 3,4-dichloro-2-fluorophenyl, 4-bromo-3-chloro-2- fluorophenyl, 4-fluoro-3-methylphenyl, RJ-l-phenylethyl, 3-chloro-4-(3- fluorobenzyloxy)phenyl, 3 -chloro-4-(pyridin-2-ylmethoxy)phenyl, 2-fluoro-4-(pyridin- 2-ylmethoxy)phenyl, 3-fluoro-4-(pyridin-2-ylmethoxy)phenyl, 1 -(3-fluorobenzyl)- 1H- 5-indazole, 3-chloro-4-phenoxyphenyl, 3-chloro-4-(2,3-dichlorophenoxy)phenyl, 3- chloro-4-(2,4-dichlorophenoxy)phenyl, 3-chloro-4-(2,5-dichlorophenoxy)phenyl, 3- chloro-4-(2-fluorophenoxy)phenyl, 3 -chloro-4-(3 -fluorophenoxy)phenyl, 3 -chloro-4- (4-fluorophenoxy)phenyl, 3-chloro-4-(pyridin-2-yloxy)phenyl, 3-chloro-4-(pyridin-3- yloxy)phenyl, 3-methyl-4-(6-methylpyridin-3-yloxy)phenyI, 3-chIoro-4-(6- methylpyridin-3 -yloxy)phenyl, 3 -chloro-4-( 1 -methyl- lH-imidazol-2-ylthio)phenyl, 3 - chloro-4-( 1 -methyl- 1 H-pyrazol-5-yloxy)phenyl, or 3 -chloro-4-( 1 -methyl-3 - (trifluoromethyl)-lH-pyrazol-5-yloxy)phenyl.

The term ¾alogen' used herein refers to fluoro, chloro, bromo, or iodo, unless otherwise indicated.

The term 'alkyl ¹ used herein refers to saturated monovalent hydrocarbons having straight, cyclic or branched moieties, unless otherwise indicated.

Examples of more preferred compounds of formula (I) according to the present invention are:

1 ) N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylammo)pyriniidin-5-yl)oxazol-4-yl)methyl)acryl amide;

2) N-((2-(4-amino-6-(3 -chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimidin-5-yl)-4,5-dihydrooxazol-4-yl) memyl)acrylamide;

3) N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylammo)pyrirnidin-5-yl)oxazol-4-yl)methyl)-2- ((dimethylamino)methyl)acrylamide;

4) E -N-((2-(4-amino-6-(3 -chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)-4-(d imethylamino)but-2- enamide;

5) N-((2-(4-amino-6-(3 -chloro-4-(pyridin-2- ylmethoxy)phenylarmno)pyrimidm-5-yl)oxazol-4-yl)memyl)-2-hyd roxyacetamide;

6) N-((2-(4-amino-6-(3 -chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)-3-hy droxypropanamide;

7) N-((2-(4-amino-6-(2-fluoro-4-(pyridin-2- ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acry lamide;

8) N-((2-(4-amino-6-(3 -fluoro-4-(pyridin-2 ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acry lamide;

9) N-((2-(4-amino-6-(3-cMoro-4-(3-fluorobeiizyloxy)phenylamino) pyrimidin 5-yl)oxazol-4-yl)methyl)acrylamide;

10) N-((2-(4-amino-6-(3-chloro-4-(2,3 dic orophenoxy)phenylamino)pyrin^

11) N-((2-(4-amino-6-(3-chloro-4-(2,4 dic orophenoxy)phenylamino)pyrinndin-5-yl)oxazol-4-yl)methyl)acr ylamidp;

12) N-((2-(4-amino-6-(3-chloro-4-(2,5- dicWorophenoxy)phenylamino)pyrimidm^

13) N-((2-(4-amino-6-(3-c oro-4-phenoxyphenylan ino)pyrimidin-5- yl)oxazol-4-yl)methyl)acrylamide;

14) E^-N-((2-(4-amino-6-(3-chloro-4-phenoxyphenylamino)pyrimidin -5- yl)oxazol-4-yl)methyl)-4-(dimethylamino)but-2-enamide;

15) N-((2-(4-amino-6-(3-c oro-4-(2-fluorophenoxy)phenylamino)pyrimidin-5 yl)oxazol-4-yl)methyl)acrylamide;

16) N-((2-(4-amino-6-(3-cUoro-4-(3-fluorophenoxy)phenylaniino)py rimidin-5 yl)oxazol-4-yl)methyl)acrylamide;

17) N-((2-(4-amino-6-(3 -chloro-4-(3 -fluorophenoxy)phenylamino)pyrimidin-5 yl)oxazol-4-yl)methyl)acrylamide;

18) N-((2-(4-amino-6-(3-cMoro-4-(pyridin-2-yloxy)phenylamino)pyr imidin-5 yl)oxazol-4-yl)methyl)acrylamide;

19) N-((2-(4-amino-6-(3-cUoro-4-(pyridin-3-yloxy)phenylamino)pyr imidin- yl)oxazol-4-yl)methyl)acrylamide;

20) N-((2-(4-amino-6-(3-c oro-4-(2-fluorophenoxy)phenylamino)pyrimidin-5 yl)oxazol-4-yl)methyl)-2-hydroxyacetamide;

21) N-((2-(4-amino-6-(3 -chloro-4-(2-fluorophenoxy)phenylamino)pyrimidin-5 yl)oxazol-4-yl)methyl)-3-hydroxypropanamide;

22) N-((2-(4-amino-6-(3-chloro-4-(2-fluorophenoxy)phenylaniino)p yrimidin-5 yl)oxazol-4-yl)methyl)-3-methoxypropanamide;

23) N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3 yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylami de; 24) N-((2-(4-amino-6-(3 -methyl-4-(6-methylpyridin-3 yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)-2- ((dimethylamino)methyl)acrylamide;

25) (E -N-((2-(4-amino-6-(3-methyl-4-(6-rnethylpyridin-3 yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)-4-(dime thylamino)but-2- enamide;

26) N-((2-(4-amino-6-(3-chloro-4-(6-methylpyridin-3 yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)aciylami de;

27) N-((2-(4-amino-6-(3-chloro-4-(l -methyl- 1 H-imidazol-2 yltMo)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylami de;

28) N-((2-(4-amino-6-(3-chloro-4-(l-methyl-lH-pyrazol-5- yloxy)phenylainmo)pyrimidm-5-yl)oxazol-4-yl)memyl)acrylamide ;

29) N-((2-(4-amino-6-(3-chloro-4-(l -methyl-3-(trifluoromethyl)- 1 H-pyrazol-5 yloxy)phenylammo)pyrimidm-5-yl)oxazol-4-yl)methyl)acrylamide ;

30) N-((2-(4-amino-6-(3,4-dicUoro-2-fluorophenylaniino)pyrimidin -5 yl)oxazol-4-yl)methyl)acrylamide;

31) N-((2-(4-amino-6-(4-fluoro-3-methylphenylamino)pyrimidin-5-y l)oxazol- 4-yl)methyl)acrylamide;

32) N-((2-(4-ammo-6-(3-c oro-4-fluorophenylamino)pyrimidin-5-yl)oxazol-4- yl)methyl)acrylamide;

33) N-((2-(4-ammo-6-(3-cUoro-4-fluorophenylammo)pyrirnidin-5-yl) oxazol-4- yl)methyl)-2-((dimethylamino)methyl)acrylamide;

34) (E -N-((2-(4-amino-6-(3 -chloro-4-fluorophenylamino)pyrimidin-5- yl)oxazol-4-yl)methyl)-4-(dimethylamino)but-2-enamide;

35) N-((2-(4-(3-cUoro-4-(pyridm-2-ylmemoxy)phenylamino)pyrirmdin -5 yl)oxazol-4-yl)methyl)acrylamide;

36) N-((2-(4-(3 -cMoro-4-(pyridin-2-ylmemoxy)phenylammo)pyrimidin-5 yl)oxazol-4-yl)methyl)-2-((dimetliylamino)methyl)aa lamide;

37) N-((2-(4-acetamido-6-(3-chloro-4-(l-methyl-3-(trifluoromethy l)-lH- pyrazol-5-yloxy)phenylamino)pyrimidm-5-yl)oxazol-4-yl)methyl )acrylamide;

38) N-((2-(4-acetamido-6-(3 -chloro-4-(pyridin-2- ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acry lamide;

39) (E^-N-((2-(4-(3-cMoro-4-(pyridin-2-ylmemoxy)phenylamino)pyri midin-5 yl)oxazol-4-yl)methyl)-4-(dimethylamino)but-2-enamide;

40) N-((2-(4-(3,4-dicUoro-2-fluorophenylamino)pyrimidin-5-yl)oxa zol-4- yl)methyl)acrylamide;

41) N-((2-(4-(3-chloro-4-fluorophenylamino)pyrimidin-5-yl)oxazol -4- yl)methyl)acrylamide;

42) N-((2-(4-(3-cUoro-4-fluorophenylamino)pyridin-5-yl)oxazol-4- yl)methyl)- 2-((dimethylamino)methyl)acrylamide;

43) (E^-N-((2-(4-(3-cUoro-4-fluorophenylamino)pyrimidin-5-yl)oxa zol-4- yl)methyl)-4-(dimethylamino)but-2-enamide;

44) N-((5-(4-(3 -chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrimidin-5- yl)isooxazol-3-yl)methyl)acrylamide;

45) N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylaniino)pyrimid in-5- yl)isooxazol-3-yl)methyl)acrylamide;

46) N-(2-(5-(4-(3-cWoro-4-(3-fluorobenzyloxy)phenylamino)pyridin -5- yl)isooxazol-3-yl)ethyl)acrylamide;

47) 1 -(2-(5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)pyrin idin-5- yl)isooxazol-3-yl)pyrrolidin- 1 -yl)prop-2-en- 1 -one;

48) l-(3-(5-(4-(3-cUoro-4-(3-fluorobenzyloxy)phenylamino)pyrimid in-5- yl)isooxazol-3 -yl)piperidin- 1 -yl)prop-2-en- 1 -one;

49) 1 -(4-(5-(4-(3-cWoro-4-(3-fluorobenzyloxy)phenylamino)pyrimidi n-5- yl)isooxazol-3 -yl)piperidin- 1 -yl)prop-2-en- 1 -one;

50) N-((5-(4-(l -(3-fluorobenzyl)-l H-indazole-5-ylamino)pyrimidin-5- yl)isooxazol-3-yl)methyl)acrylamide;

51) N-((5-(4-(4-bromo-3-chloro-2-fluorophenylamino)pyrimidin-5- yl)isooxazol-3-yl)methyl)acrylamide;

52) K -N-((5-(4-(l-phenylethylamino)pyrimidin-5-yl)isooxazol-3- yl)methyl)acrylamide;

53) (E^-N-((5-(4-(3-c oro-4-(pyridin-2-yb iethoxy)phenylamino)pyrimi yl)isooxazol-3-yl)methyl)-4-(dimethylamino)but-2-enamide;

54) N-((5-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylannno)pyrimi din-5- yl)isooxazol-3-yl)methyl)-2-((dimethylamino)methyl)acrylamid e;

55) ^-N-((5-(4-(3-c oro-4-(3-fluorobenzyloxy)phenylamino)pyrimidin-5- yl)isooxazol-3-yl)methyl)-4-(dimethylamino)but-2-enamide; 56) ^-N-((5-(4-(3-cUoro-4-(pyridin-2-ylmemoxy)phenylamino)pyridi n-5- yl)isooxazol-3-yl)methyl)-4-hydroxybut-2-enamide;

57) N-((5-(4-(3-cMoro-4-(pyridin-2-ylmethoxy)phenylaniino)pyrimi din-5- yl)isooxazol-3-yl)methyl)-2-((diethylamino)methyl)acrylaniid e;

58) N-((5-(4-(3-c oro-4-(pyridm-2-ylmemoxy)phenylarmno)pyridin-5- yl)isooxazol-3-yl)memyl)-2-(pyrrolidin-l-ylmethyl)acrylamide ;

59) N-((5-(4-(3-cMoro-4-(pyridin-2-ylmemoxy)phenylam

yl)isooxazol-3-yl)memyl)-2-(morpholinomethyl)acrylamide;

60) N-((5-(4-(3 -c oro-4-(pyridin-2-ylmemoxy)phenylarmno)pyrimidin-5- yl)isooxazol-3-yl)memyl)-2-((4-memylpiperazin-l-yl)methyl)ac rylamide;

61) N-((5-(4-(3-cUoro-4-(pyridin-2-ylmemoxy)phenylamino)pyrimidi n-5- yl)isooxazol-3-yl)memyl)-2-(hydroxymethyl)acrylamide;

62) N-((5-(4-(3 -cUoro-4-(pyridin-2-ylmemoxy)phenylamino)pyrimidin-5 - yl)isooxazol-3-yl)memyl)-2-(memylsulfonylmemyl)aa larnide;

63) 2-(arnmomethyl)-N-((5-(4-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyiimidin-5-yl)isooxazol-3-yl)memyl)acr ylamid

64) 2-(acetamidomethyl)-N-((5-(4-(3-chloro-4-(pyridin-2- ylmemoxy)pheriylamino)pyrimidin-5-yl)isooxazol-3-yl)memyl)ac rylamid

65) N-((5-(4-(3-chloro-4-(pyridin-2-ylmemoxy)phenylamino)pyrimid in-5- yl)isooxazol-3-yl)memyl)-2-(me1hylsulfonamidomemyl)acrylamid e;

66) N-(3-(4-(3-cMoro-4-(pyridin-2-ylmemoxy)phenylamino)pyrimidin -5- yl)phenyl)acrylamide; and

67) N-((5-(4-(3-cUoro-4-(3-fluorobenzyloxy)phenylamino)pyrimidin -5- yl)isooxazol-3-yl)methyl)-N-methylacrylamide.

A compound of formula (la), which belongs to the compound of formula (I) according to the present invention, may be prepared, for example, by the procedure shown in Reaction Scheme (I) or (II).

<Reaction Scheme (I)>

wherein,

R and Z have the same meanings as defined above. In Reaction Scheme (I), a compound of formula (XI) is added to a mixture with

1 to 2 equivalents of sulfuryl chloride in an organic solvent (e.g., carbon tetrachloride) in the presence of a catalytic amount of 2,2'-azobis(2-methylpropionitrile). The mixture is stirred and heated to 80°C under reflux to form an acid chloride (X), followed by a condensation reaction with D, L-serine methylester hydrochloride at a temperature ranging from 0°C to room temperature in an organic solvent (e.g., tetrahydrofuran or dichloromethane) in the presence of an organic base (e.g., N,N- diisopropylethylamine) to obtain a compound of formula (IX).

Subsequently, the compound of formula (IX) is reacted with ammonia gas at 60°C in an organic solvent (e.g., toluene or a mixture of toluene and ethanol) to form a compound of formula (VIII) substituted with amine, followed by a cyclization reaction under the condition using p-toluenesolfonic acid, methyl N- (triethylammoniumsulfonyl)carbamate (Burgess reagent) or

(diethylamino)sulfurtrifluoride (DAST) at a temperature ranging from -78°C to a reflux condition (e.g., a temperature of 70°C) in an organic solvent (e.g., tetrahydrofuran or dichloromethane) to form a compound of formula (VII).

Then, the compound of formula (VII) is subjected to a substitution reaction with Z-N¾ in an organic solvent (e.g., 2-propanol or acetonitrile) to form a compound of formula (VI), followed by a reaction with l,8-diazabicyclo[5.4.0]undec-7-ene and bromotrichloromethane in an organic solvent (e.g., dichloromethane) at a temperature ranging from -40°C to room temperature to form a compound of formula (V).

Subsequently, the compound of formula (V) is reacted with a reducing agent such as lithium aluminium hydride (e.g., 1.0M lithium aluminium hydride ether) in an organic solvent (e.g., dichloromethane) at a temperature ranging from 0°C to room temperature to form a compound of formula (IV), followed by a reaction with sodium azide and triphenylphosphine in the mixture of N, N-dimethylformamide and carbon tetrachloride to form a compound of formula (III) having an azide introduced.

To the compound prepared above, triphenylphosphine and distilled water are added and heated at a temperature ranging from 60°C to 70°C in an organic solvent (e.g., tetrahydrofuran) to form a compound of formula (II). The compound of formula (II) is subjected to a condensation reaction with R-Cl in a mixture of water and an organic solvent (e.g., tetrahydrofuran), or methylene chloride in the presence of an inorganic base (e.g., sodium bicarbonate) or an organic base (e.g., pyridine or triethylamine); or is subjected to a condensation reaction with R-OH in an organic solvent (e.g., tetrahydrofuran or methylene chloride) by using a coupling agent (e.g., 1- ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(lH-7-azabenzotriazol-l- yl)-l,l,3,3-tetramethyl uropium hexafluorophosphate methaneaminium (HATU)) to obtain a compound of formula (la) of the present invention.

In addition, a compound of formula (lb), which belongs to the compound of formula (I) according to the present invention, may be prepared, for example, by the procedure shown in Reaction Scheme (II).

<Reaction Scheme II>

XX XIX XVIII

wherein,

R, Z, n _a and ¾ have the same meanings as defined above; and

Pit represents a protecting group of amine.

In Reaction Scheme (II), a compound of formula (XX) is reacted with iodine or N-iodosuccinimide in a basic condition (e.g., sodium hydroxide aqueous solution) or an acidic condition (e.g., acetic acid) to form a iodopyrimidinone compound of formula (XIX), followed by a reaction with an inorganic acid (e.g., phosphorus oxychloride) under a reflux condition, to form a compound of formula (XVIII).

The compound prepared above is subjected to a substitution reaction with Z- NH ₂ in an organic solvent (e.g., 2-propanol or acetonitrile) to form a compound of formula (XVII) having Z. Then, the compound is subjected to a Sonogashira reaction with an acetylene compound protected by trimethylsilane (TMS) in an organic solvent (e.g., tetrahydrofuran) under an organic base condition (e.g, triethylamine) by using a catalytic amount of a palladium catalyst (e.g., dichlorobis(triphenylphosphine)palladium(II)) and copper(I) iodide, to form a compound of formula (XVI).

An acetylene compound of formula (XV) is prepared from the compound of formula (XVI) by using tetrabutylammonium fluoride. Subsequently, the compound of formula (XV) is subjected to an 1,3-dipolar cycloaddtion reaction with the mixture of N-chlorosuccinimide and an oxime compound (XXI), which is prepared from an aldehyde, in an organic solvent (e.g., tetrahydrofuran) in the presence of an organic base (e.g., triethylamine) to obtain an isooxazole compound of formula (XIV). The compound is subjected to a deprotection reaction of amine which is protected by phthalimide or tert-butyloxycarbonyl (Boc), to obtain a compound of formula (XIII).

The compound of formula (XIII) is subjected to a condensation reaction with

R-Cl in a mixture of water and an organic solvent (e.g., tetrahydrofuran), or methylene chloride in the presence of an inorganic base (e.g., sodium bicarbonate) or an organic base (e.g., pyridine or triethylamine), or is subjected to a condensation reaction with R- OH in an organic solvent (e.g., tetrahydrofuran or methylene chloride) by using a coupling agent (e.g., l-emyl-3-(3-dimemylammopropyl)-carbodiimide (EDC) or 2- (l /-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uropium hexafluorophosphate memaneaminium (HATU)) to obtain a compound of formula (lb) of the present invention.

The compound of formula (I) of the present invention can also be used in the form of a pharmaceutically acceptable salt formed with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The inventive compound of formula (I) or a pharmaceutically acceptable salt thereof may selectively and efficiently inhibit the growth of cancer cells induced by epidermal growth factor receptors (EGFRs) and its mutants, and may provide enhanced anticancer effects when combined with other anticancer agents.

Further, the present invention provides a pharmaceutical composition for inhibiting the growth of cancer cells, comprising a compound of formula (I) or its pharmaceutically acceptable salt as an active ingredient.

The pharmaceutical composition of the present invention may further comprise another anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents, and antiandrogen.

The dose level of the inventive compound or pharmaceutically acceptable salt thereof will depend on a variety of factors including the subject being treated, the severity of the indication or condition being treated, the administration rate, and the responsibility of the attendant physician. The inventive compound or a pharmaceutically acceptable salt thereof as an active ingredient may be administered orally or parenterally in an effective amount ranging from about 0.01 to 200 mg/kg, preferably 30 to 100 mg/kg (body weight) once or twice daily or by on/off schedule for mammals including human. In some cases, an amount less than the above dosage may be suitable. An amount greater than the above dosage may be used unless it causes deleterious side effects and such amount can be administered in divided doses per day.

The inventive pharmaceutical composition may be formulated in accordance with any of the conventional methods in the form of oral administration such as tablet, granule, powder, capsule, syrup, emulsion or microemulsion, or in the form of parenteral administration including intramuscular, intravenous and subcutaneous routes.

The inventive pharmaceutical composition for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspension agents, emulsifying agents, diluents, and others. Examples of the carrier employed in the injectable composition of the present invention are water, saline solutions, glucose solutions, glucose-like solutions, alcohols, glycol ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspension agents, emulsifying agents, and others.

The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention.

Example 1: Preparation of A-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylamino)pyrimidin-5-yI)oxazol-4-yl)methyl)aci Iamid Step 1) Preparation of 4,6-dichloropyrimidin-5-carbonyl chloride

10 g of 4,6-dichloropyrimidin-5-carbaldehyde was dissolved in 100 mL of carbon tetrachloride, and 7.8 mL of sulfuryl chloride and 0.51 g of 2,2-azobis(2- methylpropionitrile) were added thereto, followed by stirring under reflux at 80°C for 1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered under a reduced pressure. The filtrate was distilled under a reduced pressure and dried under a reduced pressure to obtain the title compound (11.4 g, yield: 95%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.90 (s, 1H).

Step 2) Preparation of methyl 2-(4,6-dichloropyrimidin-5-carboxamido ^' )-3- hydroxypropanoate

8.6g of the compound obtained in step 1 and 12.6 g of A^-serine methylester were dissolved in 100 mL of tetrahydrofuran, and 14.2 mL of N,N- diisopropylethylamine was added thereto dropwise at 0°C. Then, the mixture was heated to room temperature, followed by stirring for 30 min. After the reaction was completed, the reaction mixture was mixed with water, and extracted with chloroform. The separated organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate, followed by filtration and distillation under a reduced pressure. The obtained residue was subjected to column chromatography (ethyl acetate : dichloromethane : methanol = 30 : 30 : 1), to obtain the title compound (10.2 g, yield: 85%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 9.31 (d, 1H), 8.96 (s, 1H), 5.15 (s, 1H), 4.58 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.67 (m, 1H).

Step 3) Preparation of methyl 2-(4-amino-6-cMoropyrirnidin-5-carboxamido ^" )-3- hydroxypropanoate

7.0 g of the compound obtained in step 2) was dissolved in 50 mL of toluene and 50 mL of ethanol in a seal tube, and ammonia gas was bubbled through the solution, followed by stirring at 60°C for 2 hours. Ammonia gas was further bubbled into the solution until the reaction is substantially completed, and reaction was continued at the same temperature for another 1 hour. After the reaction was completed, the reaction mixture was distilled under a reduced pressure and dried to obtain the title compound (6.54 g).

1H-NMR (300MHz, DMSO-d ₆ ) δ 9.11 (d, 1H), 8.22 (s, 1H), 5.15 (s, 1H), 4.51 (m, 1H), 3.74 (m, 2H), 3.69 s, 3H).

Step 4) Preparation of methyl 2-(4-amino-6-chloropyrimidin-5-yl)-4,5-dihvdrooxazol- 4-carboxylate

5.0 g of the compound obtained in step 3) was dissolved in 50 mL of dichloromethane, and 2.65 mL of (diemylamino)sulfurtrifluoride was added thereto dropwise at -78°C. The mixture was slowly heated to 0°C and stirred for 2.5 hours. After the reaction was completed, the reaction mixture was basificated (pH 8) with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, followed by filtration and distillation under a reduced pressure. The obtained residue was crystallized with a mixed solvent of ethylacetate and diethylether (3 : 1), followed by filtering and drying under a reduced pressure to obtain the title compound (2.38 g, yield: 51%).

'H-NMR (300MHz, CDCI ₃ ) δ 8.70 (s, 1H), 8.30 (s, 1H), 6.10 (s, 1H), 4.97 (m, 1H), 4.63 (m, 2H), 3.82 (s, 3H). Step 5) Preparation of methyl 2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylan mo)pyrimidin-5-yl)-4,5-dihydrooxazol-4-carboxylate

1.5 g of the compound obtained in step 4) and 1.37 g of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine prepared by the procedure disclosed in WO 2008150118 were dissolved in 25 mL of t-butanol, and 0.73 mL of hydrochloric acid 4N solution in 1 ,4-dioxane was added thereto dropwise. The mixture was heated to 70°C and stirred for 1.5 hours, followed by distillation under a reduced pressure when the reaction was complete. The solvent was removed, and 25 mL of 2-propanol was added thereto, followed by stirring at 0° for 2 hours. The resulting solid was washed with 2- propanol, followed by filtering and drying under a reduced pressure to obtain the title compound (2.10 g, yield: 79%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 11.24 (s, 1H), 8.63 (d, IE), 8.26 (s, 1H), 8.10 (m, 1H), 7.95 (m, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.43 (m, 1H), 7.32 (m, 1H), 7.25 (d, 1H), 5.31 (s, 2H), 5.05 {m, 1H), 4.63 (m, 2H), 3.71 (s, 3H).

Step 6) Preparation of methyl 2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrirnidin-5-yl)oxazol-4-carboxylate

2.0 g of the compound obtained in step 5) was dissolved in 40 mL of dichloromethane, and 1.9 mL of l,8-diazabicyclo[5.4.0]undec-7-ene was added thereto at -40°C, followed by adding thereto 1.3 mL of bromotrichloromethane dropwise for 20 min. The mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure to remove the solvent, and then crystallized with ethyl acetate. The resulting solid was washed with ethyl acetate, followed by filtering and drying to obtain the title compound (0.4 g, yield: 20%).

1H-NMR (300MHz, DMSO-de) δ 10.16 (s, 1H), 8.88 (s, 1H), 8.58 (m, 1H), 8.11 (m, 1H), 7.85 (m, 2H), 7.54 (m, 3H), 7.37 (m, 2H), 7.22 (d, 1H), 5.26 (s, 2H), 3.87 (s, 3H).

Step 7) Preparation of (2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methanol

0.35 g of the compound obtained in step 6) was dissolved in 10 mL of dichloromethane at 0°C, and 1.6 mL of 1.0 M lithium aluminium hydride ether solution was added dropwise thereto. The mixture was stirred at the same temperature for 1 hour. After the reaction was completed, an aqueous solution of Rochelle salt (potassium sodium tartrate, NaKGiHUOe) was added thereto. The resulting mixture was stirred for 1 hour, and extracted two times with a mixed solvent of chloroform and 2-propanol (3 : 1). The isolated organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by filtering and distilling under a reduced pressure. The obtained residue was subjected to column chromatography (ethyl acetate : dichloromethane : methanol = 10 : 10 : 1), to obtain the title compound (0.27 g, yield: 82%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.70 (j, 1H), 8.58 (d, 1H), 8.15 (s, 1H), 7.72 (m, 3H), 7.64 (d, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 6.92 (d, 1H), 5.25 s, 2H), 4.72 (s, 2H).

Step 8) Preparation of (5-(4-(amuiomethyl)oxazol-2-yl)-A^-(3-chloro-4-(pyridin-2- ylmethoxy)phenyl ^' )pyrimidin-4.6-diamine

0.27 g of the compound obtained in step 7) was dissolved in 10 mL of N,N- dimethylformamide and 2 mL of carbon tetrachloride, and 50 mg of sodium azide and 400 mg of triphenylphosphine were added thereto. The mixture was heated to 90°C and stirred for 30 min. Subsequently, the mixture was distilled under a reduced pressure to remove carbon tetrachloride, and water was added thereto, followed by extraction with ethyl acetate. The isolated organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by filtering and distilling under a reduced pressure. The obtained residue was dried under a reduced pressure, dissolved in 10 mL of tetrahydrofuran, and 437 mg of triphenylphosphine and 0.1 mL of distilled water were added thereto, followed by stirring at 60°C for 2 hours. After the reaction was completed, the reaction mixture was distilled under a reduce pressure to remove the solvent, and then subjected to column chromatography (chloroform : methanol = 1 : 1), to obtain the title compound (50 mg, yield: 19%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.71 (s, 1H), 8.58 (d, 1H), 8.19 (s, 1H), 7.72 (m, 2H), 7.64 {d, 2H), 7.41 (in, 1H), 7.24 (m, 1H), 6.98 (d, 1H), 5.28 (s, 2H), 3.90 (s, 2H);

MS (ESI*): m/z = 424.3 [M+H] ⁺ .

Step 9) Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylamino ^' )pyrimidin-5-yl ^' )oxazol-4-yl)methyl)acrylamide

45 mg of the compound obtained in step 8) and 27 mg of sodium bicarbonate were dissolved in 2 mL of tetrahydrofuran and 0.5 mL of distilled water at 0°C, and 8.6 of acryloyl chloride was added thereto, followed by stirring at the same temperature for 10 min. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added thereto and the mixture was extracted two times with chloroform. The isolated layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, followed by filtering and distilling under a reduced pressure. The obtained residue was subjected to column chromatography (chloroform : methanol = 15 : 1), to obtain the title compound (20 mg, yield: 39%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.65 (s, 1H), 8.59 (d, 1H), 8.18 (s, 1H), 7.72 (m, 3H), 7.65 (d, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 6.96 (d, 1H), 6.35 (m, 1H), 6.13 (m, 2H), 5.70 (m, 2H), 5.27 (s, 2H), 4.53 (d, 2H);

MS (ESf): m/z = 478.2 [M+H] ⁺ .

Example 2: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyriiiiidm-5-yl)-4,5-dihydrooxazol-4- yl)methyl)acrylamide

The procedure of Example 1 was repeated except for step 7) was performed with the compound obtained in step 5) of Example 1, instead of the compound of step 6), to obtain the title compound (5 mg, final yield: 10%).

1H-NM (300MHz, CDC1 ₃ ) δ 11.07 (s, 1H), 8.58 (m, 1H), 8.13 (s, 1H), 7.75- 7.63 (m, 3H), 7.38 (dd, 1H), 7.24 (m, 1H), 6.96 (d, 1H), 6.32 (dd, 1H), 6.13 (m, 1H), 5.91 (bt, 1H), 5.70 (dd, lH), 5.28 (s, 2H), 4.90 (bs, 2H), 4.50 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H).

Example 3: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- yImethoxy)phenylaniino)pyrimidin-5-yI)oxazol-4-yl)methyl)-2- ((dimethylamino)methyl)acryIamide

Step 1) Preparation of 2-( ^' (dimethylamino)methyl)acrylic acid 1 g of malonic acid and 0.63 g of paraformaldehyde were dissolved in 10 mL of 1,4-dioxane, and 4.8 mL of a 2.0 M dimethylamine solution in tetrahydrofuran was added thereto. Then, the mixture was heated to 70°C and stirred for 1 hour. After the reaction was completed, the mixture was distilled under a reduced pressure. The concentrated liquid-phase residue was crystallized by addition of acetone and then filtered under a reduced pressure to obtain the title compound in a white crystalline (0.4 g, yield: 32%).

1H-NMR (300MHz, D ₂ 0) δ 6.62 (s, 1H), 6.11 (s, 1H), 4.16 (s, 2H), 2.88 (s, 6H);

MS (ES ): m/z = 130.0 [M+H] ⁺ .

Step 2) Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylanimo)pyrimidin-5-yl)oxazol-4-yl)methyl)-2- ((dimethylamino)methyl)acrylamide

4 mg of the compound obtained in step 1) above was dissolved in 2 mL of dichloromethane, and 7 mg of N-(3-dimemylammopropyl)-N'-emylcarbodiirnide hydrochloride and 12 pL of N,N-diisopropylemylamine were added thereto, followed by stirring at room temperature for 5 min. Subsequently, 10 mg of the compound obtained in step 8) of Example 1 was added thereto and stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added thereto and the reaction mixture was extracted two times with chloroform. The isolated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The obtained residue was subjected to column chromatography (chloroform : methanol = 15 : 1), to obtain the title compound (6 mg, yield: 47%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.79 (s, 1H), 9.85 (m, 1H), 8.61 m, 1H), 8.21 (s, 1H), 7.77 (m, 2H), 7.68 (s, 2H), 7.47 (m, 1H), 7.26 (m, 1H), 6.99 (d, 1H), 6.28 (d, 1H), 5.44 (s, 1H), 5.30 (s, 2H), 4.52 (d, 2H), 3.13 (s, 2H), 2.19 (s, 6H);

MS (ESf ): m/z = 535.4 [M+H] ⁺ .

Example 4: Preparation of (E N-((2-(4-amino-6-(3-chloro-4-(pyridiii-2- ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyI)-4- (dimethyIamino)but-2-enainide

Step 1) Preparation of (E)-methyl-4-(dimethylamino ^' )but-2-enoate hydrochloride 10 g of methyl-4-bromocrotonate was dissolved in 60 mL of tetrahydrofuran, and 59. 4 mL of a 2.0 M dimethylamine solution in tetrahydrofuran was added thereto at 0°C. Then, the mixture was stirred at room temperature for 1 hour, and filtered and distilled under a reduced pressure. The concentrated residue was dissolved in 30 mL of 2-propanol and acidified (pH 2) with 10% hydrochloric acid solution in 2-propanol at 0°C. The resulting solid was filtered under a reduced pressure and washed with 2- propanol, followed by drying under a reduced pressure to obtain the title compound (2.8 g, yield: 33%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 6.93 (m, 1H), 6.30 (m, 1H), 3.91 (m, 2H), 3.71 (s, 3H), 2.71 (s, 6H).

Step 2) Preparation of (E -4-(dimethylamino)but-2-enoic acid

1 g of the compound obtained in step 1) above was dissolved in 6.6 mL of methanol, and 2.2 mL of an aqueous solution of 40% sodium hydroxide added thereto. The mixture was heated to 45 °C and stirred for 30 min. Then the mixture was acidified (pH 2) with 10% hydrochloric acid solution in 2-propanol and filtered under a reduced pressure. The filtrate was distilled under a reduced pressure, dissolved in 3 mL of 2-propanol, and heated to 35°C, followed by stirring for 10 min. Subsequently, 3 mL of acetone was added thereto, stirred at 40°C for 30 min, and stirred again at room temperature for 12 hours. The resulting solid was filtered under a reduced pressure and washed with a mixed solvent of 2-propanol and acetone (1 : 2), followed by drying under a reduced pressure to obtain the title compound (500 mg, yield: 54%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 6.85 (m, 1H), 6.18 (m, 1H), 3.87 (d, 2H), 2.69 {s, 6H).

Step 3) Preparation of ^Ej-N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)p\ imidin-5-vnoxazol-4-yl)memyl)-4-(dimemylamino)but-2- enamide

The procedure of Example 3 was repeated except using 2.3 mg of the compound obtained from above step 2) instead of 2-((dimethylamino)methyl)acrylic acid in step 2) of Example 3 without step 1) of Example 3 to obtain the title compound (2 mg, yield: 31%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.65 (s, 1H), 8.60 (d, 1H), 8.20 (s, 1H), 7.75 (m, 3H), 7.67 (d, 1H), 7.44 (m, 1H), 7.26 (w, 1H), 6.98 (d, 1H), 6.88 (m, 1H), 6.26 (m, 1H), 6.04 {d, 1H), 5.29 (5, 2H), 4.53 (d, 2H), 3.21 (s, 2H), 2.34 (5, 6H);

MS (ESI*): m/z = 535.3 [M+H] ⁺ .

Example 5: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidm-5-yl)oxazoM-yI)methyl)-2-hydro xyacetami 5 mg of glycolic acid and 27 mg of 2-(lH-7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyl uranium hexafluorophosphate methaneaminium were dissolved in 1.0 mL of dichloromethane at room temperature, and stirred for 10 min. 30 mg of the compound obtained in step 8) of Example 1 and 42 μΐ, of N,N-diisopropylemylamine were added thereto and stirred for 2 hours at the same temperature. After the reaction was completed, the mixture was distilled under a reduced pressure to remove the solvent, and extracted two time with a mixed solvent of chloroform and 2-propanol(3 : 1). The isolated organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by filtering and distilling under a reduced pressure. The resulting residue was subjected to column chromatography (dichloromethane : methanol =5 : 1) to obtain the title compound (2 mg, yield: 5.9%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.59 (s, 1H), 8.19 (s, 1H), 8.18-7.70 (m, 4H), 7.54-7.49 (m, 2H), 6.99 (w, 1H), 5.28 (s, 2H), 4.72 (s, 2H), 4.52 (d, 2H).

Example 6: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)oxazol-4-yl)methyl)-2- hydroxypropanamide

7 μL of 3-hydroxy propionic acid and 27 mg of 2-(lH-7-azabenzotriazol-l-yl)- 1, 1, 3, 3-tetramethyl uranium hexafluorophosphate methaneaminium were dissolved in 10 mL of dichloromethane at room temperature, and stirred for 10 min. 30 mg of the compound obtained in step 8) of the Example 1 and 42 i of N,N- diisopropylethylamine were added thereto and stirred for 2 hours at the same temperature. After the reaction was completed, the mixture was distilled under a reduced pressure to remove the solvent, and extracted two times with a mixed solvent of chloroform and 2-propanol (3 : 1). The isolated organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate, followed by filtering and distilling under a reduced pressure. The resulting residue was subjected to column chromatography (dichloromethane : methanol =5 : 1) to obtain the title compound (2 mg, yield: 5.7%).

Ή-NMR (300MHz, CDC1 ₃ ) δ 8.58 (s, 1H), 8.19 (s, 1H), 7.78-7.67 (m, 3H), 7.38-7.40 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 5.28(5, 2H), 4.46 s, 2H), 3.49(t, 2H), 2.53 (t, 2H).

Example 7: Preparation of 7V-((2-(4-amino-6-(2-fluoro-4-(pyridin-2- ylmethoxy)phenyIamino)pyriim^m-5-yl)oxazoM-yl)methyl)aciylam ide

Step 1) Preparation of 2-((3-fluoro-4-nitrophenoxy ^' )methyl)pyridine

2 g of 3-fluoro-4-nitrophenol was dissolved in 50 mL of acetonitrile, and 3.2 g of 2-(bromomethyl)pyridine hydrobromide and 5.3 g of potassium carbonate were added thereto, followed by stirring for 2 hours at 80°C. After the reaction was completed, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with chloroform. The isolated organic layer was washed two times with water, and dried over anhydrous magnesium sulfate, followed by filtering and distilling under a reduced pressure. The resulting residue was dried under a reduced pressure to obtain the title compound (3 g, yield: 95%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 8.59 (m, 1H), 8.15 (t, 1H), 7.85 (m, 1H), 7.54 (d, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.06 (m, 1H), 5.34 (s, 2H).

Step 2) Preparation of 2-fluoro-4-(pyridin-2-ylmethoxy)phenylamine

3.4 g of iron was diluted with 10 mL of 50% aqueous ethanol, and 0.4 mL of 35% aqueous hydrochloric acid was added thereto, followed by heating to 110°C. 3 g of the compound obtained in step 1) above was added thereto and refluxed at 110°C for 2 hours. After the reaction was completed, the mixture was filtered under a reduced pressure through a Celite pad, and the filtrate was distilled under a reduce pressure. The resulting residue was mixed with a saturated aqueous solution of sodium bicarbonate and extracted two times with chloroform. The isolated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, followed by drying under a reduced pressure to obtain the title compound (2.2 g, yield: 73%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 8.55 d, 1H), 7.79 (m, 1H), 7.48 (d, 1H), 7.30 (m, 1H), 6.79 (m, 1H), 6.72 (t, 1H), 6.61 (w, 1H), 5.05 (m, 1H), 4.65 (s, 2H).

Step 3} Preparation of N-((2-(4-amino-6-(2-fluoro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimidin-5-yl)oxazol-4-vnmethyl)acryla mide

The procedure of Example 1 was repeated except for using 595 mg of the compound obtained from step 2) above, instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine in step 5) of Example 1, to obtain the title compound (30 mg, final yield: 76%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.81 (s, 1H), 8.61 (d, 1H), 8.21 (m, 2H), 7.73 (m, 2H), 7.51 (d, 1H), 6.86 (m, 1H), 6.82 (s, 1H), 6.34 (m, 1H), 6.15 (m, 2H), 5.70 (m, 1H), 5.21 (s, 2H), 4.52 (d, 2H);

MS (ESf): m/z = 462.2 [M+H] ⁺ .

Example 8: Preparation of N-((2-(4-amino-6-(3-fluoro-4-(pyridin-2- yImethoxy)phenyIammo)pyrimidm-5-yl)oxazol-4-yl)methyI)aci Iamide

The procedure of Example 7 was repeated except for using 2 g of 2-fluoro-4- nitrophenol, instead of 3-fluoro-4-nitrophenol in step 1), to obtain the title compound (40 mg, final yield: 51%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.69 (s, 1H), 8.59 (d, 1H), 8.20 (s, 1H), 7.74 (m, 1H), 7.71 (s, 1H), 7.64 (m, 2H), 7.22 (m, 2H), 6.99 (i, 1H), 6.36 (m, 1H), 6.14 (m, 1H), 6.00 (m, 1H), 5.71 (m, 1H), 5.27 (s, 2H), 4.54 (m, 2H);

MS (ES ): m/z = 462.2 [M+H] ⁺ .

Example 9: Preparation of N-((2-(4-amino-6-(3-chloro-4-(3- fluorobenzyloxy)phenylammo)pyriniidin-5-yl)oxazol-4-yl)methy l)acrylamide The procedure of Example 1 was repeated except for using 3-chloro-4-(3- fluoro-benzyloxy)-phenylamine prepared by the procedure disclosed in WO 2008150118, instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine in step 5), to obtain the title compound (9 mg, final yield: 47%).

1H-NMR (300MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.88 (m, 1H), 7.80-7.79 (d, 1H), 7.64-7.03 (m, 6H), 6.30 (s, 1H), 6.28-6.27 (d, 1H), 5.70-5.66 (m, 1H), 5.18 (s, 2H), 4.48 (s, 2H);

MS (ESI*): m/z = 495.3 [M+H] ⁺ .

Example 10: Preparation of iV-((2-(4-amino-6-(3-chloro-4-(2,3- dich!orophenoxy)phenylainmo)pyriiiiidm-5-yl)oxazoM-yl)methyl )aciylaim

Step 1) Preparation of 3-chloro-4-(2,3-dichloro-phenoxy ^' )-phenylamine

2.6 g of potassium bicarbonate was dissolved in 60 mL of N,N- dimethylformamide, and 2.8 g of 2,3-dichlorophenol and 3.0 g of 3-chloro-4- fluoronitrobenzene were added thereto, followed by stirring at 100°C for 1.5 hours. After the reaction was completed, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The isolated organic layer was washed two times with water, and dried over anhydrous magnesium sulfate, followed by filtering and distilling under a reduced pressure, to obtain a residue.

Subsequently, 4.83 g of iron was diluted with 70 mL of 50% aqueous ethanol, and 2.0 mL of 35% aqueous hydrochloric acid was added thereto, followed by heating to 110°C. The obtained residue was added thereto and refluxed at 110°C for 3 hours. After the reaction was completed, the mixture was filtered under a reduced pressure through a Celite pad and distilled under a reduced pressure. The resulting residue was mixed with a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted two times with a mixed solvent of chloroform and 2-propanol (3 : 1). The isolated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, followed by drying under a reduced pressure to obtain the title compound (4.32 g, yield : 86%). 1H-NMR (300MHz, CDC1 ₃ ) δ 7.15-7.12 (m, 1H), 7.06-7.03 (m, 1H), 6.89-6.86 (m, 1H), 6.78-6.77 (m, 1H), 6.58-6.53 (m, 2H), 3.70 (bs, 2H).

Step 2) Preparation of N-((2-(4-amino-6-f3-chloro-4-(Z3- dicMorophenoxy)phenylamino)pyrimidin-5-vnoxazol-4^

The procedure of Example 1 was repeated except for using the compound obtained from the step 1) above, instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine in step 5) of Example 1, to obtain the title compound (11 mg, final yield: 39%).

1H-NMR (300MHz, CDCI3+CD ₃ OD) δ 8.20 (s, 1H), 7.94-7.93 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 7.00-6.97 (m, 1H), 6.60 (m, 1H), 6.34 (m, 1H), 6.10 (m, 1H), 5.80 (m, 1H), 4.56-4.54 (m, 2H);

MS (ESI ⁺ ): m/z = 531.3 [M+H] ⁺ .

Example 11: Preparation of 7V-((2-(4-amino-6-(3-chloro-4-(2,4- dichlorophenoxy)phenylammo)pyrimidin-5-yl)oxazol-4-yI)methyl )acryIamide

The procedure of Example 10 was repeated except for using 2,4- dichlorophenol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (14 mg, final yield: 41%).

1H-NMR (300MHz, CDCI3+CD ₃ OD) δ 8.24 s, 1H), 7.96-7.95 (m, 1H), 7.75 (s, 1H), 7.55 (m, 1H), 7.49-7.48 (m, 1H), 7.18-7.14 (m, 1H), 6.98-6.95 (d, 1H), 6.78-6.75 (d, 1H), 6.41-6.35 (m, 1H), 6.20-6.17 (m, 1H), 5.75-5.71 (m, 1H), 4.58-4.56 (TM, 2H);

MS (ESf): m/z = 531.3 [M+H] ⁺ .

Example 12: Preparation of N-((2-(4-amino-6-(3-chloro-4-(2,5- dichlorophenoxy)phenylanimo)pyriniidm-5-yl)oxazol-4-yl)methy l)aciylaniide

The procedure of Example 10 was repeated except for using 2,5- dichlorophenol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (14 mg, final yield: 40%). 1H-NMR (300MHz, CDCI3+CD ₃ OD) δ 8.37 (s, 1H), 7.97-7.96 (m, 1H), 7.75 (s, 1H), 7.50 (m, 1H), 7.40-7.37 (m, 1H), 7.05-6.75 (m, 2H), 6.60 (m, 1H), 6.17 (m, 1H), 5.73 (m, 1H), 4.55-4.54 (m, 2H);

MS (ESI ⁺ ): m/z = 531.3 [M+H] ⁺ .

Example 13: Preparation of 7V-((2-(4-amino-6-(3-chloro-4- phenoxyphenylammo)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylami de

The procedure of Example 10 was repeated except for using phenol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (29 mg, final yield: 67%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.86 (bs, 1H), 8.25 (s, 1H), 7.92- 7.91 (d, 1H), 7.74 (J, 1H), 7.55-7.52 (m, 1H), 7.37-7.31 (m, 2H), 7.10-6.97 (m, 4H), 6.41-6.35 (m, 1H), 6.20-6.17 (m, 1H), 5.75-5.71 (m, 1H), 4.58-4.56 (d, 2H);

MS (ESf): m/z = 463.3 [M+H] ⁺ .

Example 14: Preparation of Zi -7V-((2-(4-amino-6-(3-chloro-4- phenoxyphenylammo)pyrimidin-5-yl)oxazoM-yl)methyl)-4-(dimeth ylamino)but-

2-enamide The procedure of Example 4 was repeated except for using 3-chloro-4- phenoxybenzenamine instead of 3-c oro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (17 mg, final yield: 43%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.23 (s, 1H), 7.91-7.90 (m, 1H), 7.72 (5, 1H), 7.53-7.50 (m, 1H), 7.35-7.30 (m, 2H), 7.11-6.92 (m, 5H), 6.07-6.00 (m, 1H), 4.55-4.53 (d, 2H), 4.23-4.20 (m, 1H), 3.09-3.07 (m, 2H), 2.25 (s, 6H);

MS (ESI ⁴ ): m/z = 520.2 [M+H] ⁺ .

Example 15: Preparation of N-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenyIammo)pyrimidin-5-yI)oxazol-4-yl)methyl)a crylamide

The procedure of Example 10 was repeated except for using 2-fluorophenol, instead of 2,3-dichlorophenol in step 1) to obtain the title compound (7 mg, final yield: 21%). 1H-NMR (300MHz, CDCI3+CD3OD) δ 8.20 (s, 1H), 7.87 (m, 1H), 7.73 (s, 1H), 7.49 (m, 1H), 7.19 (m, 1H), 7.07 (m, 2H), 6.94 (m, 2H), 6.36 (m, 2H), 6.16 (m, 1H), 5.70 (m, 1H), 4.53 ( , 2H).

Example 16: Preparation of A^((2-(4-amino-6-(3-chloro-4-(3- fluorophenoxy)phenylainmo)pyriinidm-5-yI)oxazoM-yl)methyl)ac i Iamide

The procedure of Example 10 was repeated except for using 3-fluorophenol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (14 mg, final yield: 38%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.24 (y, 1H), 7.95-7.94 (m, 1H), 7.72 (s, 1H), 7.59-7.56 (m, 1H), 7.25-7.24 (m, 1H), 7.09-7.06 (m, 1H), 6.11-6.1 \ (m, 2H), 6.67-6.64 (m, 1H), 6.63 (m, 1H), 6.19-6.15 m, 1H), 5.73-5.69 (m, 1H), 4.56 (s, 2H);

MS (ES ): m/z = 481.3 [M+H] ⁺ .

Example 17: Preparation of N-((2-(4-amino-6-(3-chloro-4-(4- fluorophenoxy)phenylammo)pyrimidin-5-yl)oxazol-4-yl)methyl)a crylamide

The procedure of Example 10 was repeated except for using 4-fluorophenol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (21 mg, final yield: 44%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.24 (s, 1H), 7.90-7.89 (m, 1), 7.73 (s, 1H), 7.51-7.50 (m, 1H), 7.02-6.93 (m, 5H), 6.40-6.34 (m, 1H), 6.19-6.10 (m, 1H), 5.74-5.70 (m, 1H);

MS (ESf): m/z = 481.2 [M+H] ⁺ .

Example 18: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-2- yloxy)phenylaniino)pyrimidin-4-yl)metliyl)acrylamide

The procedure of Example 10 was repeated except for using 2-hydroxy pyridine instead of 2,3-dichlorophenol in step 1) to obtain the title compound (7 mg, final yield: 30%).

1H-NMR (300MHz, CDCI3+CD3OD) δ 10.93 (s, 1H), 8.20 (j, 1H), 7.90 (s, 1H), 7.73-7.71 (m, 2H), 7.54 (dd, IH), 7.18 (d, 2H), 7.01-6.96 (m, 2H), 6.37 (d, IH), 6.18 (t, IH), 5.68 (d, IK), 4.53 (d, 2H).

Example 19: Preparation of N-((2-(4-amino-6-(3-chloro-4-(pyridin-3- yloxy)phenylamino)pyrimidm-5-yI)oxazoM-yl)methyl)acrylamide

The procedure of Example 10 was repeated except for using 3 -hydroxy pyridine instead of 2,3-dichlorophenol in step 1) to obtain the title compound (20 mg, final yield: 44%).

1H-NMR (300MHz, CDC1 ₃ ) δ 11.10 (s, IK), 8.64 (t, IH), 8.33 (m, 2H), 8.17 (m, 2H), 8.05 (s, IK), 7.70 (m, IK), 7.49 (s, IK), 7.39 (m, IH), 7.25 (m, 2H), 6.20 (m, 2H), 5.62 (m, 2H), 4.39 (d, 2H);

MS (ESf): m/z = 464.3 [M+H] ⁺ .

Example 20: Preparation of vV-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylammo)pyrimidin-5-yI)oxazoI-4-yl)methyl)- 2- hydroxyacetamide

The procedure of Example 5 was repeated except for using 3-chloro-4-(2- fluorophenoxy)benzenamine instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (12 mg, final yield: 20%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.18 (s, IK), 7.89-7.88 (m, IH), 7.70 (m, IH), 7.52-7.48 (m, IH), 7.11-6.91 (m, 4K), 4.54-4.52 (d, 2H), 3.78 (s, 2H);

MS (ESf): m/z = 485.3 [M+H] ⁺ .

Example 21: Preparation of N-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylanmio)pyrimidin-5-yl)oxazol-4-yl)methyl) -3- hydroxypropanamide

The procedure of Example 6 was repeated except for using 3-chloro-4-(2- fluorophenoxy)benzenamine instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (15 mg, final yield: 25%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.21 (s, IK), 7.89-7.88 (m, IH), 7.70 (s, IH), 7.53-7.49 (m, 1H), 7.18 (m, 1H), 7.08-7.05 (m, 2H), 6.95-6.92 (m, 2H), 6.50 (m, 1H), 4.49-4.47 (d, 2H), 3.94-3.90 (t, 2H), 2.52-2.48 (f, 2H).

Example 22: Preparation of iV-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylammo)pyrimidin-5-yl)oxazol-4-yI)methyl)- 3- methoxypropanamide

The procedure of Example 20 was repeated except for using 3- methoxypropanoic acid instead of glycolic acid to obtain the title compound (1 1 mg, final yield: 30%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.22 (s, 1H), 7.92-7.91 (m, 1H), 7.68 (s, 1H), 7.54-7.50 (m, 1H), 7.12-7.05 (m, 2H), 6.96-6.93 (m, 1H), 6.75 (m, 1H), 4.48-4.46 (d, 2H), 3.67-3.63 (t, 2H), 3.34 (s, 2H), 2.54-2.50 (t, 2H);

MS (ESf): m/z = 513.4 [M+H] ⁺ .

Example 23: Preparation of N-((2-(4-amino-6-(3-methyl-4-(6-methyIpyridin-3- yloxy)phenylammo)pyrimidin-5-yl)oxazol-4-yI)methyl)acrylamid e

Step 1) Preparation of 3-methyl-4-(6-memylpyridin-3-yloxy)-phenylamine

The procedure of step 1) of Example 10 was repeated except for using 6- methyl-pyridin-3-ol and l-fluoro-2-methyl-4-nitrobenzene instead of 2,3- dichlorophenol and 3-chloro-4-fluoronitrobenzene in step 1) to obtain the title compound (10.6 g, final yield: 81%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.18 (s, 1H), 7.03-6.99 (d, 2H), 6.73 (d, 1H),

6.59 (s, 1H), 6.51 (dd, 1H), 3.56 (bs, 2H), 2.49 (s, 3H), 2.10 (s, 3H).

Step 2) Preparation of N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3- yloxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl acrylamide

The procedure of Example 1 was repeated except for using 3-methyl-4-(6- methylpyridin-3-yloxy)-phenylamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine in step 5) to obtain the title compound (34 mg, final yield: 76%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.65 (bs, 1H), 8.28-8.27 (d, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.53-7.52 (d, 1H), 7.48-7.44 (m, 1H), 7.11-7.09 (m, 2H), 6.92-6.89 (d, 1H), 6.40-6.34 (m, 1H), 6.20-6.11 (m,lH), 5.74-5.70 (m, 1H), 4.58-4.56 (d, 2H), 2.54 (s, 3H), 2.28 (s, 3H);

MS (ESI ⁺ ): m/z = 458.4 [M+H] ⁺ . Example 24: Preparation of N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin-3- yloxy)phenylanimo)pyrimidin-5-yl)oxazol-4-yI)methyl)-2- ((dimethylamino)methyl)acrylamide

The procedure of Example 3 was repeated except for using 3-methyl-4-(6- methylpyridin-3-yloxy)-phenylamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine, to obtain the title compound (35 mg, final yield: 55%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.77 (bs, 1H), 8.27-8.26 (d, 1H), 8.23 (s, 1H),

7.68 (s, 1H), 7.54-7.53 (m, 1H), 7.48-7.45 (m, 1H), 7.10-7.09 (m, 2H), 6.92-6.89 (d,

1H), 6.28 (s, 1H), 5.45 (s, 1H), 4.54-4.52 (d, 2H), 3.14 (s, 2H), 2.53 (s, 3H), 2.27 (s, 3H), 2.19 (s, 6H);

MS (ESf): m/z = 515.0 [M+H] ⁺ .

Example 25: Preparation of (^-N-((2-(4-amino-6-(3-methyl-4-(6-methylpyridin- 3-yloxy)phenylammo)pyrimidm-5-yl)oxazol-4-yl)methyl)-4-(dime thylanuno)but- 2-enamide

The procedure of Example 4 was repeated except for using 3-methyl-4-(6- methylpyridin-3-yloxy)-phenylamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine to obtain the title compound (20 mg, final yield: 39%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.48 (bs, 1H), 8.25 (m, 1H), 8.20 (s, 1H), 7.70

(5, 1H), 7.51-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.08-7.03 (m, 2H), 6.91-6.82 (m, 2H), 6.00-5.92 (m, 1H), 4.53-4.51 (d, 2H), 3.04-3.02 (w, 2H), 2.51 (s, 3H), 2.25 (s, 3H), 2.22 (s, 6H);

MS (ESf): m/z = 515.6 [M+H] ⁺ .

Example 26: Preparation of N-((2-(4-amino-6-(3-chloro-4-(6-methylpyridin-3- yloxy)phenylammo)pyriniidin-5-yl)oxazol-4-yl)methyl)acrylami de

The procedure of Example 10 was repeated except for using 5-hydroxy-2- methylpyridine instead of 2,3-dichlorophenol in step 1) to obtain the title compound (1 mg, final yield: 2%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.23 (d, 1H), 8.21 (s, 1H), 7.92 (d, 1H), 7.75 (s, 1H), 7.55 m, 1H), 7.16 (m, 2H), 7.02 (m, 2H), 6.50 (m, 1H), 6.37 (m, 1H), 6.15 (m, 1H), 5.71 {m, 1H), 4.55 d, 2H), 2.54 (s, 3H).

Example 27: Preparation of ^-((2-(4-amino-6-(3-chloro-4-(l-methyl-lH-imidazol- 2-ylthio)phenylaniino)pyriinidin-5-yl)oxazol-4-yl)methyl)acr yIaniide

The procedure of Example 10 was repeated except for using 2-mercapto-l- methylimidazole instead of 2,3-dichlorophenol in step 1) to obtain the title compound (29 mg, final yield: 63%).

1H-NMR (300MHz, CD ₃ OD) δ 8.11-8.10 (m, 2H), 7.92-7.91 (m, 1H), 7.48-7.44 (m, 1H), 7.40 (s, 1H), 7.18 (s, 1H), 6.66-6.63 (m, 1H), 6.30-6.27 (m, 2H), 5.70-5.66 (i, 1H), 4.48 (s, 2H), 3.71 (s, 3H);

MS (ESI ): m/z = 483.2 [M+H] ⁺ .

Example 28: Preparation of N-((2-(4-amino-6-(3-chIoro-4-(l-methyl-lH-pyrazol- 5-yloxy)phenylanimo)pyrimidin-5-yl)oxazol-4-yl)metliyl)acryl amide

The procedure of Example 10 was repeated except for using 2-methyl-2H- pyrazol-3-ol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (68 mg, yield: 31%).

1H-NMR (300MHz, CDC1 ₃ +CD ₃ 0D) δ 10.96 (bs, 1H), 8.21 (s, 1H), 7.93-7.91 (m, 1H), 7.74 (s, 1H), 7.57-7.53 (m, 1H), 7.14-7.11 (d, 1H), 6.50 (m, 1H), 6.40-6.33 (m, 1H), 6.20-6.11 (m, 1H), 5.73-5.69 (m, 1H), 5.52-5.51 (m, 1H), 4.55-4.53 (d, 2H), 3.80 (s, 3H);

MS (ES : m/z = 467.2 [M+H] ⁺ .

Example 29: Preparation of N-((2-(4-amino-6-(3-chloro-4-(l-methyl-3-

(rrifluoromethyl)-lH-pyrazol-5-yloxy)phenylammo)pyrimidin -5-yl)oxazol-4- yl)methyl)acrylamide

The procedure of Example 10 was repeated except for using 5 -hydroxy- 1 - methyl-3-trifluoromethyl-lH-pyrazol instead of 2,3-dichlorophenol in step 1) to obtain the title compound (25 mg, final yield: 67%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.64 (t, 1H), 8.19 (d, 1H),

8.16 (s, 1H), 8.05 (s, 1H), 7.72 (w, 1H), 7.49 (s, 2H), 7.41 (d, 1H), 6.25 (m, 2H), 6.02 (s, 1H), 5.62 (m, 1H), 4.39 {d, 2H), 3.84 (s, 3H);

MS (ESf): m/z = 535.3 [M+H] ⁺ .

Example 30: Preparation of N-((2-(4-amino-6-(3,4-dichloro-2- fluorophenylammo)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamid e

The procedure of Example 1 was repeated except for using 3,4-dichloro-2- fluoroaniline instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine in step 5) to obtain the title compound (26 mg, final yield: 45%).

1H-NMR (300MHz, DMSO-de) δ 8.38-8.30 (m, 1H), 8.13 (s, 1H), 8.04 (s, 1H),

7.61-7.48 (m, 3H), 6.32-6.23 (m, 1H), 6.16-6.09 (m, 1H), 4.35 (s, 2H);

MS (ES ): m/z = 423.2 [M+H] ⁺ .

Example 31: Preparation of N-((2-(4-amino-6-(4-fluoro-3- methylphenylammo)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamid e

The procedure of Example 1 was repeated except for using 4-fluoro-3- methylaniline instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine in step 5) to obtain the title compound (30 mg, final yield: 20%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.53 s, 1H), 8.31 (s, 1H), 7.66 (s, 1H), 7.26

(m, 2H), 7.00 (m, 1H), 6.35 (t, 1H), 6.14 d, 2H), 5.95 (d, 1H), 4.76 (s, 2H), 2.41 (s, 3H).

Example 32: Preparation of N-((2-(4-amino-6-(3-chloro-4- fluorophenylamino)pyrimidm-5-yl)oxazol-4-yl)methyl)acrylamid e

The procedure of Example 1 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-chloro-4-(pyridm-2-ylmethoxy)benzenamine in step 5) to obtain the title compound (19 mg, final yield: 16%).

1H-NMR (300MHz, CDC1 ₃ +CD ₃ 0D) δ 8.07 (j, IH), 7.75 (dd, IH), 7.69 (s, IH), 7.42-7.37 (m, IH), 7.06 (t, IH), 6.28 (d, IH), 6.20 (d, IH), 5.63 (d, IH), 4.42 (s,

2H);

MS (ESI ⁺ ): m/z = 389.2 [M+H] ⁺ .

Example 33: Preparation of ^-((2-(4-amino-6-(3-chloro-4- fluorophenyIammo)pyrimidin-5-yI)oxazol-4-yl)methyl)-2- ((dimethyIamino)methyl)acrylamide

The procedure of Example 3 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-cUoro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (43 mg, final yield: 32%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.90 (bs, IH), 9.65 (bs, IH), 8.14 (s, IH),

7.79-7.77 (m, IH), 7.60 (s, IH), 7.46-7.42 (m, IH), 7.08 (f, IH), 6.21 (s, IH), 5.43 (s,

1 H), 4.44 (s, 2H), 3.06(s, 2H), 2.10(s, 6H);

MS (ESI^: m/z = 446.2 [M+H] ⁺ .

Example 34: Preparation of (^-A ^L ((2-(4-amino-6-(3-chloro-4- fluorophenylammo)pyrimidm-5-yl)oxazoM-yl)methyl)-4-((dimethy lamino)but-2- enamide The procedure of Example 4 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (63 mg, final yield: 47%).

1H-NMR (300MHz, CDC1 ₃ +CD ₃ 0D) δ 8.75 (s, IH), 8.11 (s, IH), 8.03 (m, 1H), 7.040, 1H), 6.72-6.61 (m, 1H), 6.02-5.91 (m, 1H), 4.02 (s, 2H), 2.89 (s, 2H), 2.07 (s, 6H);

MS (ESI ⁴ ): m/z = 446.3 [M+H] ⁺ . Example 35: Preparation of N-((2-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenyIamino)pyrimidm-5-yl)oxazol-4-y^

Step 1) Preparation of ethyl 4-hydroxy-pyrimidin-5-carboxylate 16 mL of 2-ethoxymethylene-malonate diethylester was mixed with 6.6 g of formamidine hydrochloride, and the mixture was stirred at 160°C under reflux for 20 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solid thus obtained by concentration was filtered under a reduced pressure and washed with acetone. The solid was dried under a reduced pressure to obtain the title compound (7.7 g, yield: 56%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.81 (s, 1H), 8.51 (s, 1H), 4.40 (dd, 2H), 1.35 (t,

3H).

Step 2) Preparation of ethyl 4-chloro-pyrimidin-5-carboxylate

2 g of the compound obtained in step 1) above was dissolved in 3.5 mL of phosphorus oxychloride, and 18 mL of thionylchloride and 50 \ih of dimethylformamide were added thereto. The mixture was stirred at 120°C under reflux for 5 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure. 50 mL of toluene was added to the residue, the resulting residue was distilled under a reduced pressure (repeated twice) and the resulting solid was dried to obtain the title compound (2.1 g, yield: 95%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 9.18 (s, 2H), 4.36 {dd, 2H), 1.33 (t, 3H). Step 3) Preparation of ethyl 4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino ^" )- pyrimidin-5-carboxylate 2.1 g of the compound obtained in step 2) above and 2.64 g of 3-chloro-4- (pyridin-2-ylmethoxy)benzenamine were dissolved in 20 mL of 2-propanol, and the mixture was stirred for 3 hours. After the reaction was completed, the resulting solution was cooled to room temperature and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : dichloromethane: methanol = 7 : 7 : 1) to obtain the title compound (2.0 g).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.32 (s, 1H), 9.01 (s, 1H), 8.79 (s, 1H), 8.60 (d, 1H), 7.82 (d, 1H), 7.75 (t, 1H), 7.73 {d, 1H), 7.43 (dd, 1H), 7.01 (dd, 1H), 5.29 (s, 2H), 4.34 (m, 2H), 1.26 (t, 3H).

Step 4) Preparation of 4-[3-cMoro-4-(pyridin-2-ylmethoxy ^" )-phenylamino -pyrimidin- 5- carboxylate

2.0 g of the compound obtained in step 3) above was dissolved in 15 mL of ethanol, and 13 mL of 2N aqueous sodium hydroxide was added thereto. The mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and 3N aqueous sodium hydroxide was gradually added to the residue at 0°C to acidify to pH 2~3. The solid thus obtained was filtered and dried under a reduced pressure to obtain the title compound (1.8 g, yield: 97%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.76 (s, 1H), 8.59 (d, 1H), 7.94 (t, 1H), 7.87 (s, 1H), 7.65( 1H), 7.46-7.43 (m, 2H), 7.21 (d, 1H), 5.29 (s, 2H).

Step 5) Preparation of methyl 2-((4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino ^' )- pyrimidin-5-carbonylVaminoV3-hvdroxypropanoate

1.9 g of the compound obtained in step 4) above and 1.53 g of l-ethyl-3-(3- dimethylaminopropyl)carboimide hydrochloride were dissolved in 10 mL of N,N- dimethylformamide, and 2.8 mL of NN-diisopropylethylamine and 5 mg of N- hydroxybenzotriazole were gradually added thereto, followed by stirring at room temperature for 5 minutes. 828 mg of A^-serine methylester was added to the mixture and stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was added with water and extracted with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 15 : 1) to obtain the title compound (1.2 g, yield: 49%).

. 1H-NMR (300MHz, CD ₃ OD) δ 8.72 (s, IH), 8.60 (s, IH), 8.51 (s, IH), 7.81 (d, 2H), 7.67 (d, IH), 7.39 (d, IH), 7.30-7.28 (m, IH), 6.98 (d, IH), 5.22 (s, 2H), 4.75- 4.74 (m, IH), 4.05 (d, IH), 3.93 (d, IH), 3.79 (s, 3H). Step 6) Preparation of methyl 2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino- pyrimidin-5-yl)-4,5-dihvdrooxazol-4-carboxylate

The procedure of step 4) of Example 1 was repeated using 1.3 g of the compound obtained in step 5) above. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 20 : 1) to obtain the title compound (1.1 g, yield: 89%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.91 (s, IH), 8.79 (s, IH), 8.72 (s, IH), 8.58 (s, IH), 7.83 (s, IH), 7.74-7.72 t, IH), 7.65 (d,- IH), 7.47 (dd, IK), Ί.26-12 (m, IH), 6.98 {d, IH), 5.28 (s, 2H), 5.03-4.99 (m, IH), 4.67-4.60 (m, 2H), 3.84 (s, 3H).

Step 7) Preparation of methyl 2-(4(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)- pyrimidin-5-yl)-oxazol-4-carboxylate

The procedure of step 6) of Example 1 was repeated using 1.1 g of the compound obtained in step 6) above. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 20 : 1) to obtain the title compound (709 mg, yield: 65%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.50 (s, IH), 9.00 (s, IK), 8.83 (s, IH), 8.43 (d, IH), 8.30 (s, IK), 7.92 (d, IK), 7.83 (t, IH), 7.38 (d, IH), 7.44 (dd, IK), 7.01 (d, IK), 5.30 (s, 2H), 4.00 (s, 3H).

Step 8) Preparation of (2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)- pyrimidin-5-ylVoxazol-4-yl)-methanol The procedure of step 7) of Example 1 was repeated using 100 mg of the compound obtained in step 7) above. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 20 : 1) to obtain the title compound (40 mg, yield: 43%).

1H-NMR (300MHz, CDC1 ₃ +CD ₃ 0D) δ 10.76 (s, 1H), 8.94 (5, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 7.90-7.75 (m, 3H), 7.54 (s, 1H), 7.32 (d, 2H), 7.03 (d, 1H), 5.30 (s, 2H), 4.71 (s, 2H).

Step 9) Preparation of (5- 4-aminomethyl-oxazol-2-vn-pyrimidin-4-yl)-(3-chloro-4- (pyridin-2-ylmethoxy)-phenyl)-amine

The procedure of step 8) of Example 1 was repeated using 20 mg of the compound obtained in step 8) above. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 5 : 1) to obtain the title compound (16 mg, yield: 80%).

1H-NMR (300MHz, CDCI ₃ +CD ₃ OD) δ 8.95 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 7.90 s, 1H), 7.87-7.82 (m, 1H), 7.75 (s, 2H), 7.53 (d, 1H), 7.38 (d, 2H), 7.08 (d, 1H), 5.31 (s, 2H), 3.79 (s, 2H);

MS (ES ): m/z = 409.2 [M+H] ⁺ .

Step 10) Preparation of N-(2-(4-(3-cliloro-4-(pyridin-2-ylmethoxy)-phenylamino ^' )- pyrimidin-5-yl ^" )-oxazol-4-ylmethyl)acrylamide

The procedure of step 9) of Example 1 was repeated using 15 mg of the compound obtained in step 9) above. The resulting residue was subjected to column chromatography (dichloromethane : methanol = 20 : 1) to obtain the title compound (1.8 mg, yield: 10%).

1H-NMR (300MHz, CDC1 ₃ ) 5 10.56 (s, 1H), 8.95 (s, 1H), 8.72 (s, 1H), 8.59 (d, 1H), 7.86 (s, 1H), 7.76-7.67 (m, 3H), 7.53 (dd, 1H), 7.00 (d, 1H), 6.40 (s, 1H), 6.19 (s, 1H), 5.73 (d, 1H), 5.30 (s, 2H), 4.56 (d, 2H);

MS (ES ): m/z = 463.3 [M+H] ⁺ . Example 36: Preparation of N-((2-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenyIammo)pyrimidin-5-yl)oxazol-4-yl)methyl)-2-

((dimethylainino)methyI)acrylamide 2.5 mg of the compound obtained in step 1) of Example 3 was dissolved in 1 mL of dichloromethane, and 4.6 mg of N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride, 0.6 mg of N-hydroxybenzotriazole and 8 μΐ _^ of N,N- diisopropylethylamine were gradually added thereto, followed by stirring at room temperature for 5 minutes. 6.5 mg of the compound obtained in step 9) of Example 35 was added thereto, followed by stirring at room temperature for 3 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added thereto, and the resulting mixture was extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 15 : 1) to obtain the title compound (3 mg, yield: 38%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.71 (s, 1H), 9.70 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.60 (d, 1H), 7.86 (d, 1H), 7.76 (t, 1H), 7.67 (m, 2H), 7.57 (m, 1H), 7.23 (m, 1H), 7.01 (d, 1H), 6.30 (s, 1H), 5.45 (s, 1H), 5.30 (s, 2H), 4.52 (d, 2H), 3.14 (s, 2H), 2.19 (s, 6H);

MS (ESI*): m/z = 520.3 [M+H] ⁺ .

Example 37: Preparation of N-((2-(4-acetamido-6-(3-chIoro-4-(l-methyl-3- (trifluoromethyl)-lH-pvrazoI-5-yloxy)phenyIanim^

yl)methyl)acrylamide

23 mg of the compound obtained in Example 29 was dissolved in 0.5 mL of acetic anhydride and stirred at 70°C for 2 hours. After the reaction was completed, the mixture was distilled under a pressure, and the resulting residue was subjected to column chromatography (chloroform : methanol = 30 : 1) to obtain the title compound (17 mg, yield: 69%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.79 (s, 1H), 9.75 (s, 1H), 8.50 (s, 1H), 7.98 (d, 1H), 7.78 (s, 1H), 7.60 (m, 1H), 7.20 (d, 1H), 6.38 (m, 1H), 6.15 (m, 2H), 5.73 (m, 2H), 4.58 (d, 2H), 3.88 (s, 3H), 2.56 (s, 3H);

MS (ESI ⁺ ): m/z = 577.3 [M+H] ⁺ . Example 38: Preparation of N-((2-(4-acetamido-6-(3-chloro-4-(pyridin-2- ylmethoxy)phenylainmo)pyrimidm-5-yI)oxazol-4-yl)methyl)acryl aini

10 mg of the compound obtained in Example 1 was dissolved in 0.5 mL of acetic anhydride, and stirred at 130°C for 1 hour. After the reaction was completed, the mixture was distilled under a pressure, and the resulting residue was subjected to column chromatography (chloroform : methanol = 20 : 1) to obtain the title compound (3 mg, yield: 29%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.32 (s, 1H), 10.01 (s, 1H), 8.60 (d, 1H), 8.43 s, 1H), 7.76 (m, 2H), 7.67 (d, 1H), 7.40 (m, 1H), 7.00 (d, 1H), 6.37 (m, 1H), 6.30 (m, 1H), 6.16 (TM, lH), 5.71 (m, 1H), 5.29 (s, 2H), 4.95 (s, 1H), 4.55 (d, 1H), 2.55 (s, 3H).

Example 39: Preparation of E iV-((2-(4-(3-chIoro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yI)oxazol-4-yI)methyl)-4-

(dimethylarnino)but-2-enamide

3.9 mg of the compound obtained in step 2) of Example 4 was dissolved in 1 mL of dichloromethane, and 5.6 mg of N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride, 0.8 mg of JV-hydroxybenzotriazole and 10 of N _j N-diisopropylemylamine were gradually added thereto and stirred at room temperature for 5 minutes. 8 mg of the compound obtained in step 9) of Example 35 was added to the mixture and stirred at room temperature for 3 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added thereto, and the resulting mixture was extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 8 : 1) to obtain the title compound (2 mg, yield: 19%). 1H-NMR (300MHz, CDC1 ₃ ) δ 10.55 (s, 1H), 8.95 (j, 1H), 8.72 (s, 1H), 8.60 (d, 1H), 7.85 (d, 1H), 7.73 (m, 1H), 7.67 (m, 2H), 7.52 (m, 1H), 7.25 (m, 1H), 7.01 d, 1H), 6.90 (m, 1H), 6.08 (m, 1H), 5.29 (5, 2H), 4.54 (d, 2H), 3.1 1 d, 2H), 2.19 (5, 6H).

Example 40: Preparation of N-((2-(4-(3,4-dichloro-2- fluorophenylammo)pyrimidin-5-yI)oxazol-4-yl)methyl)acrylamid e

The procedure of Example 35 was repeated except for using 3,4-dichloro-2- fluoroaniline instead of 3-cUoro-4-(pyridm-2-ylmemoxy)-phenylamine to obtain the title compound (4 mg, final yield: 18%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.76 (m, 2H), 8.70 (s, 1H), 8.47 (m, 1H), 8.23

(m, 1H), 7.42 (m, 1H), 5.75 (d, 1H), 5.27 (s, 1H), 4.66 (d, 2H).

Example 41: Preparation of N-((2-(4-(3-chloro-4-fluorophenylammo)pyrimidin-5- yl)oxazol-4-yl)methyl)acrylamide

The procedure of Example 35 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-cUoro-4-^yridin-2-ylmethoxy)benzenarnine to obtain the title compound (3 mg, final yield: 7%).

1H-NMR (300MHz, CDCI ₃ ) δ 10.72 (s, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 7.95 (m, 1H), 7.73 (s, 1H), 7.58 (m, 1H), 7.24 (m, 1H), 7.17 (m, 1H), 6.40 (d, 1H), 6.15 (m, 1H), 6.01 (w, 1H), 5.74 (d, 1H), 4.57 (d, 2H);

MS (ESI" : m/z = 374.2 [M+H] ⁺ .

Example 42 : N-((2-(4-(3-cUoro^-fluorophenylamino)pyridin-5-yl)oxazol-4- yl)methyl)-2-((dimethylamino)methyl)acrylamide

The procedure of Example 36 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (10 mg, final yield: 49%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.87 (s, 1H), 9.70 (s, 1H), 8.99 (s, 1H), 8.77 (5, 1H), 7.96 (m, 1H), 7.67 (s, 1H), 7.63 (m, 1H), 7.17 (t, 1H), 6.31 (d, 1H), 5.46 (s, 1H), 4.54 (d, 2H), 3.15 (d, 2H), 2.21 (s, 6H);

MS (ESI*): m/z = 431.3 [M+H] ⁺ .

Example 43: Preparation of (¾)-N-((2-(4-(3-chloro-4- fluorophenylammo)pyrimidm-5-yl)oxazol-4-yI)methyl)-4-(dimeth yIammo)but-2- enamide

The procedure of Example 39 was repeated except for using 3-chloro-4- fluoroaniline instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (12 mg, final yield: 44%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.73 (s, 1H), 8.97 (s, 1H), 8.75 (s, 1H), 7.96 (d, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.16 (t, 1H), 6.90 {m, 1H), 6.25 (m, 1H), 6.10 (d, 1H), 4.55 (d, 2H), 3.15 (rf, 2H), 2.31 (s, 6H);

MS (ESI ⁺ ): m/z = 431.2 [M+H] ⁺ .

Example 44: Preparation of iV-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrinudm-5-yl)isooxazol-3-yl)methyl)acr ylamide

Step 1) Preparation of 5-iodopyrimidin-4(3H)-one

10 g of 4(3H)-pyrimidone was dissolved in 156 mL of acetic acid, and 25.8 g of N-iodosuccinimide was added thereto at 70°C and heated to 100°C, followed by stirring for 30 minutes. After the reaction was completed, the mixture was cooled to room temperature then cooled in ice to induce the crystallization of the product, followed by filtering under a reduced pressure. The solid thus obtained was washed with water and dried under a reduced pressure to obtain the title compound (16 g, yield: 67%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 12.88 (bs, 1H), 8.42 (s, 1H), 8.17 (s, 1H). Step 2) Preparation of 4-chloro-5-iodopyrimidine hydrochloride

10 g of the compound obtained in step 1) above was added to 60 mL of phosphorus oxychloride and stirred at 110°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and distilled under a reduced pressure to remove solvent therefrom. Toluene was added to the residue, and the resulting residue was concentrated under a reduced pressure to remove the solvent, and this procedure was repeated 3 times. The solid thus obtained was dried under a reduced pressure to obtain the title compound (13 g).

1H-NMR (300MHz, DMSO-de) δ 13.27 bs, 1H), 9.18 (s, 1H), 8.98 (s, 1H).

Step 3 Preparation of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-iodopyrimidin- 4-amine

7 g of the compound obtained in step 2) above and 6.5 g of 3-chloro-4- (pyridin-2-ylmethoxy)benzenamine were dissolved in 100 mL of 2-propanol, and the mixture was heated to 100°C and stirred for 2 hours. After the reaction was completed, the resulting solution was cooled to 0°C and stirred for 2 hours. The solid thus obtained was filtered under a reduced pressure and washed with 2-propanol, followed by drying under a reduced pressure to obtain the title compound (12.5 g).

1H-NMR (300MHz, DMSO-de) δ 9.56 (m, 1H), 8.67 (w, 2H), 8.05 (m, 1H), 7.65 (m, 2H), 7.34 (m, 3H), 5.36 (s, 2H).

Step 4) Preparation of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5- ((trimemylsilyl)etlimyl)pyrimidin-4-amine

5.67 g of the compound obtained in step 3) above, 181 mg of dichlorobis(triphenylphosphine)palladium(II) and 98 mg of copper(I) iodide were dissolved in 60 mL of tetrahydrofuran, and 7.2 mL of triethylamine and 2.15 mL of trimethylsilylacetylene were added to the mixture and stirred at room temperature for 24 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added thereto, and the resulting mixture was extracted twice with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : hexane = 1 : 10) to obtain the title compound (1.8g, yield: 34%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.62 (s, 1H), 8.60 (d, 1H), 8.41 (s, 1H), 7.80 (d, 1H), 7.75 (m, 1H), 7.65 (d, 1H), 7.37 (m, 1H), 7.23 (m, 2H), 7.00 (d, 1H), 5.29 (s, 2H), 1.77 (5, 1H), 0.32 (s, 9H).

Step 5) Preparation of N-(3-cMoro-4-(pyridm-2-ylmemoxy)phenyl)-5-ethinyl pyrimidin~4- amine

1.8 g of the compound obtained in step 4) above was dissolved in 30 mL of tetrahydrofuran, and 8.8 mL of 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran was added thereto and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the title compound (1.4g, yield: 94%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.65 (j, 1H), 8.60 (m, 1H), 8.45 (s, 1H), 7.76 (m, 2H), 7.64 (d, 1H), 7.41 (m, 1H), 7.24 (m, 2H), 6.99 (d, 1H), 5.29 (s, 2H), 3.67 (s, 1H). Step 6) Preparation of 2-( ( 5-f4-(3-chloro-4-(pyridin-2- ylmemoxy)phenylammo)pyrimidin-5-ylfe^

6.8 mL of oxalylchloride was dissolved in 250 mL of dichloromethane, and cooled to -78°C. 8.9 mL of dimethyl sulfoxide was added to the mixture and stirred for 10 minutes. 10 g of N-(2-hydroxyemyl)phmalimide was gradually added to the mixture and stirred for 30 minutes, and 36.5 mL of triethylamine was added thereto. The resulting mixture was heated to 0°C and stirred for 1 hour. After the reaction was completed, the resulting mixture was added with a saturated aqueous solution of ammonium chloride, and extracted twice with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. 5.5 g of the solid thus obtained was dissolved in 50 mL of pyridine, and 6.1 g of hydroxylamine hydrochloride was added thereto, followed by stirring at 65°C for 5 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, ethyl acetate was added thereto and washed three times with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was crystallized with diethyl ether. The resulting solid was filtered under a reduced pressure and washed with diethyl ether. The solid thus obtained was dried under a reduced pressure. 588 mg of the solid was dissolved in 10 mL of tetrahydrofuran, and 595 mg of N-cUorosuccinimide and 36 μί, of pyridine were added thereto, followed by stirring at 70°C for 2 hours. 500 mg of the compound obtained in step 5) and 621 μί, of triethylamine were added to the mixture and stirred at 70°C for 12 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the title compound (450 mg, yield: 56%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.61 s, 1H), 8.59 (s, 1H), 8.56 (d, 1H), 7.90 (w, 5H), 7.67 (d, 1H), 7.54 (d, 1H), 7.40 (m, 1H), 7.35 (m, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 5.25 {d, 2H), 4.92 (d, 2H).

Step 7) Preparation of 5-(3-(arnmomemyl)isooxazol-5-vn-N-(3-chloro-4-(pyridin-2- ylmemoxy)phenyl)pyrimidm-4-amine

450 mg of the compound obtained in step 6) above was dissolved in 10 mL of ethanol, and 203 uL of hydrazine hydrate was added thereto, followed by stirring at 70°C for 1 hour. After the reaction was completed, the reaction mixture was cooled to 0°C, and the solid thus obtained was washed with chloroform, filtered and the filtrate therefrom was distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 15 : 1) to obtain the title compound (200 mg, yield: 59%).

1H-NMR (300MHz, DMSO-d ₆ ) δ 8.79 (m, 1H), 8.61 (s, 1H), 8.57 (d, 1H), 7.86 {t, 1H), 7.71 (d, 1H), 7.55 (d, 1H), 7.45 (m, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 7.04 (s, 1H), 5.26 (i , 2H), 3.79 (5, 2H).

Step 8) Preparation of _. N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy phenylamino^pyrimidin-S-vnisooxazol-S-vnmethvnacrylamide mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 69 mg of N- hydroxybenzotriazole and 895 μΐ, of N^V-diisopropylethylamine were added thereto, followed by stirring at room temperature for 10 minutes. 700 mg of the compound obtained in step 7) was added to the mixture and stirred at room temperature for 3 hours. After the reaction was completed, the resulting mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 50 : 1) to obtain the title compound (300 mg, yield: 38%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.67 (s, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 7.74 (τη, 2H), 7.67 (d, 1H), 7.38 (m, 1H), 7.27 (ττι, 1H), 7.01 (m, 2H), 6.71 (s, 1H), 6.37 (m, 1H), 6.20 (/«, 1H), 5.74 (m, 1H), 5.28 (s, 2H), 4.64 (d, 2H);

MS (ES ): m/z = 463.1 [M+H] ⁺ .

Example 45: Preparation of N-((5-(4-(3-chloro-4-(3- fluorobeiizyloxy)phenylainmo)pvrinu m-5-yl)isooxaz

The procedure of Example 44 was repeated except for using 3-chloro-4-(3- fluorobenzyloxy)benzenamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine in step 3) to obtain the title compound (6 mg, final yield: 11%).

1H-NMR (300MHz, CD ₃ OD) δ 8.57 (m, 2H), 7.71 (m, 1H), 7.40 (rn, 2H), 7.30

(m, 2H), 7.11 (τη, 2H), 6.85 (s, 1H), 6.30 (τη, 2H), 5.72 (t, 1H), 5.19 (s, 2H), 4.53 (TTI, 2H);

MS (ESf): m/z = 480.4 [M+H] ⁺ . Example 46: Preparation of iV-(2-(5-(4-(3-chIoro-4-(3- fluorobenzyIoxy)phenylammo)pyridm-5-yl)isooxazol -yl)ethyI)acrylamide

The procedure of Example 44 was repeated except for using 3-chloro-4-(3- fluorobenzyloxy)benzenamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine in step 3), and N-(3-hydroxypropyl) pthalimide instead of N- (2-hydroxyethyl)pthalimide in step 6) to obtain the title compound (29 mg, final yield: 51%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.71 (s, IH), 8.60 (s, IH), 8.06 (s, IH), 7.77 (m,

IH), 7.41 (m, 4H), 7.22 (m, 2H), 6.97 (m, 2H), 6.55 (s, IH), 6.25 (d, IH), 6.08 (m, 2H), 5.63 (d, IH), 5.16 (s, 2H), 3.79 (m, 2H), 3.03 (m, 2H);

MS (ESf): m/z = 494.2 [M+H] ⁺ . Example 47: Preparation of l-(2-(5-(4-(3-chloro-4-(3- fluorobenzyloxy)phenylammo)pyrimidm-5-yl)isooxazoI -yl)pyrroUdin-l-yl)prop-

2- en-l-one

Step 1) Preparation of N-(3-cMoro-4-(3-fluoroben2yloxy phenyl)-5-etliinylpyrimidin- 4-amine

The procedure of steps 1) to 5) of Example 44 was repeated except for using

3- chloro-4-(3-fluorobenzyloxy)benzenamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine to obtain the title compound (184 mg).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.64 (s, IH), 8.44 (s, IH), 7.73 (d, IH), 7.40 (m,

3H), 7.20 (m, 3H), 6.94 (m, 2H), 5.19 (y, 2H), 3.66 {d, IH).

Step 2) Preparation of tert-butyl 2-(5-(4-(3-chloro-4-(3- fluorobenzyloxy)phenylarrimo)pyrimidin-5-yl)isooxazol-3-yl)p yn ^{^}

500 mg of the N-Boc-L-prolinole was dissolved in 25 mL of dichloromethane, and 1.26 g of Dess-Martin periodinane was added thereto and stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction mixture and extracted twice with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The solid thus obtained was dissolved in 5 mL of pyridine, and 517 mg of hydroxylamine hydrochloride was added thereto, followed by stirring at 65°C for 1 hour. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, followed by adding ethyl acetate thereto and washing three times with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : hexane = 1 : 1). 91 mg of the solid thus obtained was dissolved in 2 mL of tetrahydrofuran, and 75 mg of N-chlorosuccinimide and 4 μί, of pyridine were added thereto, followed by stirring at room temperature for 2 hours. 100 mg of the compound obtained in step 1) and 47 μΐ. of triethylamine were added to the mixture and stirred at 65°C for 3 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (dichloromethane : ethyl acetate = 40 : 1) obtain the title compound (138 mg, yield: 86%).

'.H-NMR (300MHz, CDC1 ₃ ) δ 9.03 (s, 2H), 8.70 (s, 1H), 8.19 (s, 1H), 7.75 (d, 1H), 7.38 (m, 2H), 7.22 (m, 2H), 7.01 (m, 2H), 6.61 (s, 1H), 5.14 (s, 2H), 3.57 (m, 3H), 2.30 m, 4H), 1.42 (5, 9H).

Step 3) Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl ^' )-5-(3-(pyrrolidine-2- vDisooxazol-5-yl)pwolidin-4-amine

138 mg of the compound obtained in step 2) above was dissolved in 1 mL of dichloromethane, and 1 mL of tnfluoroacetic acid was added thereto, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted twice with dichloromethane. The resulting residue was subjected to column chromatography (dichloromethane : ethyl acetate : methanol = 10 : 10 : 1) obtain the title compound (54 mg, yield: 49%).

1H-NMR (300MHz, CD ₃ OD) δ 8.59 (d, 2H), 7.71 (m, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.09 (m, 2H), 6.90 (s, 1H), 5.19 (s, 2H), 3.53 (m, 3H), 2.30 m, 4H).

Step 4) Preparation of _. l-(2-(5-(4-(3-chloro-4-(3- fluorobenzyloxy)phenylamino)pyrimidin-5- yl)isooxazol-3 -vDpyrrolidin- 1 -yl)prop-2- en-l-one bicarbonate were dissolved in a mixture of 2 mL of tetrahydrofuran and 0.5 mL of distilled water at 0°C, and 8.8 μL of acryloyl chloride was added thereto, followed by stirring at same temperature for 1 hour. After the reaction was completed, the reaction mixture was added with a saturated aqueous solution of sodium bicarbonate, and extracted twice with chloroform. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (dichloromethane : ethyl acetate : methanol = 50 : 150 : 1) to obtain the title compound (20 mg, yield: 35%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.70 (d, 2H), 8.11 (s, 1H), 7.74 (d, 1H), 7.36 (m, 3H), 7.19 (m, 2H), 6.68 (m, 2H), 6.51 (s, 1H), 6.46 (rn, 1H), 5.77 (m, 1H), 5.45 (m, 1H), 5.15 (s, 2H), 3.71 (m, 3H), 2.26 (m, 4H).

Example 48: Preparation of l-(3-(5-(4-(3-chloro-4-(3- fluorobenzyloxy)phenyIammo)pyrimidm-5-yI)isooxazol-3-yl)pipe ridm-l-yl)prop-

2- en-l-one The procedure of Example 47 was repeated except for using N-Boc-piperidin-

3- methanol instead of N-Boc-Z-prolinole in step 2) to obtain the title compound (15 mg, final yield: 38%).

1H-NMR (300MHz, CD ₃ OD) δ 8.54 (d, 2H), 7.68 (d, 1H), 7.40 (m, 2H), 7.24

(m, 2H), 7.04 (m, 2H), 6.88 (s, 1H), 5.14 (s, 2H), 3.43 (m, 1H), 3.19 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.16 (m, 1H), 1.79 (m, 4H).

Example 49: Preparation of l-(4-(5-(4-(3-chloro-4-(3- fluorobenzyIoxy)phenylammo)pyrimidin-5-yl)isooxazoI-3-yl)pip eridin-l-yl)prop-

2-en-l-one

The procedure of Example 47 was repeated except for using N-Boc-4- piperidinemethanol instead of N-Boc-Z,-prolinole in step 2) to obtain the title compound (7 mg, final yield: 21%). 1H-NMR (300MHz, CDC1 ₃ ) δ 8.65 (d, 2H), 8.15 (s, 1H), 7.74 (s, 1H), 7.37 (m, 2H), 7.21 (w, 2H), 6.97 (m, 2H), 6.66 (m, 1H), 6.50 (s, 1H), 6.32 (m, 1H), 5.74 (d, 1H), 5.15 (s, 2H), 4.80 (m, 1H), 4.10 (m, 1H), 3.16 (τη, 1H), 3.09 (m, 1H), 3.00 (m, 1H), 2.02 (m, 4H), 1.83 (/n, 3H).

Example 50: Preparation of N-((5-(4-l-(3-fIuorobenzyl)-lH-indazole-5- ylamino)pyrinudin-5-yl)isooxazol-3-yl)methyl)acrylan ide

The procedure of Example 44 was repeated except for using l-(3-fluoro- benzyl)- lH-indazole-5-ylamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine to obtain the title compound (5 mg, final yield: 6%).

1H-NMR (300MHz, CD ₃ OD) δ 8.58 (s, 1H), 8.52 (s, 1H), 8.21-8.18 (m, 2H), 8.04 (s, 1H), 7.98 (s, 1H), 7.90-7.87 (m, 2H), 7.57-7.47 m, 2H), 6.89 (s, 1H), 6.31-6.29 (m, 2H), 5.74-5.70 (m, 1H), 4.60 (5, 2H).

Example 51: Preparation of iV-((5-(4-(4-bromo-3-chloro-2- fluorophenylammo)pyrimidm-5-yl)isooxazol-3-yl)methyl)aci laimde

The procedure of Example 44 was repeated except for using 4-bromo-3- chloro-2-fluoroaniline instead of 3-c oro-4-(pyridin-2-ylmethoxy)benzenamine in step 2) to obtain the title compound (17 mg, final yield: 38%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.78 (m, 2H), 8.73 (5, 1H), 8.50 (m, 1H), 8.26

(m, 1H), 7.45 (m, 1H), 5.77 (d, 1H), 5.30 (s, 1H), 4.68 (d, 2H);

MS (ES ): m/z = 452.07 [M+H] ⁺ .

Example 52: Preparation of (R)-N-((5-(4-phenylethylamino)pyrimidin-5- yl)isooxazol-3-yl)methyl)acrylamide

The procedure of Example 44 was repeated except for using (R)-(+)- - methylbenzylamine instead of 3-chloro-4-(pyridin-2-ylmethoxy)benzenamine to obtain the title compound (70 mg, final yield: 31 %).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.59 (s, 1H), 8.46 (s, 1H), 7.40-7.27 (m, 4H),

6.56 (s, 1H), 6.41-6.35 (m, 1H), 6.20-6.11 (m, 2H), 5.76-5.72 (m, 1H), 5.55-5.50 (m, IH), 4.68-4.66 (d, 2H), 1.63-1.61 (d, 3H).

Example 53: Preparation of f¾ -N-((5-(4-(3-chIoro-4-(pyridin-2- ylmethoxy)phenylamino)pyrimidin-5-yl)isooxazol-3-yl)methyl)- 4-

(dimethylamino)but-2-enamide

The procedure of Example 44 was repeated except for using (E)-4- (dimethylamino)but-2-enoic acid instead of acrylic acid in step 8) to obtain the title compound (5 mg, final yield: 8%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.71 (s, IH), 8.62 (s, 2H), 8.06 s, IH), 7.76 (m, 2H), 7.67 (d, IK), 7.40 (d, IK), 7.26 (m, IH), 7.02 (d, IH), 6.94 (m, IH), 6.68 (s, IK), 6.16 (m, IH), 6.05 (d, IK), 5.31 (s, 2H), 4.69 (d, 2K), 3.11 (d, 2K), 2.29 (s, 6H);

MS (ESf): m/z = 520.1 [M+H] ⁺ .

Example 54: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)isooxazol-3-yl)methyl)-2 -

((dimethylamino)methyl)acrylamide

The procedure of Example 44 was repeated except for using 2- ((dimethylamino)methyl)acrylic acid instead of acrylic acid in step 8) to obtain the title compound (13 mg, final yield: 20%).

1H-NMR (300MHz, CDC1 ₃ ) δ 9.89 (s, IK), 8.70 (s, IK), 8.60 (m, 2H), 8.10 (s, IH), 7.77 (m, 2H), 7.66 (d, IK), 7.40 (d, IK), 7.25 (i, IH), 7.01 (d, IK), 6.68 (s, IK), 6.31 (s, IK), 5.49 (s, IK), 5.30 (s, 2H), 4.64 (d, 2H), 3.18 (s, 2K), 2.26 (s, 6H);

MS (ESI*): m/z = 520.1 [M+H] ⁺ .

Example 55: Preparation of (¾>-N-((5-(4-(3-chloro-4-(3- fluorobenzyloxy)phenylamino)pyrimidin-5-yl)isooxazol-3-yl)me thyl)-4-

(dimethylamino)but-2-enamide

The procedure of Example 53 was repeated except for using 3-chloro-4-(3- fluorobenzyloxy)benzenamine instead of 3-chloro-4-(pyridin-2- ylmethoxy)benzenamine to obtain the title compound (16 mg, final yield: 30%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.70 (s, 1H), 8.60 (s, 1H), 8.07 (d, 1H), 7.73 d, 1H), 7.70 ( , 2H), 7.27 (m, 2H), 7.04 (m, 3H), 6.67 (s, 1H), 6.05 (m, 2H), 5.16 (s, 2H), 4.62 (d, 2H), 3.07 (d, 2H), 2.26 (s, 6H).

Example 56: Preparation of (Z)-iV-((5-(4-(3-chloro-4-(pyridin-2- yImethoxy)phenyIammo)pyridin-5-yl)isooxazol-3-yI)methyI)-4-h ydroxybut-2- enamide Step 1) Preparation of (Z)-4-(t-butyldiphenylsilyloxy ^' )but-2-en-l-ol

10 g of the c -?-2-buten-l,4-diol was dissolved in 100 mL of Ν,Ν'- dimethylformamide, and 27.6 mL of t-butyl(chloro)diphenylsilane and 15.5 g of imidazole were added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the resulting mixture was added with water and extracted with ethyl acetate. The separated organic layer was washed three times with water, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : n-hexane = 1 : 20) to obtain the title compound (17 g, yield: 46%).

1H-NMR (300MHz, CDC1 ₃ ) δ 7.74 (m, 4H), 7.46 (m, 6H), 5.70 (m, 2H), 4.30

(d, 2H), 4.04 (f, 2H), 1.71 (t, 1H), 1.09 (s, 9H).

Step 2) Preparation of (Z)-4-(t-butyldiphenylsilyloxy)but-2-enoic acid 3.6 mL of oxalyl chloride was dissolved in 150 mL of dichloromethane, and cooled to -78°C. A mixture of 4.7 mL of dimethyl sulfoxide and 50 mL of dichloromethane was slowly added thereto and stirred for 5 minutes. A solution of 9 g of the compound obtained in step 1) in 50 mL of dichloromethane was slowly added to the mixture at -78°C and stirred for 20 minutes. 19.2 mL of trimethylamine was added to the resulting mixture and heated to 0°C, followed by stirring for 30 minutes. After the reaction was completed, the resulting mixture was added with a saturated aqueous solution of ammonium chloride and extracted twice with dichloromethane. The separating organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was added with diethyl ether was added to the resulting residue, filtered and distilled under a reduced pressure. The compound thus obtained was dissolved in a mixture of 80 mL of tetrahydrofuran 80 mL of t-butanol. A solution of 10 g of sodium dihydrogen phosphate in 40 mL of water was added to the resulting mixture at 0°C and stirred for 10 minutes. 9.9 mL of dimethyl sulfoxide was added to the resulting mixture and stirred for 10 minutes, and 9.4 g of sodium chlorite was added thereto, followed by stirring for 1 hour. After the reaction was completed, the reaction mixture was added with a saturated aqueous solution of sodium bicarbonate, and acidified with 1 N hydrochloride aqueous solution to pH 3, followed by extracting twice with ethyl acetate. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : n-hexane = 1 : 10) to obtain the title compound (6.9 g, yield: 73%).

1H-NMR (300MHz, CDC1 ₃ ) δ 7.66 (m, 4H), 7.39 (m, 6H), 6.58 (m, 1H), 5.71

(m, lH), 4.78 (m, 2H), 1.07 (s, 9H).

Step 3) Preparation of (Z)-4-(pteridin-5-yl)art-butyldiphenylsilyloxy)-N-((5-(4-(3- cMoro-4-(pyridin-2-ylmemoxy)phenylamino)pyisooxazol-3-yl)met hyl)but-2-enamide

The procedure of Example 44 was repeated except for using the compound obtained in step 2) above instead of acrylic acid in step 8) of Example 44 to obtain the title compound (45 mg, final yield: 56%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.69 (s, 1H), 8.59 (m, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.74 (m, 1H), 7.72 (d, 1H), 7.65 (w, 4H), 7.37 (m, 7H), 7.22 (m, 1H), 6.98 (d, 1H), 6.55 (s, 1H), 6.30 (m, 1H), 5.73 (m, 1H), 5.28 (s, 2H), 4.82 (m, 2H), 4.54 (d, 2H), 1.05 (j, 9H).

Step 4) Preparation of ^-N-((5-(4-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyridin-5-yl)isooxazol-3-vnmethvn-4-hvd roxybut-2-enamide

45 mg of the compound obtained in step 3) above was dissolved in 2 mL of tetrahydrofuran, and 123 ih of 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran was added thereto at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was added with a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform: methanol = 15 : 1) to obtain the title compound ( 8 mg, yield: 26%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.58 (d, 1H), 7.76 (m, 2H), 7.68 (d, 1H), 7.38 (m, 1H), 7.24 (m, 1H), 7.01 (d, 1H), 6.69 (s, 1H), 6.37 m, 1H), 5.90 {d, 1H), 5.28 (s, 2H), 4.62 (d, 2H), 4.49 (d, 2H);

MS (ESf : m/z = 493.1 [M+H] ⁺ .

Example 57: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- yImethoxy)phenylaimno)pyrimidin-5-yl)isooxazoI-3-yl)methyl)- 2- ((diethylamino)methyl)acrylamide

Step 1) Preparation of 2-((diemylamino)methyl)acrylic acid

1 g of malonic acid and 0.63 g of paraformaldehyde were dissolved in 15 mL of ethanol and 1 mL of diethylamine was added thereto. The mixture was heated to 75°C and stirred for 2 hours. After the reaction was completed, the mixture was distilled under a reduced pressure. The concentrated liquid residue was subjected to column chromatography (chloroform : methanol = 2 : 1) to obtain the title compound (500 mg, yield: 33%).

1H-NMR (300MHz, CDC1 ₃ ) δ 11.50 (s, 1H), 6.38 (d, 1H), 5.58 m, 1H), 3.61

(s, 2H), 2.96 (q, 4H), 1.27 (t, 6H).

Step 2) N-((5-(4-(3-cMoro-4-(pyridm-2-ylmemoxy)phenylamino)pyrimidin -5- yl)isooxazol-3-yl)methyl)-2-((diethylamino)methyl)acrylamide

The procedure of Example 44 was repeated except for using the compound obtained step 1) above instead of acrylic acid in step 8) of Example 44 to obtain the title compound (5 mg, final yield: 7%). 1H-NMR (300MHz, CDC1 ₃ ) δ 10.29 (s, 1H), 8.73 s, 1H), 8.62 (m, 2H), 8.11 (J, 1H), 7.79 (m, 2H), 7.68 (d, 1H), 7.41 (m, 1H), 7.25 (m, 1H), 7.04 d, 1H), 6.69 (s, 1H), 6.34 (j, 1H), 5.51 (s, 1H), 5.33 (5, 2H), 4.66 (d, 2H), 3.34 (j, 2H), 2.58 (9, 4H), 1.06 (t, 6H);

MS (ESI*): m/z = 548.2 [M+H] ⁺ .

Example 58: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyridin-5-yl)isooxazol-3-yl)methyl)-2-( pyrrolidin-l- ylmethyl)acrylamide

The procedure of Example 57 was repeated except for using pyrrolidine instead of diethylamine in step 1) to obtain the title compound (30 mg, final yield: 45%).

1H-NMR (300MHz, CDC1 ₃ ) δ 10.10 (m, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.60 (s, 1H), 8.03 (s, 1H), 7.77 (m, 2H), 7.64 (m, 2H), 7.35 (m, 1H), 7.25 (m, 1H), 6.99 (d, 1H), 6.65 (s, 1H), 6.17 (s, 1H), 5.50 (s, 1H), 5.30 (j, 2H), 4.66 d, 2H), 3.35 (s, 2H), 2.50 (m, 4H), 1.75 (m, 4H);

MS (ESf): m/z = 546.2 [M+H] ⁺ .

Example 59: Preparation of iV-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidm-5-yl)isooxazoI-3-yI)methyl)-2-

(morpholinomethyl)acrylamide

The procedure of Example 57 was repeated except for using morpholine instead of diethylamine in step 1) to obtain the title compound (7 mg, final yield: 10%).

1H-NMR (300MHz, CDC1 ₃ ) δ 9.74 (s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.58 (5, 1H), 8.05 (5, 1H), 7.74 (m, 2H), 7.64 (d, 1H), 7.37 (m, 1H), 7.24 (m, 1H), 7.00 (d, 1H), 6.65 (s, 1H), 6.35 d, 1H), 5.52 (s, 1H), 5.29 (s, 2H), 4.65 (d, 2H), 3.72 (t, 4H), 3.27 (s, 2H), 2.50 (m, 4H);

MS (ESI*): m/z = 562.5 [M+H] ⁺ .

Example 60: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)isooxazol-3-yl)methyl)-2 -((4- methylpiperazin-l-yl)methyl)acrylamide

The procedure of Example 57 was repeated except for using 1- raethylpiperazine instead of diethylamine in step 1) to obtain the title compound (20 mg, final yield: 29%).

1H-NMR (300MHz, CDC1 ₃ ) δ 9.85 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.58 (s, 1H), 8.07 (s, 1H), 7.74 ( , 2H), 7.64 (d, 1H), 7.38 (d, 1H), 7.24 (m, 1H), 7.00 (d, 1H), 6.66 (s, 1H), 6.33 (s, 1H), 5.50 (s, 1H), 5.29 (s, 2H), 4.63 (d, 2H), 3.26 (s, 2H), 2.51 (m, 8H), 2.28 (s, 3H);

MS (ESf): m/z = 575.3 [M+H] ⁺ .

Example 61: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)isooxazoI-3-yI)methyl)-2 -

(hydroxymethyl)acrylamide

Step 1) Preparation of 2-((t-butyldimethylsilyloxy)methyl ^' )-N-((5-(4-(3-chloro-4- (pyridm-2-ylmemoxy)phenylamino)pyrimidm^

The procedure of Example 44 was repeated except for using 2-((t- butyldimethylsilyloxy)methyl)acrylic acid prepared according to International Patent Publication No. WO2008/1501 18 instead of acrylic acid in step 8) to obtain the title compound (87 mg, final yield: 59%).

Ή-NMR (300MHz, CDC1 ₃ ) δ 8.59 (m, 3H), 7.86 (d, 1H), 7.70 (m, 2H), 7.63 (d, 1H), 7.48 (m, 1H), 7.24 (m, 1H), 6.94 (d, 1H), 6.55 (s, 1H), 6.14 (j, 1H), 5.54 (s, 1H), 5.26 (s, 2H), 4.48 (d, 2H), 4.38 (s, 2H), 0.84 (s, 9H), 0.07 (s, 6H).

Step 2) Preparation of _. N-( ( 5-( 4-( 3 -chloro-4-( p yridin-2- ylmethoxy)phenylamino)pyrimidin-5-yl)isooxazol-3-yl)methvn-2 - (hvdroxymethyl)acrylamide

80 mg of the compound obtained in step 1) above was dissolved in 2 mL of tetrahydrofuran, and 264 μί, of tetrahydrofuran solution containing 1.0 M tetrabutylammonium fluoride was added thereto at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was' completed, the reaction mixture was added with a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform: methanol = 15 : 1) to obtain the title compound (40 mg, yield: 61%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.64 (s, 1H), 8.57 s, 1H), 8.55 (s, 1H), 7.79 (TO, 1H), 7.73 (TO, 2H), 7.38 (TO, 1H), 7.28 (t, 1H), 7.02 (d, 1H), 6.72 (s, 1H), 6.04 (s, 1H), 5.61 (s, 1H), 5.27 (s, 2H), 4.63 (s, 2H), 4.36 (s, 2H);

MS (ESI*): m/z = 493.0 [M+H] ⁺ .

Example 62: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- yImethoxy)phenyIainino)pyrimidin-5-yl)isooxazol-3-yl)methyl) -2-

(methylsulfonylmethyl)acrylamide

1 g of 2-(bromomethyl)acrylic acid and 619 mg of sodium methanesulfinate were dissolved in 20 mL of methanol and stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure and purified with column chromatography (chloroform : methanol = 5 : 1). 12 mg of the solid thus obtained and 25 mg of the compound obtained in step 7) of Example 44 were dissolved in 2 mL of tetrahydrofuran, and 18 mg of N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride and 2 of pyridine were added thereto, followed by stirring at room temperature for 1 hour. After the reaction was completed, the resulting mixture was added with a saturated aqueous solution of sodium bicarbonate, and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 15 : 1) to obtain the title compound (4 mg, yield: 12%).

1H-NMR (300MHz, CDCI ₃ ) δ 8.67 (d, 1H), 8.61 (d, 1H), 7.92 (s, 1H), 7.75 (TO, 1H), 7.68 (TO, 1H), 7.37 (TO, 1H), 7.24 (TO, lH), 7.01 (d, 1H), 6.95 (TO, lH), 6.76 (s, 1H), 6.17 (5, 1H), 5.90 (s, 1H), 5.30 (s, 2H), 4.70 (d, 2H), 4.15 (s, 2H), 2.93 (J, 3H);

MS (ES ): m/z = 555.1 [M+H] ⁺ . Example 63: Preparation of 2-(aminomethyl)-N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)isooxazoI-3-yl)methyl)ac rylamide

Step 1) Preparation of 2-( ^' a2idomethyl)-N-((5-( ^' 4-(3-chloro-4-(pyridin-2- ylmemoxy)phenylamino)pyrimid -5-yl)isooxazol-^^

700 mg of the compound obtained in Example 61 was dissolved in 40 mL of NN'-dimethylformamide and 10 mL of carbon tetrachloride, and 111 mg of sodium azide and 894 mg of triphenylphosphine were added thereto, followed by stirring for 90°C for 30 minutes. After the reaction was completed, the mixture was distilled under a reduced pressure to remove carbon tetrachloride, and added with ethyl acetate and washed twice with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate : dichloromethane : methanol = 10 : 10 : 1) to obtain the title compound (450 mg, yield: 65%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.70 (s, 1H), 8.61 (s, 1H), 8.59 (m, 1H), 8.04 (s, 1H), 7.75 (m, 2H), 7.65 (d, 1H), 7.37 (m, 1H), 7.24 (m, 1H), 7.00 (d, 1H), 6.80 (m, 1H), 6.66 (s, 1H), 6.03 (s, 1H), 5.71 (s, 1H), 5.29 (s, 2H), 4.68 (d, 2H), 4.12 (s, 2H), 3.42 (s, 2H).

Step 2) Preparation of 2-(aminomethyl)-N-((5-(4-(3-chloro-4-(pyridin-2- ylmemoxy)phenylammo)pyrimidin-5-yl)isooxazol-3-yl)methyl)acr ylamide

390 mg of the compound obtained in step 1) above was dissolved in 4 mL of tetrahydrofuran, and 626 mg of triphenylphosphine and 300μL of water were added thereto and stirred 60°C for 3 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (chloroform : methanol = 8 : 1) to obtain the title compound (130 mg, yield: 35%).

1H-NMR (300MHz, DMSO-de) δ 9.06 (m, 1H), 8.85 (m, 1H), 8.64 s, 1H),

8.62 (s, 1H), 8.58 (m, 1H), 7.87 (f, 1H), 7.72 (d, 1H), 7.56 {d, 1H), 7.46 m, 1H), 7.35 (m, 1H), 7.21 (d, 1H), 6.96 (j, 1H), 5.82 (s, 1H), 5.52 (s, 1H), 5.27 (s, 2H), 4.48 (s, 2H), 3.30 (s, 2H), 3.28 (s, 2H); MS (ESI*): m/z = 492.2 [M+H] ⁺ .

Example 64: Preparation of 2-(acetamidomethyl)-iV-((5-(4-(3-chIoro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidm-5-yl)isooxazol-3-yl)methyI)aci ^

50 mg of the compound obtained in Example 63 was dissolved in 3 mL of tetrahydrofuran, and 30 ih of triethylamine and 20 μΐ, of acetic anhydride were added thereto at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (ethyl acetate : dichloromethane : methanol = 5 : 5 : 1) to obtain the title compound (20 mg, yield: 37%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.67 (s, 1H), 8.59 (s, 1H), 8.57 (m, 1H), 8.23 (m, 1H), 7.77 (m, 2H), 7.69 (d, 1H), 7.39 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 7.02 (d, 1H), 6.69 (s, 1H), 6.05 (s, 1H), 5.61 (s, 1H), 5.29 (s, 2H), 4.61 (d, 2H), 4.10 (d, 2H), 1.97 (s, 3H);

MS (ESf): m/z = 534.3 [M+H] ⁺ .

Example 65: Preparation of N-((5-(4-(3-chloro-4-(pyridin-2- ylmethoxy)phenylammo)pyrimidin-5-yl)isooxazol-3-yl)methyl)-2 - (methylsulfonamidomethyl)acrylamide

30 mg of the compound obtained in Example 63 was dissolved in 3 mL of tetrahydrofuran at 0°C, and 25 uL of triethylamine and 7 μΐ-, of methanesulfonyl chloride were added thereto, followed by stirring at 0°C for 1 hour. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (ethyl acetate : dichloromethane : methanol = 5 : 5 : 1) to obtain the title compound (10 mg, yield: 29%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.66 (s, 1H), 8.62 (s, 1H), 8.57 (m, 1H), 7.74

(m, 4H), 7.38 (m, 1H), 7.03 (m, 1H), 6.74 (s, 1H), 5.94 (s, 1H), 5.70 (5, 1H), 5.29 (s, 2H), 4.65 (d, 2H), 3.99 (s, 2H), 2.96 (5, 3H);

MS (ESf): m/z = 570.3 [M+H] ⁺ . Example 66: Preparation of iV-(3-(4-(3-chIoro-4-(pyridm-2- ylmethoxy)phenylamino)pyrimidin-5-yl)phenyl)acrylamide Step 1) Preparation of 5-(3-aminophenyl ^" )-N-(3-chloro-4-(pyridin-2- ylmemoxy)phenyl)pyrimidin-4-amine

300 mg of the compound obtained in step 3) of Example 44 and 142 mg of 3- aminophenylboronic acid hydrochloride were dissolved in 6 mL of methanol, and 7.7 mg of palladium acetate and 284 mg of potassium carbonate were added thereto and stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (chloroform : methanol = 15 : 1) to obtain the title compound (120 mg, yield: 44%).

Ή-NMR (300MHz, CDC1 ₃ ) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.21 (s, 1H), 7.76 (t,

2H), 7.69 (d, 1H), 7.65 (d, 1H), 7.34 (m, 2H), 7.24 (d, 1H), 6.97 d, 1H), 6.80 (m, 1H), 6.73 (s, 1H), 5.28 (s, 2H), 3.88 (s, 2H).

Step 2) Preparation of N-(3 -(4-(3 -chloro-4-( p yridin-2- ylmemoxy)phenylammo)pyrimidm-5-yl)phenyl)acrylamide

51 mg of the compound obtained in step 1) above and 32 mg of sodium bicarbonate were dissolved in a mixture of 2 mL of tetrahydrofuran and 0.5 mL of distilled water at 0°C. 10 μί, of acryloyl chloride was added to the mixture and stirred for 30 minutes. After the reaction was completed, the resulting mixture was added with a saturated aqueous solution of sodium bicarbonate and extracted twice with chloroform. The separated organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (chloroform : methanol = 15 : 1) to obtain the title compound (12 mg, yield: 21%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.68 (s, 1H), 8.59 d, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.74 (m, 3H), 7.65 (t, 2H), 7.50 (t, 1H), 7.35 (m, 1H), 7.22 (m, 2H), 6.95 (s, 1H), 6.94 (d, 1H), 6.48 (d, 1H), 6.33 (m, 1H), 5.82 (d, 2H), 5.26 (s, 2H); MS (ES ): m/z = 458.1 [M+H] ⁺ .

Example 67: Preparation of N-((5-(4-(3-chIoro-4-(3- fluorobenzyloxy)phenyIanuno)pyriinidm-5-yI)^^

methylacrylamide

The procedure of Example 47 was repeated except for using t-butyl 2- hydroxyethyl(methyl)carbamate instead of N-Boc-L-prolinole in step 2) to obtain the title compound (10 mg, final yield: 50%).

1H-NMR (300MHz, CDC1 ₃ ) δ 8.69 {s, 1H), 8.61 {s, 1H), 8.08 (s, 1H), 7.73 (m,

1H), 7.40 (m, 2H), 7.19 (m, 2H), 6.97 (m, 2H), 6.67 (s, 1H), 6.58 (m, 1H), 6.45 (w, 1H),

5.78 (m, 1H), 5.15 (s, 2H), 4.71 (s, 2H), 3.16 (s, 2H), 1.23 (s, 3H).

The compounds obtained in Examples 1 to 67 are represented by the following structural formula, as shown in Table 1 below.

<Table 1>

CI

N-((2-(4-amino-6-(3 -chloro-4-(pyridin-3 - yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)acrylamide Η ₂ Ν ' ^J

N-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylamino)pyrimidin-5- yl)oxazol-4-yl)methyl)-2- hydroxyacetamide

N-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylamino)pyrimidin-5- yl)oxazol-4-yl)methyl)-3 - hydroxypropanamide

N-((2-(4-amino-6-(3-chloro-4-(2- fluorophenoxy)phenylamino)pyrimidin-5- yl)oxazol-4-yl)methyl)-3 - ° N ^' methoxypropanamide

N-((2-(4-amino-6-(3-methyl-4-(6- methylpyridin-3 - yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)acrylamide

N-((2-(4-amino-6-(3-methyl-4-(6- methylpyridin-3 - yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)-2- ((dimethylamino)methyl)acrylamide

(E -N-((2-(4-amino-6-(3-methyl-4-(6- methylpyridin-3 - yloxy)phenylamino)pyiimidin-5-yl)oxazol- 4-yl)methyl)-4-(dimethylamino)but-2- H ₂ N N ⁴ ' enamide

N-((2-(4-amino-6-(3-chloro-4-(6- methylpyridin-3 - yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)acrylamide

N-((2-(4-amino-6-(3 -chloro-4-( 1 -methyl- lH-imidazol-2- ylthio)phenylamino)pyriniidin-5- yl)oxazol-4-yl)methyl)acrylamide H ₂ N N

N-((2-(4-amino-6-(3 -chloro-4-( 1 -methyl- lH-pyrazol-5- yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)acrylamide

N-((2-(4-amino-6-(3-chloro-4-(l-methyl-3-

(trifluoromethyl)- 1 H-pyrazol-5- yloxy)phenylamino)pyrimidin-5-yl)oxazol- 4-yl)methyl)acrylamide

((dimethylamino)methyl)acrylamide Ν

methylacrylamide

Preparation Example 1

Tablets for oral administration comprising each of the compounds prepared from Examples 1 to 67 as an active ingredient were prepared based on the recipes of

Table 2.

<Table 2>

Preparation Example 2

Hard gelatin capsules for oral administration comprising each of the compounds prepared from Examples 1 to 67 as an active ingredient were prepared based on the recipes of Table 3.

<Table 3>

Preparation Example 3

Injectable formulations comprising each of the compounds prepared from Examples 1 to 67 as an active ingredient were prepared based on the recipes of Table 4, wherein the pH value was not adjusted when a salt of the compound of formula (I) was used as an active ingredient.

<Table 4> Preparation Example 4

Injectable formulations comprising each of the compounds prepared from Examples 1 to 67 as an active ingredient were prepared based on the recipes of Table 5.

<Table 5>

Test Examples

The compounds prepared from Examples 1 to 67 were tested for their inhibitory efficacies on the growth of cancer cells and on the activities of EGFR ^* " enzymes and EGFR ¹⁷⁹⁰¹ ^ mutant enzymes, as follows.

Test Example 1 : Inhibition of the growth of cancer cells

A skin cancer cell line, A431 (ATCC CRL-1555) overexpressing EGFR (Erb- Bl) and a breast cancer cell line, SK-Br3 (ATCC HTB-30) overexpressing Erb-B2 were used to test the inhibiting degrees of the inventive compounds on the growth of the cancer cells using a culture medium, DMEM (Dulbecco's Modified Eagle's Medium) supplemented with 4.5 g/i glucose, 1.5 g/£ sodium bicarbonate and 10% FBS (fetal bovine serum).

The cancer cell lines stored in a liquid nitrogen tank were each quickly thawed at 37°C, and centrifuged to remove the medium. The collected cell pellet was mixed with a culture medium, incubated in a culture flask at 37°C under 5% C0 ₂ for 2 to 3 days, and the medium was removed. The remaining cells were washed with DPBS (Dulbecco's Phosphate Buffered Saline) and separated from the flask by using Tripsin- EDTA. The separated cells were diluted with a culture medium to l xlO ⁵ cells/mL for A431 and 2xl0 ⁵ cells/mL for SK-Br3, respectively. 100 iL of each diluted cell solution was seeded into a 96-well plate, and incubated at 37°C under 5% C0 ₂ for 1 day.

The compounds obtained in Examples 1 to 67 were each dissolved in 99.5% DMSO (cell culture grade) to a concentration of 25 mM. When the test compound is not soluble in DMSO, 1% aqueous HC1 solution was added thereto and maintained in a 40°C water bath for 30 min until the compound dissolves completely.

The test compound solution was diluted with a culture medium to a final concentration of 100 μΜ, and then diluted 10 times serially to 10 ^"6 μΜ (a final concentration of DMSO was less than 1%).

After removing the medium from each well of the 96-well plate, 100 iL of a test compound solution was added to each well, and the plate was incubated at 37°C under 5% C0 ₂ for 72 hours. After removing the medium, 50 xL of 10% trichloroacetic acid was added to each well, and the plate was kept at 4°C for 1 hour to fix the cells to the bottom of the plate. The added trichloroacetic acid was removed from each well, and thus the plate was dried, and 100 μΐ, of 0.4% SRB (sulforhodamine-B) dye solution dissolved in 1% aqueous acetic acid was added thereto, and the resulting mixture was reacted for 10 min. After removing the dye solution, the plate was washed with water, and dried. When the dye solution was not effectively removed by water, 1% aqueous acetic acid was used. 150 iL of 10 mM trisma base was added to each well, and the absorbance at 540 nm was determined by using a microplate reader.

IC50 of each test compound, the concentration at which 50% inhibition occurs, was evaluated based on the difference between the final density and the initial density of the cells untreated with the test compound which was regarded as 100%. In addition, Gefitinib (EGFR inhibitor) and Lapatinib (dual EGFR/Erb-B2 inhibitor) as controls were used in a similar manner to determine ΙΟ ₅₀ values. The calculation of IC50 was carried out by using Microsoft Excel, and the results are shown in Table 6. <Table 6>

As shown in Table 6, most compounds of formula (I) of the present invention effectively inhibited the growth of A431 cell lines overexpressing EGFR and SK-Br3 cell lines overexpressing Erb-B2, which was comparable or higher than Gefitinib (EGFR inhibitor) and Lapatinib (dual EGFR/Erb-B2 inhibitor) commercially available.

Test Example 2: Inhibition of EGFR ^*1 enzyme

10 μΕ of an EGFR (EGFR type 1 kinase, Upstate, 10 ng^iL) was added to each well of a 96-well plate. As an EGFR inhibitor, 10 ih of a serially diluted solution of each of the compounds obtained in Examples 1 to 67 was added to each well, and the plate was incubated at room temperature for 10 min. 10 LL of Poly (Glu, Tyr) 4:1 (Sigma, 10 ng/mL) and 10 μί of ATP (50uM) were successively added thereto and the mixture was incubated at room temperature for 1 hour to initiate a kinase reaction. Then, 10 μΐ, of 100 mM EDTA was added to each well and stirred for 5 min to terminate the kinase reaction. 10 i of 10x anti-phosphotyrosine antibody (Pan Vera), 10 μΐ, of 10x PTK (protein tyrosine kinase) green tracer (Pan Vera) and 30 ih of FP (fluorescence polarization) diluted buffer were added thereto, and the mixture was incubated in the dark at room temperature for 30 min. The FP value of each well was determined by using VICTORIII fluorescence meter (Perkin Elmer) at 488 nm (excitation filter) and 535 nm (emission filter). IC50, the concentration at which 50% inhibition was observed, was determined, wherein the maximum (0% inhibition) value was set at the polarized light value measured for the well untreated with an EGFR inhibitor and the minimum value corresponded to 100% inhibition. In addition, Gefitinib (EGFR inhibitor) and Lapatinib (dual EGFR/Erb-B2 inhibitor) as controls were used in a similar manner to determine IC50 values. The calculation of IC50 was carried out by using Microsoft Excel, and the results are shown in Table 7.

Test Example 3: Inhibition of EGFR mutant enzyme (T790M)

The procedure of Example 2 was repeated except for using EGFR mutant receptor (EGFR T790M kinase, Upstate) instead of EGFR enzyme. The results are shown in Table 7.

<Table 7>

As shown in Table 7, the compounds of the present invention effectively inhibited the activities of both EGFR* ¹ and EGFR T790M mutant kinase. Therefore, the pyrimidine compounds of the present invention can effectively inhibit the activities of EGFR or its mutant kinase, as well as the growth of specific cancer cells induced by the overexpression of EGFR.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.